bims-cagime 2024-03-24 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2024‒03‒24
forty papers selected by
Kıvanç Görgülü, Technical University of Munich

Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.
Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice.
Cancer cells hijack physiological metabolic signals to seed liver metastasis.
A fast-acting lipid checkpoint in G1 prevents mitotic defects.
Integrin-αvβ6 targeted peptide-toxin therapy in a novel αvβ6-expressing immunocompetent model of pancreatic cancer.
Plasma membrane damage is a new trigger of cellular senescence.
Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer.
Activation of GPR81 by lactate drives tumour-induced cachexia.
SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
Intervention with metabolites emulating endogenous cell transitions accelerates muscle regeneration in young and aged mice.
Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.
Handgrip Strength Predicts Survival in Patients With Pancreatic Cancer.
Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond.
FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis.
Vascular regulation of disseminated tumor cells during metastatic spread.
Tissue fibrosis associated depletion of lipid-filled cells.
The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
Lac-Phe mediates the effects of metformin on food intake and body weight.
Pancreatic Cysts Greater Than 1 cm Are Associated With an Increased Risk for Developing Pancreatic Cancer in Individuals From Pancreatic-Cancer Prone Kindreds Undergoing Surveillance.
Sulfide oxidation promotes hypoxic angiogenesis and neovascularization.
Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.
Trends Over Time in Recurrence Patterns and Survival Outcomes after Neoadjuvant Therapy and Surgery for Pancreatic Cancer.
High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment.
Three-dimensional topology-based analysis segments volumetric and spatiotemporal fluorescence microscopy.
CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.
The activation mechanism of Atg15, a vacuolar phospholipase required for the disintegration of organelle membranes.
Caveolin-1 protects endothelial cells from extensive expansion of transcellular tunnel by stiffening the plasma membrane.
Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
Towards a general-purpose foundation model for computational pathology.
Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction.
Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.
Dual-energy computed tomography in a multiparametric regression model for diagnosing lymph node metastases in pancreatic ductal adenocarcinoma.
MemPrep, a new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress.
Cell membrane tension gradients, membrane flows and cellular processes.
Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse.
Common mouse models of chronic kidney disease are not associated with cachexia.
A Panoramic View of Cell Population Dynamics in Mammalian Aging.
Role of the fatty pancreatic infiltration in pancreatic oncogenesis.
Lipid-Restricted Culture Media Reveal Unexpected Cancer Cell Sensitivities.
Addressing Biological Questions with Preclinical Cancer Imaging.

Mol Cell. 2024 Mar 14. pii: S1097-2765(24)00172-2. [Epub ahead of print]

Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.

Pinki Gahlot, Bojana Kravic, Giulia Rota, Johannes van den Boom, Sophie Levantovsky, Nina Schulze, Elena Maspero, Simona Polo, Christian Behrends, Hemmo Meyer.

  Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis.

Keywords:  ESCRT; ITCH; Troyer syndrome; lipid sensing; lysophagy; lysosomal membrane permeabilization; lysosomal repair; spartin; spastic paraplegia; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2024.02.029
Mol Metab. 2024 Mar 14. pii: S2212-8778(24)00046-2. [Epub ahead of print] 101915

Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice.

Seun Akindehin, Arkadiusz Liskiewicz, Daniela Liskiewicz, Miriam Bernecker, Cristina Garcia-Caceres, Daniel J Drucker, Brian Finan, Gerald Grandl, Robert Gutgesell, Susanna M Hofmann, Ahmed Khalil, Xue Liu, Perla Cota, Mostafa Bakhti, Oliver Czarnecki, Aimée Bastidas-Ponce, Heiko Lickert, Lingru Kang, Gandhari Maity, Aaron Novikoff, Sebastian Parlee, Ekta Pathak, Sonja C Schriever, Michael Sterr, Siegfried Ussar, Qian Zhang, Richard DiMarchi, Matthias H Tschöp, Paul T Pfluger, Jonathan D Douros, Timo D Müller.

  OBJECTIVE: The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr).METHODS: Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice.
RESULTS: Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance, and acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice.
CONCLUSIONS: GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.

Keywords:  GIP; GIPR:GLP-1R co-agonism; GLP-1; Obesity; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.molmet.2024.101915
Cancer Res. 2024 Mar 19.

