bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒09‒11
47 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Functional biomarkers derived from computed tomography and magnetic resonance imaging differentiate PDAC subgroups and reveal gemcitabine-induced hypo-vascularization.
  2. The lysosomal proteome of senescent cells contributes to the senescence secretome.
  3. Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids.
  4. Transitioning cancer cells and the surrounding tumor environment in pancreatic cancer.
  5. An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
  6. Genetic Mouse Models to Study Pancreatic Cancer-Induced Pain and Reduction in Well-Being.
  7. Targeting senescence as an anti-cancer therapy.
  8. A Fluorescence-Microscopic System for Monitoring the Turnover of the Autophagic Substrate p62/SQSTM1.
  9. Serum levels of iCAF-derived Osteoglycin predict favorable outcome in pancreatic cancer.
  10. Gene Ontology (GO)-Driven Inference of Candidate Proteomic Markers Associated with Muscle Atrophy Conditions.
  11. Obesity and cancer-extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases.
  12. A phosphoinositide signalling pathway mediates rapid lysosomal repair.
  13. Insulin-Lowering Diets in Metastatic Cancer.
  14. Nutritional Niches of Cancer Therapy-Induced Senescent Cells.
  15. Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice.
  16. Atractylenolide I ameliorates cancer cachexia through inhibiting biogenesis of IL-6 and tumour-derived extracellular vesicles.
  17. Combinatorial approaches for mitigating resistance to KRAS-targeted therapies.
  18. Diet and Exercise in Cancer Metabolism.
  19. Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis.
  20. Integrating single cell transcriptomics and volume electron microscopy confirms the presence of pancreatic acinar-like cells in sea urchins.
  21. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.
  22. Is "cellular senescence" a misnomer?
  23. Cancer Cachexia: Signaling and Transcriptional Regulation of Muscle Catabolic Genes.
  24. Regulation of pancreatic cancer therapy resistance by chemokines.
  25. Is Weight Loss During Chemotherapy for Pancreatic Cancer Prognostic?
  26. Evolving management of early stage pancreatic adenocarcinoma in older patients.
  27. Cancer cachexia: Pathophysiology and association with cancer-related pain.
  28. Tracing metabolic flux in vivo: basic model structures of tracer methodology.
  29. Metabolic flux between organs measured by arteriovenous metabolite gradients.
  30. Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.
  31. Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers.
  32. Comparing Survival after Resection of Pancreatic Cancer with and without Pancreatic Cysts: Nationwide Registry-Based Study.
  33. Big data in basic and translational cancer research.
  34. Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance.
  35. A new view of activating mutations in cancer.
  36. Proximity Ligation in Situ Assay to Monitor Autophagy-Related Protein Interactions and Autophagy in Cancer Cells.
  37. Capillary forces generated by biomolecular condensates.
  38. Tracing metabolic flux to assess optimal dietary protein and amino acid consumption.
  39. Mechanical and metabolic interplay in the brain metastatic microenvironment.
  40. An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer.
  41. FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.
  42. An integrative web-based software tool for multi-dimensional pathology whole-slide image analytics.
  43. Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.
  44. 3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk.
  45. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
  46. ATG5: A central autophagy regulator implicated in various human diseases.
  47. SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1.
  1. Eur J Nucl Med Mol Imaging. 2022 Sep 08.
    Functional biomarkers derived from computed tomography and magnetic resonance imaging differentiate PDAC subgroups and reveal gemcitabine-induced hypo-vascularization.
    Irina Heid, Marija Trajkovic-Arsic, Fabian Lohöfer, Georgios Kaissis, Felix N Harder, Moritz Mayer, Geoffrey J Topping, Friderike Jungmann, Barbara Crone, Moritz Wildgruber, Uwe Karst, Lucia Liotta, Hana Algül, Hsi-Yu Yen, Katja Steiger, Wilko Weichert, Jens T Siveke, Marcus R Makowski, Rickmer F Braren.
      PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a molecularly heterogeneous tumor entity with no clinically established imaging biomarkers. We hypothesize that tumor morphology and physiology, including vascularity and perfusion, show variations that can be detected by differences in contrast agent (CA) accumulation measured non-invasively. This work seeks to establish imaging biomarkers for tumor stratification and therapy response monitoring in PDAC, based on this hypothesis.METHODS AND MATERIALS: Regional CA accumulation in PDAC was correlated with tumor vascularization, stroma content, and tumor cellularity in murine and human subjects. Changes in CA distribution in response to gemcitabine (GEM) were monitored longitudinally with computed tomography (CT) Hounsfield Units ratio (HUr) of tumor to the aorta or with magnetic resonance imaging (MRI) ΔR1 area under the curve at 60 s tumor-to-muscle ratio (AUC60r). Tissue analyses were performed on co-registered samples, including endothelial cell proliferation and cisplatin tissue deposition as a surrogate of chemotherapy delivery.
    RESULTS: Tumor cell poor, stroma-rich regions exhibited high CA accumulation both in human (meanHUr 0.64 vs. 0.34, p < 0.001) and mouse PDAC (meanAUC60r 2.0 vs. 1.1, p < 0.001). Compared to the baseline, in vivo CA accumulation decreased specifically in response to GEM treatment in a subset of human (HUr -18%) and mouse (AUC60r -36%) tumors. Ex vivo analyses of mPDAC showed reduced cisplatin delivery (GEM: 0.92 ± 0.5 mg/g, vs. vehicle: 3.1 ± 1.5 mg/g, p = 0.004) and diminished endothelial cell proliferation (GEM: 22.3% vs. vehicle: 30.9%, p = 0.002) upon GEM administration.
    CONCLUSION: In PDAC, CA accumulation, which is related to tumor vascularization and perfusion, inversely correlates with tumor cellularity. The standard of care GEM treatment results in decreased CA accumulation, which impedes drug delivery. Further investigation is warranted into potentially detrimental effects of GEM in combinatorial therapy regimens.
    Keywords:  CA accumulation; CT; DCE-MRI; Gemcitabine; PDAC
    DOI:  https://doi.org/10.1007/s00259-022-05930-6
  2. Aging Cell. 2022 Sep 10. e13707
    The lysosomal proteome of senescent cells contributes to the senescence secretome.
    Miguel Rovira, Rebecca Sereda, David Pladevall-Morera, Valentina Ramponi, Ines Marin, Mate Maus, Julio Madrigal-Matute, Antonio Díaz, Fernando García, Javier Muñoz, Ana María Cuervo, Manuel Serrano.
      Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age-related diseases. Senescent cells present a remarkable increase in lysosomal mass and elevated autophagic activity. Here, we report that two main autophagic pathways macroautophagy (MA) and chaperone-mediated autophagy (CMA) are constitutively upregulated in senescent cells. Proteomic analyses of the subpopulations of lysosomes preferentially engaged in each of these types of autophagy revealed profound quantitative and qualitative changes in senescent cells, affecting both lysosomal resident proteins and cargo proteins delivered to lysosomes for degradation. These studies have led us to identify resident lysosomal proteins that are highly augmented in senescent cells and can be used as novel markers of senescence, such as arylsulfatase ARSA. The abundant secretome of senescent cells, known as SASP, is considered their main pathological mediator; however, little is known about the mechanisms of SASP secretion. Some secretory cells, including melanocytes, use the small GTPase RAB27A to perform lysosomal secretion. We found that this process is exacerbated in the case of senescent melanoma cells, as revealed by the exposure of lysosomal membrane integral proteins LAMP1 and LAMP2 in their plasma membrane. Interestingly, a subset of SASP components, including cytokines CCL2, CCL3, CXCL12, cathepsin CTSD, or the protease inhibitor SERPINE1, are secreted in a RAB27A-dependent manner in senescent melanoma cells. Finally, proteins previously identified as plasma biomarkers of aging are highly enriched in the lysosomes of senescent cells, including CTSD. We conclude that the lysosomal proteome of senescent cells is profoundly reconfigured, and that some senescent cells can be highly active in lysosomal exocytosis.
    Keywords:  SASP; aging; autophagy; cellular senescence; exocytosis; lysosome
    DOI:  https://doi.org/10.1111/acel.13707
  3. Nat Commun. 2022 Sep 05. 13(1): 5219
    Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids.
    S Randriamanantsoa, A Papargyriou, H C Maurer, K Peschke, M Schuster, G Zecchin, K Steiger, R Öllinger, D Saur, C Scheel, R Rad, E Hannezo, M Reichert, A R Bausch.
      The development dynamics and self-organization of glandular branched epithelia is of utmost importance for our understanding of diverse processes ranging from normal tissue growth to the growth of cancerous tissues. Using single primary murine pancreatic ductal adenocarcinoma (PDAC) cells embedded in a collagen matrix and adapted media supplementation, we generate organoids that self-organize into highly branched structures displaying a seamless lumen connecting terminal end buds, replicating in vivo PDAC architecture. We identify distinct morphogenesis phases, each characterized by a unique pattern of cell invasion, matrix deformation, protein expression, and respective molecular dependencies. We propose a minimal theoretical model of a branching and proliferating tissue, capturing the dynamics of the first phases. Observing the interaction of morphogenesis, mechanical environment and gene expression in vitro sets a benchmark for the understanding of self-organization processes governing complex organoid structure formation processes and branching morphogenesis.
    DOI:  https://doi.org/10.1038/s41467-022-32806-y
  4. Nat Genet. 2022 Sep 05.
    Transitioning cancer cells and the surrounding tumor environment in pancreatic cancer.
      
    DOI:  https://doi.org/10.1038/s41588-022-01162-4
  5. Cancer Res. 2022 Sep 09. pii: CAN-22-0237. [Epub ahead of print]
    An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
    Danna Sheinboim, Shivang Parikh, Paulee Manich, Irit Markus, Sapir Dahan, Roma Parikh, Elisa Stubbs, Gali Cohen, Valentina Zemser-Werner, Rachel E Bell, Sara Arciniegas Ruiz, Ruth Percik, Ronen Brenner, Stav Leibou, Hananya Vaknine, Gali Arad, Yariv Gerber, Lital Keinan Boker, Tal Shimony, Lior Bikovski, Nir Goldstein, Keren Constantini, Sapir Labes, Shimonov Mordechai, Hila Doron, Ariel Ionescu, Tamar Ziv, Eran Nizri, Guy Choshen, Hagit Eldar-Finkelman, Yuval Tabach, Aharon Helman, Shamgar Ben-Eliyahu, Neta Erez, Eran Perlson, Tamar Geiger, Danny Ben-Zvi, Mehdi Khaled, Yftach Gepner, Carmit Levy.
      Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiological data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0237
  6. Cells. 2022 Aug 24. pii: 2634. [Epub ahead of print]11(17):
    Genetic Mouse Models to Study Pancreatic Cancer-Induced Pain and Reduction in Well-Being.
    Michael Hirth, Yong Xie, Christiane Höper, Amandine Prats, Thilo Hackert, Matthias P Ebert, Rohini Kuner.
      In addition to the poor prognosis, excruciating abdominal pain is a major challenge in pancreatic cancer. Neurotropism appears to be the underlying mechanism leading to neuronal invasion. However, there is a lack of animal models suitable for translationally bridging in vitro findings with clinical trials. We characterized KPC (KrasG12D/+; Trp53R172H/+; P48-Cre) and KPPC (KrasG12D/+; Trp53R172H/R172H; P48-Cre) mice with genetically determined pancreatic ductal adenocarcinoma (PDAC) and compared them with an orthotopic pancreatic cancer mouse model, healthy littermates and human tissue. We analyzed behavioral correlates of cancer-associated pain and well-being, and studied neuronal remodeling and cytokine expression. Histologically, we found similarities between KPC and KPPC tissue with human samples. Compared to healthy littermates, we detect nerve fiber hypertrophy, which was not restricted to a certain fiber type. Interestingly, while KPPC mice showed significantly reduced well-being, KPC mice emerged to be better suited for studying long-lasting cancer pain that emerges over a slow course of tumor progression. To address the neuroinflammatory correlate of loss of well-being, we studied cytokine levels in KPPC mice and observed a significant upregulation of CXCL16, TNFRSF5, CCL24, CXCL1, CCL22, CLL20 and CX2CL1. In summary, we demonstrate that the KPC mouse model is best suited to studying cancer pain, whereas the KPPC model can be employed to study cancer-associated reduction in well-being.
    Keywords:  KPC; KPPC; cytokines; nerve hypertrophy; pain; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3390/cells11172634
  7. Mol Oncol. 2022 Sep 05.
    Targeting senescence as an anti-cancer therapy.
    Laura Bousset, Jesús Gil.
      Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one -two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.
    Keywords:  Cellular senescence; chemotherapy; oncogene-induced senescence (OIS); radiotherapy; senolytics; therapy-induced senescence (TIS)
    DOI:  https://doi.org/10.1002/1878-0261.13312
  8. Methods Mol Biol. 2022 ;2543 71-82
    A Fluorescence-Microscopic System for Monitoring the Turnover of the Autophagic Substrate p62/SQSTM1.
    Hongzhong Jin, Qi Wu, Guido Kroemer, Oliver Kepp.
      In conditions of cellular stress and nutrient shortage, macroautophagy (hereafter referred to as autophagy) assures the degradation of dysfunctional macromolecules and organelles as it liberates energy resources via the breakdown of dispensable cellular components. Morphologically, autophagy is characterized by the formation of double-membraned autophagosomes that facilitate the isolation of autophagic cargo for subsequent lysosomal degradation at low pH. Sequestosome-1 (SQSTM1, better known as ubiquitin-binding protein p62), is an autophagosomal cargo receptor that targets proteins for selective autophagic degradation. Indeed, the redistribution of tandem mCherry and enhanced green fluorescent protein (mCherry-EGFP)-conjugated p62 from the cytosol into nascent autophagosomes constitutes a phenotype applicable to microscopic analysis. Furthermore, the differential pH sensitivity of mCherry and EGFP allows the visualization of autophagic flux due to the selective decrease of the EGFP signal upon fusion of autophagosomes with lysosomes. Here, we describe a method employing automated confocal cellular imaging for the study of autophagic degradation that is amenable to systems biology approaches.
    Keywords:  Autophagic flux; Autophagy; Image analysis; Lysosomal degradation
    DOI:  https://doi.org/10.1007/978-1-0716-2553-8_7
  9. Int J Cancer. 2022 Sep 07.
    Serum levels of iCAF-derived Osteoglycin predict favorable outcome in pancreatic cancer.
    Mark P G Dings, Paul Manoukian, Cynthia Waasdorp, Judith S E Quik, Marin Strijker, Sophie C Lodestijn, Sanne M van Neerven, Leandro F Moreno, Rodrigo Leite de Oliveira, Bert A Bonsing, Marco J Bruno, Olivier R Busch, Michael Doukas, Casper H van Eijck, Nadia Haj Mohammad, Ignace H de Hingh, I Quintus Molenaar, Marc G Besselink, Louis Vermeulen, Jan Paul Medema, Hanneke W M van Laarhoven, Maarten F Bijlsma.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Stroma-targeting agents have been proposed to improve the poor outcome of current treatments. However, clinical trials using these agents showed disappointing results. Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and -suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. RNA-sequencing reads from patient-derived xenografts (PDXs) were mapped to the human and mouse genome to allocate the expression of genes to the tumor or stroma. Survival meta-analysis for stromal genes was performed and applied on human protein atlas data to identify circulating biomarkers. The candidate protein was perturbed in co-cultures and assessed in existing and novel single-cell gene expression analysis from control, pancreatitis, pancreatitis-recovered and PDAC mouse models. Serum levels of the candidate biomarker were measured in two independent cohorts totaling of 148 PDAC patients and related them to overall survival. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis indicated that Ogn is derived from a subgroup of inflammatory CAFs. Ogn-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts (HR=0.47, p=0.042, and HR=0.53, p=0.006). Altogether, we conclude that high circulating OGN levels inform on a previously unrecognized subgroup of CAFs and predict favorable outcome in resectable PDAC. This article is protected by copyright. All rights reserved.
    Keywords:  CAF subtypes; Stroma; liquid biopsy center; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/ijc.34276
  10. Molecules. 2022 Aug 27. pii: 5514. [Epub ahead of print]27(17):
    Gene Ontology (GO)-Driven Inference of Candidate Proteomic Markers Associated with Muscle Atrophy Conditions.