Cancer cells hijack physiological metabolic signals to seed liver metastasis.

Andres Rettig, Karuna Ganesh.

Metastasis arises from cancer-cell intrinsic adaptations and permissive tumor microenvironments (TME) that are distinct across different organs. Deciphering the mechanisms underpinning organotropism could provide novel preventive and therapeutic strategies for cancer patients. Rogava and colleagues identified Pip4kc as a driver of liver metastasis, acting by sensitizing cancer cells to insulin-dependent PI3K/AKT signaling, which could be reversed by dual pharmacological inhibition of PI3K and SGLT2 or a ketogenic diet. The study highlights the importance of tumor: microenvironment communication in the context of systemic physiology and points towards potential combination therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0835
Nat Commun. 2024 Mar 18. 15(1): 2441

A fast-acting lipid checkpoint in G1 prevents mitotic defects.

Marielle S Köberlin, Yilin Fan, Chad Liu, Mingyu Chung, Antonio F M Pinto, Peter K Jackson, Alan Saghatelian, Tobias Meyer.

Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.

DOI: https://doi.org/10.1038/s41467-024-46696-9
Pancreatology. 2024 Feb 24. pii: S1424-3903(24)00057-7. [Epub ahead of print]

Integrin-αvβ6 targeted peptide-toxin therapy in a novel αvβ6-expressing immunocompetent model of pancreatic cancer.

Nicholas F Brown, Elizabeth R Murray, Lauren C Cutmore, Philip Howard, Luke Masterson, Francesca Zammarchi, John A Hartley, Patrick H van Berkel, John F Marshall.

Previously we reported that a novel αvβ6-specific peptide-drug conjugate (SG3299) could eliminate established human pancreatic ductal adenocarcinoma (PDAC) xenografts. However the development of effective therapies for PDAC, which is an essential need, must show efficacy in relevant immunocompetent animals. Previously we reported that the KPC mouse transgenic PDAC model that closely recapitulates most stages of development of human PDAC, unlike in humans, failed to express αvβ6 on their tumours or metastases. In this study we have taken the KPC-derived PDAC line TB32043 and engineered a variant line (TB32043mb6S2) that expresses mouse integrin αvβ6. We report that orthotopic implantation of the αvβ6 over-expressing TB32043mb6S2 cells promotes shorter overall survival and increase in metastases. Moreover, systemic treatment of mice with established TB32043mb6S2 tumours in the pancreas with SG2399 lived significantly longer (p < 0.001; mean OS 48d) compared with PBS or control SG3511 (mean OS 25.5d and 26d, respectively). Thus SG3299 is confirmed as a promising candidate therapeutic for the therapy of PDAC.

DOI: https://doi.org/10.1016/j.pan.2024.02.013
Trends Cell Biol. 2024 Mar 15. pii: S0962-8924(24)00051-5. [Epub ahead of print]

Plasma membrane damage is a new trigger of cellular senescence.

Nadine Martin, Céline Margand, David Bernard.

  By blocking proliferation and inducing a secretory phenotype, cellular senescence has beneficial and deleterious effects, the latter being linked to aging. Suda et al. recently reported that plasma membrane (PM) damage (PMD) triggers senescence, suggesting that PMD inducers promote senescence and that the PMD repair machinery can regulate it.

Keywords:  ESCRT; aging; calcium; cellular senescence; plasma membrane damage

DOI:  https://doi.org/10.1016/j.tcb.2024.03.002
Cancer Cell. 2024 Mar 18. pii: S1535-6108(24)00079-5. [Epub ahead of print]

Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer.

Pierluigi Di Chiaro, Lucia Nacci, Fabiana Arco, Stefania Brandini, Sara Polletti, Andrea Palamidessi, Benedetta Donati, Chiara Soriani, Francesco Gualdrini, Gianmaria Frigè, Luca Mazzarella, Alessia Ciarrocchi, Alessandro Zerbi, Paola Spaggiari, Giorgio Scita, Simona Rodighiero, Iros Barozzi, Giuseppe R Diaferia, Gioacchino Natoli.

  Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.

Keywords:  PDAC; extracellular matrix; histology; laser microdissection; pancreatic cancer; perineural invasion; spatial transcriptomics; tumor heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2024.02.017
Nat Metab. 2024 Mar 18.