    Angelique Stalmach, Ines Boehm, Marco Fernandes, Alison Rutter, Richard J E Skipworth, Holger Husi.
      Skeletal muscle homeostasis is essential for the maintenance of a healthy and active lifestyle. Imbalance in muscle homeostasis has significant consequences such as atrophy, loss of muscle mass, and progressive loss of functions. Aging-related muscle wasting, sarcopenia, and atrophy as a consequence of disease, such as cachexia, reduce the quality of life, increase morbidity and result in an overall poor prognosis. Investigating the muscle proteome related to muscle atrophy diseases has a great potential for diagnostic medicine to identify (i) potential protein biomarkers, and (ii) biological processes and functions common or unique to muscle wasting, cachexia, sarcopenia, and aging alone. We conducted a meta-analysis using gene ontology (GO) analysis of 24 human proteomic studies using tissue samples (skeletal muscle and adipose biopsies) and/or biofluids (serum, plasma, urine). Whilst there were few similarities in protein directionality across studies, biological processes common to conditions were identified. Here we demonstrate that the GO analysis of published human proteomics data can identify processes not revealed by single studies. We recommend the integration of proteomics data from tissue samples and biofluids to yield a comprehensive overview of the human skeletal muscle proteome. This will facilitate the identification of biomarkers and potential pathways of muscle-wasting conditions for use in clinics.
    Keywords:  biomarker; cancer cachexia; muscle wasting; proteomics; sarcopenia
    DOI:  https://doi.org/10.3390/molecules27175514
  11. Cancer Metastasis Rev. 2022 Sep 08.
    Obesity and cancer-extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases.
    Natalia S Pellegata, Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig.
      Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.
    Keywords:  Adrenergic signaling; Angiogenesis; Cancer; Fibrosis; Obesity
    DOI:  https://doi.org/10.1007/s10555-022-10058-y
  12. Nature. 2022 Sep 07.
    A phosphoinositide signalling pathway mediates rapid lysosomal repair.
    Jay Xiaojun Tan, Toren Finkel.
      Lysosomal dysfunction has been increasingly linked to disease and normal ageing1,2. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors3. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.
    DOI:  https://doi.org/10.1038/s41586-022-05164-4
  13. Nutrients. 2022 Aug 27. pii: 3542. [Epub ahead of print]14(17):
    Insulin-Lowering Diets in Metastatic Cancer.
    Sherry Shen, Neil M Iyengar.
      Hyperinsulinemia is an independent risk factor for cancer mortality. Insulin-lowering dietary strategies such as calorie restriction (CR), low-carbohydrate or ketogenic diets (KD), and intermittent fasting (IF) are aimed at reducing systemic stores of nutrients utilized by cancer cells, attenuating insulin-related growth signaling, and improving obesity-related metabolic parameters. In this narrative review, we searched the published literature for studies that tested various insulin-lowering diets in metastatic cancer in preclinical and clinical settings. A total of 23 studies were identified. Of these, 14 were preclinical studies of dietary strategies that demonstrated improvements in insulin levels, inhibition of metastasis, and/or reduction in metastatic disease burden in animal models. The remaining nine clinical studies tested carbohydrate restriction, KD, or IF strategies which appear to be safe and feasible in patients with metastatic cancer. These approaches have also been shown to improve serum insulin and other metabolic parameters. Though promising, the anti-cancer efficacy of these interventions, such as impact on tumor response, disease-specific-, and overall survival, have not yet been conclusively demonstrated. Studies that are adequately powered to evaluate whether insulin-lowering diets improve cancer outcomes are warranted.
    Keywords:  diet; insulin; metastatic cancer
    DOI:  https://doi.org/10.3390/nu14173542
  14. Nutrients. 2022 Sep 02. pii: 3636. [Epub ahead of print]14(17):
    Nutritional Niches of Cancer Therapy-Induced Senescent Cells.
    Àngela Llop-Hernández, Sara Verdura, Elisabet Cuyàs, Javier A Menendez.
      Therapy-induced senescence (TIS) is a state of stable proliferative arrest of both normal and neoplastic cells that is triggered by exposure to anticancer treatments. TIS cells acquire a senescence-associated secretory phenotype (SASP), which is pro-inflammatory and actively promotes tumor relapse and adverse side-effects in patients. Here, we hypothesized that TIS cells adapt their scavenging and catabolic ability to overcome the nutritional constraints in their microenvironmental niches. We used a panel of mechanistically-diverse TIS triggers (i.e., bleomycin, doxorubicin, alisertib, and palbociclib) and Biolog Phenotype MicroArrays to identify (among 190 different carbon and nitrogen sources) candidate metabolites that support the survival of TIS cells in limiting nutrient conditions. We provide evidence of distinguishable TIS-associated nutrient consumption profiles involving a core set of shared (e.g., glutamine) and unique (e.g., glucose-1-phosphate, inosine, and uridine) nutritional sources after diverse senescence-inducing interventions. We also observed a trend for an inverse correlation between the intensity of the pro-inflammatory SASP provoked by different TIS agents and diversity of compensatory nutritional niches utilizable by senescent cells. These findings support the detailed exploration of the nutritional niche as a new metabolic dimension to understand and target TIS in cancer.
    Keywords:  cancer; glutamine; metabolism; miR146a; nutrition; senescence
    DOI:  https://doi.org/10.3390/nu14173636
  15. Mol Metab. 2022 Sep 02. pii: S2212-8778(22)00158-2. [Epub ahead of print] 101589
    Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice.
    Satish Patel, Afreen Haider, Anna Alvarez-Guaita, Guillaume Bidault, Julia Sarah El-Sayed Moustafa, Esther Guiu-Jurado, John A Tadross, James Warner, James Harrison, Samuel Virtue, Fabio Scurria, Ilona Zvetkova, Matthias Blüher, Kerrin S Small, Stephen O'Rahilly, David B Savage.
      OBJECTIVES: Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear.METHODS: Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterised the metabolic phenotypes of GDF15/FGF21 double knockout mice.
    RESULTS: Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice.
    CONCLUSIONS: Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.
    Keywords:  FGF21; GDF15; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2022.101589
  16. J Cachexia Sarcopenia Muscle. 2022 Sep 09.
    Atractylenolide I ameliorates cancer cachexia through inhibiting biogenesis of IL-6 and tumour-derived extracellular vesicles.
    Meng Fan, Xiaofan Gu, Wanli Zhang, Qiang Shen, Ruiqin Zhang, Qiaoyu Fang, Yueping Wang, Xiaodong Guo, Xiongwen Zhang, Xuan Liu.
      BACKGROUND: Atractylenolide I (AI) is a natural sesquiterpene lactone isolated from Atractylodes macrocephala Koidz, known as Baizhu in traditional Chinese medicine. AI has been found to ameliorate cancer cachexia in clinic cancer patients and in tumour-bearing mice. Here, we checked the influence of AI on biogenesis of IL-6 and extracellular vesicles (EVs) in cancer cachexia mice and then focused on studying mechanisms of AI in inhibiting the production of tumour-derived EVs, which contribute to the ameliorating effects of AI on cancer cachexia.METHODS: C26 tumour-bearing BALB/c mice were applied as animal model to examine the effects of AI (25 mg/kg) in attenuating cachexia symptoms, serum IL-6 and EVs levels. IL-6 and EVs secretion of C26 tumour cells treated with AI (0.31-5 μM) was further observed in vitro. The in vitro cultured C2C12 myotubes and 3T3-L1 mature adipocytes were used to check the potency of conditioned medium of C26 cells treated with AI (0.625-5 μM) in inducing muscle atrophy and lipolysis. The glycolysis potency of C26 cells under AI (0.31-5 μM) treatment was evaluated by measuring the extracellular acidification rate using Seahorse XFe96 Analyser. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms. STAT3 overexpression or knockout C26 cells were also used to confirm the effects of AI (5 μM).
    RESULTS: AI ameliorated cancer cachexia symptoms (P < 0.05), improved grip strength (P < 0.05) and decreased serum EVs (P < 0.05) and IL-6 (P < 0.05) levels of C26 tumour-bearing mice. AI directly inhibited EVs biogenesis (P < 0.001) and IL-6 secretion (P < 0.01) of cultured C26 cells. The potency of C26 medium in inducing C2C12 myotube atrophy (+59.54%, P < 0.001) and 3T3-L1 adipocyte lipolysis (+20.73%, P < 0.05) was significantly attenuated when C26 cells were treated with AI. AI treatment inhibited aerobic glycolysis and the pathway of STAT3/PKM2/SNAP23 in C26 cells. Furthermore, overexpression of STAT3 partly antagonized the effects of AI in suppressing STAT3/PKM2/SNAP23 pathway, EVs secretion, glycolysis and the potency of C26 medium in inducing muscle atrophy and lipolysis, whereas knockout of STAT3 enhanced the inhibitory effect of AI on these values. The inhibition of AI on STAT3/PKM2/SNAP23 pathway was also observed in C26 tumour tissues.
    CONCLUSIONS: AI ameliorates cancer cachexia by decreasing the production of IL-6 and EVs of tumour cells. The decreasing effects of AI on EVs biogenesis are based on its inhibition on STAT3/PKM2/SNAP23 pathway.
    Keywords:  STAT3; atractylenolide I; cancer cachexia; extracellular vesicle; lipolysis; muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.13079
  17. Biochem J. 2022 Sep 06. pii: BCJ20220440. [Epub ahead of print]
    Combinatorial approaches for mitigating resistance to KRAS-targeted therapies.
    Hannah R Warren, Sarah Ross, Paul D Smith, Judy M Coulson, Ian A Prior.
      Approximately 15% of all cancer patients harbor mutated KRAS. Direct inhibitors of KRAS have now been generated and are beginning to make progress through clinical trials. These include a suite of inhibitors targeting the KRASG12C mutation commonly found in lung cancer. We investigated emergent resistance to representative examples of different classes of Ras targeted therapies. They all exhibited rapid reactivation of Ras signaling within days of exposure and adaptive responses continued to change over long-term treatment schedules. Whilst the gene signatures were distinct for each inhibitor, they commonly involved upregulation of upstream nodes promoting mutant and wild type Ras activation. Experiments to reverse resistance unfortunately revealed frequent desensitization to members of a panel of anti-cancer therapeutics, suggesting that salvage approaches are unlikely to be feasible. Instead, we identified triple inhibitor combinations that resulted in more durable responses to KRAS inhibitors and that may benefit from further pre-clinical evaluation.
    Keywords:  G-proteins; drug resistance; signalling
    DOI:  https://doi.org/10.1042/BCJ20220440
  18. Cancer Discov. 2022 Sep 05. OF1-OF9
    Diet and Exercise in Cancer Metabolism.
    Jason W Locasale.
      Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for patients with cancer. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this perspective, I propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, I will discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0096
  19. Elife. 2022 Sep 07. pii: e75715. [Epub ahead of print]11
    Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis.
    Özgün Le Roux, Nicole L K Pershing, Erin Kaltenbrun, Nicole J Newman, Jeffrey I Everitt, Elisa Baldelli, Mariaelena Pierobon, Emanuel F Petricoin, Christopher M Counter.
      Despite multiple possible oncogenic mutations in the proto-oncogene KRAS, unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being the initiating event, these mutational biases are ostensibly a product of how normal cells respond to the encoded oncoprotein. Oncogenic mutations can impact not only the level of active oncoprotein, but also engagement with proteins. To attempt to separate these two effects, we generated four novel Cre-inducible (LSL) Kras alleles in mice with the biochemically distinct G12D or Q61R mutations and encoded by native (nat) rare or common (com) codons to produce low or high protein levels. While there were similarities, each allele also induced a distinct transcriptional response shortly after activation in vivo. At one end of the spectrum, activating the KrasLSL-natG12D allele induced transcriptional hallmarks suggestive of an expansion of multipotent cells, while at the other end, activating the KrasLSL-comQ61R allele led to hallmarks of hyperproliferation and oncogenic stress. Evidence suggests that these changes may be a product of signaling differences due to increased protein expression as well as the specific mutation. To determine the impact of these distinct responses on RAS mutational patterning in vivo, all four alleles were globally activated, revealing that hematolymphopoietic lesions were permissive to the level of active oncoprotein, squamous tumors were permissive to the G12D mutant, while carcinomas were permissive to both these features. We suggest that different KRAS mutations impart unique signaling properties that are preferentially capable of inducing tumor initiation in a distinct cell-specific manner.
    Keywords:  RAS; cancer; cancer biology; genetically engineered mice; mouse; oncogenes
    DOI:  https://doi.org/10.7554/eLife.75715
  20. Front Cell Dev Biol. 2022 ;10 991664
    Integrating single cell transcriptomics and volume electron microscopy confirms the presence of pancreatic acinar-like cells in sea urchins.
    Periklis Paganos, Paolo Ronchi, Jil Carl, Giulia Mizzon, Pedro Martinez, Giovanna Benvenuto, Maria Ina Arnone.
      The identity and function of a given cell type relies on the differential expression of gene batteries that promote diverse phenotypes and functional specificities. Therefore, the identification of the molecular and morphological fingerprints of cell types across taxa is essential for untangling their evolution. Here we use a multidisciplinary approach to identify the molecular and morphological features of an exocrine, pancreas-like cell type harbored within the sea urchin larval gut. Using single cell transcriptomics, we identify various cell populations with a pancreatic-like molecular fingerprint that are enriched within the S. purpuratus larva digestive tract. Among these, in the region where they reside, the midgut/stomach domain, we find that populations of exocrine pancreas-like cells have a unique regulatory wiring distinct from the rest the of the cell types of the same region. Furthermore, Serial Block-face scanning Electron Microscopy (SBEM) of the exocrine cells shows that this reported molecular diversity is associated to distinct morphological features that reflect the physiological and functional properties of this cell type. Therefore, we propose that these sea urchin exocrine cells are homologous to the well-known mammalian pancreatic acinar cells and thus we trace the origin of this particular cell type to the time of deuterostome diversification. Overall, our approach allows a thorough characterization of a complex cell type and shows how both the transcriptomic and morphological information contribute to disentangling the evolution of cell types and organs such as the pancreatic cells and pancreas.
    Keywords:  SBEM; acinar cells; evolution of cell types; morphology; pancreas; scRNAseq; sea urchin
    DOI:  https://doi.org/10.3389/fcell.2022.991664
  21. Sci Immunol. 2022 Sep 09. 7(75): eabn0704
    The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.
    Gauri Mirji, Alison Worth, Sajad Ahmad Bhat, Mohamed El Sayed, Toshitha Kannan, Aaron R Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi V Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Z Stanger, Rahul S Shinde.
      The composition of the gut microbiome can control innate and adaptive immunity and has emerged as a key regulator of tumor growth, especially in the context of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms for how the microbiome affects tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a nontargeted, liquid chromatography-tandem mass spectrometry-based metabolomic screen, we identified the gut microbe-derived metabolite trimethylamine N-oxide (TMAO), which enhanced antitumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN-dependent manner. Delivering TMAO-primed macrophages intravenously produced similar antitumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) in a mouse model of PDAC significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Last, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in patients with PDAC and improved response to anti-PD1 in patients with melanoma. Together, our study identifies the gut microbial metabolite TMAO as a driver of antitumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO.
    DOI:  https://doi.org/10.1126/sciimmunol.abn0704
  22. Geroscience. 2022 Sep 07.
    Is "cellular senescence" a misnomer?
    David Gems, Carina C Kern.
      One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as "senescent." Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation-a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype).
    Keywords:  Aging; Cellular senescence; Fibroblast; Osteoarthritis; Remodeling activation; Remodeling-associated secretory phenotype (RASP)
    DOI:  https://doi.org/10.1007/s11357-022-00652-x
  23. Cancers (Basel). 2022 Aug 31. pii: 4258. [Epub ahead of print]14(17):
    Cancer Cachexia: Signaling and Transcriptional Regulation of Muscle Catabolic Genes.
    Vinay Kumar Rao, Dipanwita Das, Reshma Taneja.
      Cancer cachexia (CC) is a multifactorial syndrome characterized by a significant reduction in body weight that is predominantly caused by the loss of skeletal muscle and adipose tissue. Although the ill effects of cachexia are well known, the condition has been largely overlooked, in part due to its complex etiology, heterogeneity in mediators, and the involvement of diverse signaling pathways. For a long time, inflammatory factors have been the focus when developing therapeutics for the treatment of CC. Despite promising pre-clinical results, they have not yet advanced to the clinic. Developing new therapies requires a comprehensive understanding of how deregulated signaling leads to catabolic gene expression that underlies muscle wasting. Here, we review CC-associated signaling pathways and the transcriptional cascade triggered by inflammatory cytokines. Further, we highlight epigenetic factors involved in the transcription of catabolic genes in muscle wasting. We conclude with reflections on the directions that might pave the way for new therapeutic approaches to treat CC.
    Keywords:  cancer; cytokine signaling; epigenetics; muscle wasting; transcription factors
    DOI:  https://doi.org/10.3390/cancers14174258
  24. Semin Cancer Biol. 2022 Sep 01. pii: S1044-579X(22)00196-1. [Epub ahead of print]
    Regulation of pancreatic cancer therapy resistance by chemokines.
    Shailendra K Gautam, Soumi Basu, Abhijit Aithal, Nidhi V Dwivedi, Mansi Gulati, Maneesh Jain.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by high resistance and poor response to chemotherapy. In addition, the poorly immunogenic pancreatic tumors constitute an immunosuppressive tumor microenvironment (TME), that render immunotherapy-based approaches ineffective. Understanding the mechanisms of therapy resistance, identifying new targets, and developing effective strategies to overcome resistance can significantly impact the management of patients with PDAC. Chemokines are small soluble factors that are significantly deregulated during PDAC pathogenesis, contributing to tumor growth, metastasis, immune cell trafficking, and therapy resistance. Thus far, different chemokine pathways have been explored as therapeutic targets in PDAC, with some promising results in recent clinical trials. Particularly, immunotherapies such as immune check point blockade therapies and CAR-T cell therapies have shown promising results when combined with chemokine targeted therapies. Considering the emerging pathological and clinical significance of chemokines in PDAC, we reviewed major chemokine-regulated pathways leading to therapy resistance and the ongoing endeavors to restore anti-tumor chemokine signaling. This review discusses the role of chemokines in regulating therapy resistance in PDAC and highlights the continuing efforts to target chemokine-regulated pathways to improve the efficacy of various treatment modalities.
    Keywords:  Pancreatic ductal adenocarcinoma; Therapy resistance; chemokine-signaling; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2022.08.010
  25. Am J Hosp Palliat Care. 2022 Sep 04. 10499091221123049
    Is Weight Loss During Chemotherapy for Pancreatic Cancer Prognostic?
    Mellar Davis, Erin Vanenkevort, Samji Varun, Amanda Young, Irina Correa Ordonez, Jason Brown, Mark Wojtowicz.
      BACKGROUND: Predicting poor survival outcomes early in palliative chemotherapy is important to the timing of palliative care. Weight loss during chemotherapy if prognostic would lead to early palliative care.METHOD: We collected demographics, stage, chemotherapy, chemotherapy cycles, weight, healthcare utilization, comorbidities (Charleson Comorbid Index), tumor markers, and weight changes over 60 days. We defined 3 groups of patients: 1. Weight gain to <.5% weight loss, 2. Weight loss< 2% and 3. Weight loss of >2%. A Chi-square test assessed differences in weight during treatment. Time-to-event analysis was expressed in a Kaplan Meier curve.
    RESULTS: 93 individuals died of pancreatic cancer in 2018 and 2019. The median age was 71.2 years. Forty-three had stage I and II, 40 stages III and IV cancers, and 10 had unknown stages. Most received FOLFIRINOX and gemcitabine/nab-paclitaxel chemotherapy. Thirty-six gained to lost < .5% during chemotherapy,8 lost < 2% and 49 patients lost > 2% of their weight. Mortality was available in 55 of 93 patients. Median survival was 16.6 months in those with weight gain to < .5% weight loss, 17.28 months for those with < 2% weight loss, and 20.5 months for those with > 2% weight loss (P = .42).
    DISCUSSION: Weight loss over 60 days did not predict a poor prognosis in this small retrospective study; larger prospective studies may clarify the prognostic importance of weight loss during chemotherapy.
    CONCLUSION: In this small retrospective study, weight loss over 60 days did not predict poor survival.
    Keywords:  pancreatic cancer; predictors; prognosis; survival; therapy; weight loss
    DOI:  https://doi.org/10.1177/10499091221123049
  26. Am J Surg. 2022 Aug 19. pii: S0002-9610(22)00494-9. [Epub ahead of print]
    Evolving management of early stage pancreatic adenocarcinoma in older patients.
    Sean Nassoiy, Wade Christopher, Rebecca Marcus, Jennifer Keller, Jessica Weiss, Shu-Ching Chang, Richard Essner, Leland Foshag, Trevan Fischer, Melanie Goldfarb.
      BACKGROUND: Due to the aging population, the number of older patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) will continue to rise.STUDY DESIGN: Utilizing the NCDB from 2010 to 2016, patients with early stage, clinically node negative PDAC who were ≥70 years old and had a Whipple were identified. Multivariable logistic regressions were used to determine independent factors for R0 resection and NAT. Cox-proportional-hazards regression analyses examined for the impact of NAT on the risk of death.
    RESULTS: Of 5086 patients, 51.7% received upfront surgery + adjuvant therapy (UFS + AT), followed by 29.9% UFS only, and the remainder NAT. NAT significantly improved OS compared to a combined cohort of those that had UFS ± AT. NAT retained its independent survival benefit when compared to only patients that had UFS + AT.
    CONCLUSION: For older patients diagnosed with early stage PDAC, NAT was associated with improved R0 resection rates and a significant survival benefit when compared to the current standard of care.
    Keywords:  Elderly; Geriatric; Neoadjuvant chemotherapy; Pancreatic ductal adenocarcinoma; Resectable pancreatic cancer
    DOI:  https://doi.org/10.1016/j.amjsurg.2022.07.026
  27. Front Pain Res (Lausanne). 2022 ;3 971295
    Cancer cachexia: Pathophysiology and association with cancer-related pain.
    Michelle L Law.
      Cachexia is a syndrome of unintentional body weight loss and muscle wasting occurring in 30% of all cancer patients. Patients with cancers most commonly leading to brain metastases have a risk for cachexia development between 20 and 80%. Cachexia causes severe weakness and fatigue and negatively impacts quality and length of life. The negative energy balance in cachectic patients is most often caused by a combination of increased energy expenditure and decreased energy intake. Basal metabolic rate may be elevated due to tumor secreted factors and a systemic inflammatory response leading to inefficiency in energy production pathways and increased energy demand by the tumor and host tissues. A growing body of research explores physiological and molecular mechanisms of metabolic dysregulation in cachexia. However, decreased energy intake and physical functioning also remain important contributors to cachexia pathogenesis. Pain associated with metastatic malignancy is significantly associated with inflammation, thus making inflammation a common link between cancer pain and cachexia. Pain may also influence appetite and food intake and exacerbate fatigue and functional decline, potentially contributing to cachexia severity. Cancer pain and cachexia often occur simultaneously; however, causal relationships remain to be established. Appropriate assessment and treatment of pain in advanced cancer patients may positively impact nutrition status and physical functioning, slowing the progression of cachexia and improving quality and length of life for patients.
    Keywords:  anorexia; cachexia; cancer; fatigue; inflammation; muscle atrophy; nutrition impact symptoms; pain
    DOI:  https://doi.org/10.3389/fpain.2022.971295
  28. Exp Mol Med. 2022 Sep 08.
    Tracing metabolic flux in vivo: basic model structures of tracer methodology.
    Il-Young Kim, Sanghee Park, Yeongmin Kim, Hee-Joo Kim, Robert R Wolfe.
      Molecules in living organisms are in a constant state of turnover at varying rates, i.e., synthesis, breakdown, oxidation, and/or conversion to different compounds. Despite the dynamic nature of biomolecules, metabolic research has focused heavily on static, snapshot information such as the abundances of mRNA, protein, and metabolites and/or (in)activation of molecular signaling, often leading to erroneous conclusions regarding metabolic status. Over the past century, stable, non-radioactive isotope tracers have been widely used to provide critical information on the dynamics of specific biomolecules (metabolites and polymers including lipids, proteins, and DNA), in studies in vitro in cells as well as in vivo in both animals and humans. In this review, we discuss (1) the historical background of the use of stable isotope tracer methodology in metabolic research; (2) the importance of obtaining kinetic information for a better understanding of metabolism; and (3) the basic principles and model structures of stable isotope tracer methodology using 13C-, 15N-, or 2H-labeled tracers.
    DOI:  https://doi.org/10.1038/s12276-022-00814-z
  29. Exp Mol Med. 2022 Sep 08.
    Metabolic flux between organs measured by arteriovenous metabolite gradients.
    Hosung Bae, Katie Lam, Cholsoon Jang.
      Mammalian organs convert dietary nutrients into circulating metabolites and share them to maintain whole-body metabolic homeostasis. While the concentrations of circulating metabolites have been frequently measured in a variety of pathophysiological conditions, the exchange flux of circulating metabolites between organs is not easily measurable due to technical difficulties. Isotope tracing is useful for measuring such fluxes for a metabolite of interest, but the shuffling of isotopic atoms between metabolites requires mathematical modeling. Arteriovenous metabolite gradient measurements can complement isotope tracing to infer organ-specific net fluxes of many metabolites simultaneously. Here, we review the historical development of arteriovenous measurements and discuss their advantages and limitations with key example studies that have revealed metabolite exchange flux between organs in diverse pathophysiological contexts.
    DOI:  https://doi.org/10.1038/s12276-022-00803-2
  30. JCI Insight. 2022 Sep 08. pii: e153033. [Epub ahead of print]7(17):
    Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.
    Harish P Janardhan, Karen Dresser, Lloyd Hutchinson, Chinmay M Trivedi.
      Lymphangiectasia, an anomalous dilation of lymphatic vessels first described in the 17th century, is frequently associated with chylous effusion, respiratory failure, and high mortality in young patients, yet the underlying molecular pathogenesis and effective treatments remain elusive. Here, we identify an unexpected causal link between MAPK activation and defective development of the lymphatic basement membrane that drives lymphangiectasia. Human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells. Endothelial KRASG12D-mediated sustained MAPK activation in newborn mice caused severe pulmonary and intercostal lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Pathological activation of MAPK in murine vasculature inhibited the Nfatc1-dependent genetic program required for laminin interactions, collagen crosslinking, and anchoring fibril formation, driving defective development of the lymphatic basement membrane. Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment.
    Keywords:  Cardiovascular disease; Development; Lymph; Mouse models; Vascular Biology
    DOI:  https://doi.org/10.1172/jci.insight.153033
  31. Cancer Res. 2022 Sep 08. pii: CAN-22-1731. [Epub ahead of print]
    Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers.
    Robert B Scharpf, Archana Balan, Biagio Ricciuti, Jacob Fiksel, Christopher Cherry, Chenguang Wang, Michele L LeNoue-Newton, Hira A Rizvi, James R White, Alexander S Baras, Jordan Anaya, Blair V Landon, Marta Majcherska-Agrawal, Paola Ghanem, Jocelyn Lee, Leon Raskin, Andrew S Park, Huakang Tu, Hil Hsu, Kathryn C Arbour, Mark M Awad, Gregory J Riely, Christine M Lovly, Valsamo Anagnostou.
      The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are co-altered in RAS mutant tumors, we analyzed targeted next-generation sequence data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutational burden and mutational signatures on co-mutation patterns. These analyses revealed differential RAS prevalence and co-mutations with non-RAS genes in a cancer lineage and context-dependent manner, with differences across age, sex and ethnic groups. Allele specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multi-omic analyses of 10,217 tumors from TCGA revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS mutant tumors. The distinct genomic tracks discovered in RAS mutant tumors reflected differential clinical outcomes in the TCGA cohort and in an independent cohort of patients with KRAS G12C mutant non-small cell lung cancer that received immunotherapy containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS mutant allele-directed therapies with targeted therapies and immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1731
  32. Cancers (Basel). 2022 Aug 30. pii: 4228. [Epub ahead of print]14(17):
    Comparing Survival after Resection of Pancreatic Cancer with and without Pancreatic Cysts: Nationwide Registry-Based Study.
    Dutch Pancreatic Cancer Group
      BACKGROUND: Outcome after resection of pancreatic ductal adenocarcinoma associated with pancreatic cystic neoplasms (PCN-PDAC) might differ from PDAC not associated with PCN. This nationwide, registry-based study aimed to compare the overall survival (OS) in these patients.METHODS: Data from consecutive patients after pancreatic resection for PDAC between 2013 and 2018 were matched with the corresponding pathology reports. Primary outcome was OS for PCN-PDAC and PDAC including 1-year and 5-year OS. Cox regression analysis was used to correct for prognostic factors (e.g., pT-stage, pN-stage, and vascular invasion).
    RESULTS: In total, 1994 patients underwent resection for PDAC including 233 (12%) with PCN-PDAC. Median estimated OS was better in patients with PCN-PDAC (34.5 months [95%CI 25.6 to 43.5]) as compared to PDAC not associated with PCN (18.2 months [95%CI 17.3 to 19.2]; hazard ratio 0.53 [95%CI 0.44-0.63]; p &lt; 0.001). The difference in OS remained after correction for prognostic factors (adjusted hazard ratio 1.58 [95%CI 1.32-1.90]; p &lt; 0.001).
    CONCLUSIONS: This nationwide registry-based study showed that 12% of resected PDAC were PCN-associated. Patients with PCN-PDAC had better OS as compared to PDAC not associated with PCN.
    Keywords:  Kaplan–Meier estimates; pancreatic cyst; pancreatic neoplasms; surgical oncology; survival analyses
    DOI:  https://doi.org/10.3390/cancers14174228
  33. Nat Rev Cancer. 2022 Sep 05.
    Big data in basic and translational cancer research.
    Peng Jiang, Sanju Sinha, Kenneth Aldape, Sridhar Hannenhalli, Cenk Sahinalp, Eytan Ruppin.
      Historically, the primary focus of cancer research has been molecular and clinical studies of a few essential pathways and genes. Recent years have seen the rapid accumulation of large-scale cancer omics data catalysed by breakthroughs in high-throughput technologies. This fast data growth has given rise to an evolving concept of 'big data' in cancer, whose analysis demands large computational resources and can potentially bring novel insights into essential questions. Indeed, the combination of big data, bioinformatics and artificial intelligence has led to notable advances in our basic understanding of cancer biology and to translational advancements. Further advances will require a concerted effort among data scientists, clinicians, biologists and policymakers. Here, we review the current state of the art and future challenges for harnessing big data to advance cancer research and treatment.
    DOI:  https://doi.org/10.1038/s41568-022-00502-0
  34. Cancer Cell. 2022 Aug 30. pii: S1535-6108(22)00376-2. [Epub ahead of print]
    Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance.
    Qingzhu Shi, Qicong Shen, Yanfang Liu, Yang Shi, Wenwen Huang, Xi Wang, Zhiqing Li, Yangyang Chai, Hao Wang, Xiangjia Hu, Nan Li, Qian Zhang, Xuetao Cao.
      How glucose metabolism remodels pro-tumor functions of tumor-associated macrophages (TAMs) needs further investigation. Here we show that M2-like TAMs bear the highest individual capacity to take up intratumoral glucose. Their increased glucose uptake fuels hexosamine biosynthetic pathway-dependent O-GlcNAcylation to promote cancer metastasis and chemoresistance. Glucose metabolism promotes O-GlcNAcylation of the lysosome-encapsulated protease Cathepsin B at serine 210, mediated by lysosome-localized O-GlcNAc transferase (OGT), elevating mature Cathepsin B in macrophages and its secretion in the tumor microenvironment (TME). Loss of OGT in macrophages reduces O-GlcNAcylation and mature Cathepsin B in the TME and disrupts cancer metastasis and chemoresistance. Human TAMs with high OGT are positively correlated with Cathepsin B expression, and both levels predict chemotherapy response and prognosis of individuals with cancer. Our study reports the biological and potential clinical significance of glucose metabolism in tumor-promoting TAMs and reveals insights into the underlying mechanisms.
    Keywords:  O-GlcNAc transferase; O-GlcNAcylation; cathepsin B; glucose metabolism; lysosome; metastasis; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.012
  35. Cancer Res. 2022 Sep 07. pii: CAN-22-2125. [Epub ahead of print]
    A new view of activating mutations in cancer.
    Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang.
      A vast effort has been invested in the identification of driver mutations of cancer. However, recent studies and observations call into question whether the activating mutations or the signal strength are the major determinant of tumor development. The data argue that signal strength determines cell fate, not the mutation that initiated it. In addition to activating mutations, factors that can impact signaling strength include (i) homeostatic mechanisms that can block or enhance the signal, (ii) the types and locations of additional mutations, and (iii) the expression levels of specific isoforms of genes and regulators of proteins in the pathway. Since signal levels are largely decided by chromatin structure, they vary across cell types, states, and time windows. A strong activating mutation can be restricted by low expression, whereas a weaker mutation can be strengthened by high expression. Strong signals can be associated with cell proliferation, but too strong a signal may result in oncogene-induced senescence. Beyond cancer, moderate signal strength in embryonic neural cells may be associated with neurodevelopmental disorders, and moderate signals in aging may be associated with neurodegenerative diseases, like Alzheimer's disease. The challenge for improving patient outcomes therefore lies in determining signaling thresholds and predicting signal strength.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2125
  36. Methods Mol Biol. 2022 ;2543 167-178
    Proximity Ligation in Situ Assay to Monitor Autophagy-Related Protein Interactions and Autophagy in Cancer Cells.
    Paul Peixoto, Michaël Guittaut, Eric Hervouet.
      Proximity ligation in situ assay (PLISA) is a powerful method to quantify endogen protein-protein interactions in cells and simultaneously identify localization of these interactions. PLISA can be used to quantify autophagy flux and can as well be adapted to assess global autophagy (SQSTM1/P62-LC3B interaction) or specific autophagy, such as mitophagy (NIX-LC3B). Here, we describe a step-by-step method to monitor autophagy using PLISA in adherent cancer cells.
    Keywords:  Amplification; Autophagy; Confocal microscopy; LC3B; Ligation; PLISA
    DOI:  https://doi.org/10.1007/978-1-0716-2553-8_14
  37. Nature. 2022 Sep;609(7926): 255-264
    Capillary forces generated by biomolecular condensates.
    Bernardo Gouveia, Yoonji Kim, Joshua W Shaevitz, Sabine Petry, Howard A Stone, Clifford P Brangwynne.
      Liquid-liquid phase separation and related phase transitions have emerged as generic mechanisms in living cells for the formation of membraneless compartments or biomolecular condensates. The surface between two immiscible phases has an interfacial tension, generating capillary forces that can perform work on the surrounding environment. Here we present the physical principles of capillarity, including examples of how capillary forces structure multiphase condensates and remodel biological substrates. As with other mechanisms of intracellular force generation, for example, molecular motors, capillary forces can influence biological processes. Identifying the biomolecular determinants of condensate capillarity represents an exciting frontier, bridging soft matter physics and cell biology.
    DOI:  https://doi.org/10.1038/s41586-022-05138-6
  38. Exp Mol Med. 2022 Sep 08.
    Tracing metabolic flux to assess optimal dietary protein and amino acid consumption.
    Robert R Wolfe, Il-Young Kim, Sanghee Park, Arny Ferrando.
      There is a general consensus that a dietary protein intake of 0.8 g protein/kg/day will prevent symptoms of protein deficiency in young, healthy individuals. However, individuals in many physiological circumstances may benefit from higher rates of dietary protein intake. Stable isotope tracer methodology enables a variety of approaches to assessing the optimal dietary protein intake in humans. In this paper, we present an overview of a variety of tracer methods, with a discussion of necessary assumptions, as well as the clinical circumstances in which different methods may be preferable. Although we discuss the nontracer method of nitrogen balance, which has historically been used to estimate dietary protein requirements, this paper primarily focuses on tracer methods for estimating dietary protein and essential amino acid requirements under different physiological conditions. We will explain the following approaches: isotopic measurement of urea production; the arterial-venous tracer balance method; measurement of the fractional synthetic and breakdown rates of muscle protein; the indicator and the direct amino acid oxidation methods; and different approaches to measuring whole-body protein synthesis and breakdown. The advantages and limitations of each method are discussed in the context of the optimal approaches for use under different circumstances.
    DOI:  https://doi.org/10.1038/s12276-022-00817-w
  39. Front Oncol. 2022 ;12 932285
    Mechanical and metabolic interplay in the brain metastatic microenvironment.
    Killian Onwudiwe, Alice A Burchett, Meenal Datta.
      In this Perspective, we provide our insights and opinions about the contribution-and potential co-regulation-of mechanics and metabolism in incurable breast cancer brain metastasis. Altered metabolic activity can affect cancer metastasis as high glucose supply and demand in the brain microenvironment favors aerobic glycolysis. Similarly, the altered mechanical properties of disseminating cancer cells facilitate migration to and metastatic seeding of the brain, where local metabolites support their progression. Cancer cells in the brain and the brain tumor microenvironment often possess opposing mechanical and metabolic properties compared to extracranial cancer cells and their microenvironment, which inhibit the ease of extravasation and metastasis of these cells outside the central nervous system. We posit that the brain provides a metabolic microenvironment that mechanically reinforces the cellular structure of cancer cells and supports their metastatic growth while restricting their spread from the brain to external organs.
    Keywords:  brain metastatic microenvironment; cell stiffness; extracellular matrix; fatty acid synthesis; glycolysis; mechanotransduction; tumor mechanics; tumor metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.932285
  40. Front Cell Dev Biol. 2022 ;10 975684
    An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer.
    Duo Yun, Zhirong Yang, Shuman Zhang, Hai Yang, Dongxue Liu, Robert Grützmann, Christian Pilarsky, Nathalie Britzen-Laurent.
      Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive digestive malignancy due to frequent late-stage diagnosis, rapid progression and resistance to therapy. With increasing PDAC incidence worldwide, there is an urgent need for new prognostic biomarkers and therapy targets. Recently, RNA methylation has emerged as a new tumorigenic mechanism in different cancers. 5-methylcytosine (m5C) is one of the most frequent RNA modifications and occurs on a variety of RNA species including mRNA, thereby regulating gene expression. Here we investigated the prognostic role of m5C-regulator-associated transcriptional signature in PDAC. We evaluated m5C-regulator status and expression in 239 PDAC samples from publicly available datasets. We used unsupervised consensus clustering analyses to classify PDACs based on m5C-regulator expression. From the resulting signature of differentially expressed genes (DEGs), we selected prognosis-relevant DEGs to stratify patients and build a scoring signature (m5C-score) through LASSO and multivariate Cox regression analyses. The m5C-score represented a highly significant independent prognostic marker. A high m5C-score correlated with poor prognosis in different PDAC cohorts, and was associated with the squamous/basal subtype as well as activated cancer-related pathways including Ras, MAPK and PI3K pathways. Furthermore, the m5C-score correlated with sensitivity to pathway-specific inhibitors of PARP, EGFR, AKT, HER2 and mTOR. Tumors with high m5C-score were characterized by overall immune exclusion, low CD8+ T-cell infiltration, and higher PD-L1 expression. Overall, the m5C-score represented a robust predictor of prognosis and therapy response in PDAC, which was associated with unfavorable molecular subtypes and immune microenvironment.
    Keywords:  5-methylcytosine (m5C); immune cells infiltration; pancreatic cancer; prognosis; targeted drug therapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2022.975684
  41. J Natl Compr Canc Netw. 2022 09;pii: jnccn20227041. [Epub ahead of print]20(9): 1023-1032.e3
    FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.
    Amro M Abdelrahman, Ajit H Goenka, Roberto Alva-Ruiz, Jennifer A Yonkus, Jennifer L Leiting, Rondell P Graham, Kenneth W Merrell, Cornelius A Thiels, Christopher L Hallemeier, Susanne G Warner, Michael G Haddock, Travis E Grotz, Nguyen H Tran, Rory L Smoot, Wen Wee Ma, Sean P Cleary, Robert R McWilliams, David M Nagorney, Thorvardur R Halfdanarson, Michael L Kendrick, Mark J Truty.
      BACKGROUND: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival.METHODS: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS).
    RESULTS: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4).
    CONCLUSIONS: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.
    DOI:  https://doi.org/10.6004/jnccn.2022.7041
  42. Phys Med Biol. 2022 Sep 06.
    An integrative web-based software tool for multi-dimensional pathology whole-slide image analytics.
    Alice Shen, Fusheng Wang, Saptarshi Paul, Divya Bhuvanapalli, Jacob Alayof, Alton B Farris, George Teodoro, Daniel J Brat, Jun Kong.
      OBJECTIVE: In the era of precision medicine, human tumor atlas-oriented studies have been significantly facilitated by high-resolution, multi-modal tissue based microscopic pathology image analytics. To better support such tissue-based investigations, we have developed Digital Pathology Laboratory (DPLab), a publicly available web-based platform, to assist biomedical research groups, non-technical end users, and clinicians for pathology Whole-Slide Image (WSI) visualization, annotation, analysis, and sharing via web browsers.APPROACH: A major advancement of this work is the easy-to-follow methods to reconstruct three-dimension (3D) tissue image volumes by registering two-dimension (2D) whole-slide pathology images of serial tissue sections stained by hematoxylin and eosin (H&E), and immunohistochemistry (IHC). The integration of these serial slides stained by different methods provides cellular phenotype and pathophysiologic states in the context of a 3D tissue micro-environment. DPLab is hosted on a publicly accessible server and connected to a backend computational cluster for intensive image analysis computations, with results visualized, downloaded, and shared via a web interface.
    MAIN RESULTS: Equipped with an analysis toolbox of numerous image processing algorithms, DPLab supports continued integration of community-contributed algorithms and presents an effective solution to improve the accessibility and dissemination of image analysis algorithms by research communities.
    SIGNIFICANCE: DPLab represents the first step in making next generation tissue investigation tools widely available to the research community, enabling and facilitating discovery of clinically relevant disease mechanisms in a digital 3D tissue space.
    Keywords:  digital pathology; high performance computing; image analysis; image registration; web computing; whole slide images
    DOI:  https://doi.org/10.1088/1361-6560/ac8fde
  43. Cancers (Basel). 2022 Aug 30. pii: 4209. [Epub ahead of print]14(17):
    Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.
    Nebojsa Skorupan, Mayrel Palestino Dominguez, Samuel L Ricci, Christine Alewine.
      Pancreatic cancer has a complex tumor microenvironment which engages in extensive crosstalk between cancer cells, cancer-associated fibroblasts, and immune cells. Many of these interactions contribute to tumor resistance to anti-cancer therapies. Here, new therapeutic strategies designed to modulate the cancer-associated fibroblast and immune compartments of pancreatic ductal adenocarcinomas are described and clinical trials of novel therapeutics are discussed. Continued advances in our understanding of the pancreatic cancer tumor microenvironment are generating stromal and immune-modulating therapeutics that may improve patient responses to anti-tumor treatment.
    Keywords:  cancer-associated fibroblasts; immunotherapy; pancreatic cancer; stromal modifiers
    DOI:  https://doi.org/10.3390/cancers14174209
  44. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00357-6. [Epub ahead of print]34(9): 1394-1409.e4
    3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk.
    HPAP Consortium
      Three-dimensional (3D) chromatin organization maps help dissect cell-type-specific gene regulatory programs. Furthermore, 3D chromatin maps contribute to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell-type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and transcriptional factor-mediated control of cell-type-specific gene regulatory programs. We identified a total of 4,750 putative causal-variant-to-target-gene pairs at 194 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis.
    Keywords:  3D chromatin maps; acinar cell; alpha cell; beta cell; islets of Langerhans; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.014
  45. Nat Commun. 2022 Sep 06. 13(1): 4981
    Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity.
    Qiang Feng, Zhida Liu, Xuexin Yu, Tongyi Huang, Jiahui Chen, Jian Wang, Jonathan Wilhelm, Suxin Li, Jiwon Song, Wei Li, Zhichen Sun, Baran D Sumer, Bo Li, Yang-Xin Fu, Jinming Gao.
      Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.
    DOI:  https://doi.org/10.1038/s41467-022-32521-8
  46. Cell Biochem Funct. 2022 Sep 05.
    ATG5: A central autophagy regulator implicated in various human diseases.
    Harish Changotra, Sargeet Kaur, Suresh Singh Yadav, Girdhari Lal Gupta, Jyoti Parkash, Ajay Duseja.
      Autophagy, an intracellular conserved degradative process, plays a central role in the renewal/recycling of a cell to maintain the homeostasis of nutrients and energy within the cell. ATG5, a key component of autophagy, regulates the formation of the autophagosome, a hallmark of autophagy. ATG5 binds with ATG12 and ATG16L1 resulting in E3 like ligase complex, which is necessary for autophagosome expansion. Available data suggest that ATG5 is indispensable for autophagy and has an imperative role in several essential biological processes. Moreover, ATG5 has also been demonstrated to possess autophagy-independent functions that magnify its significance and therapeutic potential. ATG5 interacts with various molecules for the execution of different processes implicated during physiological and pathological conditions. Furthermore, ATG5 genetic variants are associated with various ailments. This review discusses various autophagy-dependent and autophagy-independent roles of ATG5, highlights its various deleterious genetic variants reported until now, and various studies supporting it as a potential drug target.
    Keywords:  ATG12-ATG5/ATG16L1; ATG5; ATG5 polymorphism; autophagosome; autophagy
    DOI:  https://doi.org/10.1002/cbf.3740
  47. J Cell Commun Signal. 2022 Sep 08.
    SHP2 regulates adipose maintenance and adipocyte-pancreatic cancer cell crosstalk via PDHA1.
    Appolinaire A Olou, Joe Ambrose, Jarrid L Jack, McKinnon Walsh, Mariana T Ruckert, Austin E Eades, Bailey A Bye, Prasad Dandawate, Michael N VanSaun.
      Adipocytes are the most abundant cell type in the adipose tissue, and their dysfunction is a significant driver of obesity-related pathologies, such as cancer. The mechanisms that (1) drive the maintenance and secretory activity of adipocytes and (2) mediate the cancer cellular response to the adipocyte-derived factors are not fully understood. To address that gap of knowledge, we investigated how alterations in Src homology region 2-containing protein (SHP2) activity affect adipocyte function and tumor crosstalk. We found that phospho-SHP2 levels are elevated in adipose tissue of obese mice, obese patients, and differentiating adipocytes. Immunofluorescence and immunoprecipitation analyses as well as in-silico protein-protein interaction modeling demonstrated that SHP2 associates with PDHA1, and that a positive association promotes a reactive oxygen species (ROS)-driven adipogenic program. Accordingly, this SHP2-PDHA1-ROS regulatory axis was crucial for adipocyte maintenance and secretion of interleukin-6 (IL-6), a key cancer-promoting cytokine. Mature adipocytes treated with an inhibitor for SHP2, PDHA1, or ROS exhibited an increased level of pro-lipolytic and thermogenic proteins, corresponding to an increased glycerol release, but a suppression of secreted IL-6. A functional analysis of adipocyte-cancer cell crosstalk demonstrated a decreased migration, invasion, and a slight suppression of cell cycling, corresponding to a reduced growth of pancreatic cancer cells exposed to conditioned media (CM) from mature adipocytes previously treated with inhibitors for SHP2/PDHA1/ROS. Importantly, PDAC cell growth stimulation in response to adipocyte CM correlated with PDHA1 induction but was suppressed by a PDHA1 inhibitor. The data point to a novel role for (1) SHP2-PDHA1-ROS in adipocyte maintenance and secretory activity and (2) PDHA1 as a regulator of the pancreatic cancer cells response to adipocyte-derived factors.
    Keywords:  Adipocytes; Cancer; PDHA1; ROS; SHP2
    DOI:  https://doi.org/10.1007/s12079-022-00691-1
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