Activation of GPR81 by lactate drives tumour-induced cachexia.

Xidan Liu, Shijin Li, Qionghua Cui, Bujing Guo, Wanqiu Ding, Jie Liu, Li Quan, Xiaochuan Li, Peng Xie, Li Jin, Ye Sheng, Wenxin Chen, Kai Wang, Fanxin Zeng, Yifu Qiu, Changlu Liu, Yan Zhang, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.

Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Furthermore, we demonstrate that adipose-specific G-protein-coupled receptor (GPR)81 ablation, similarly to global GPR81 deficiency, ameliorates lactate-induced or tumour-induced adipose and muscle wasting in male mice, revealing adipose GPR81 as the major mediator of the catabolic effects of lactate. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the well-established protein kinase A catabolic pathway, but it is mediated by a signalling cascade sequentially activating Gi-Gβγ-RhoA/ROCK1-p38. These findings highlight the therapeutic potential of targeting GPR81 for the treatment of this life-threatening complication of cancer.

DOI: https://doi.org/10.1038/s42255-024-01011-0
Cell Rep. 2024 Mar 19. pii: S2211-1247(24)00303-6. [Epub ahead of print]43(4): 113975

SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.

Sarah A Tucker, Song-Hua Hu, Sejal Vyas, Albert Park, Shakchhi Joshi, Aslihan Inal, Tiffany Lam, Emily Tan, Kevin M Haigis, Marcia C Haigis.

  The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.

Keywords:  CP: Cancer; SIRT4; glutamine; intestinal organoids; irradiation; nucleotide biosynthesis; nucleotide metabolism; sirtuin

DOI:  https://doi.org/10.1016/j.celrep.2024.113975
Cell Rep Med. 2024 Mar 19. pii: S2666-3791(24)00072-7. [Epub ahead of print]5(3): 101449

Intervention with metabolites emulating endogenous cell transitions accelerates muscle regeneration in young and aged mice.

Reyna Hernandez-Benitez, Chao Wang, Lei Shi, Yasuo Ouchi, Cuiqing Zhong, Tomoaki Hishida, Hsin-Kai Liao, Eric A Magill, Sebastian Memczak, Rupa D Soligalla, Chiara Fresia, Fumiyuki Hatanaka, Veronica Lamas, Isabel Guillen, Sanjeeb Sahu, Mako Yamamoto, Yanjiao Shao, Alain Aguirre-Vazquez, Estrella Nuñez Delicado, Pedro Guillen, Concepcion Rodriguez Esteban, Jing Qu, Pradeep Reddy, Steve Horvath, Guang-Hui Liu, Pierre Magistretti, Juan Carlos Izpisua Belmonte.

  Tissue regeneration following an injury requires dynamic cell-state transitions that allow for establishing the cell identities required for the restoration of tissue homeostasis and function. Here, we present a biochemical intervention that induces an intermediate cell state mirroring a transition identified during normal differentiation of myoblasts and other multipotent and pluripotent cells to mature cells. When applied in somatic differentiated cells, the intervention, composed of one-carbon metabolites, reduces some dedifferentiation markers without losing the lineage identity, thus inducing limited reprogramming into a more flexible cell state. Moreover, the intervention enabled accelerated repair after muscle injury in young and aged mice. Overall, our study uncovers a conserved biochemical transitional phase that enhances cellular plasticity in vivo and hints at potential and scalable biochemical interventions of use in regenerative medicine and rejuvenation interventions that may be more tractable than genetic ones.

Keywords:  histone acetylation; myogenic lineage; one-carbon metabolism; regeneration; reprogramming; small molecules

DOI:  https://doi.org/10.1016/j.xcrm.2024.101449
J Cachexia Sarcopenia Muscle. 2024 Mar 18.

Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

John D Groarke, Jeffrey Crawford, Susie M Collins, Shannon L Lubaczewski, Danna M Breen, Magdalena A Harrington, Ira Jacobs, Ruolun Qiu, James Revkin, Michelle I Rossulek, Aditi R Saxena.

  BACKGROUND: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors.METHODS: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities.
PERSPECTIVE: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life.
TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05546476.

Keywords:  GDF-15; cachexia; cancer; ponsegromab; weight loss

DOI:  https://doi.org/10.1002/jcsm.13435
Pancreas. 2024 Mar 21.

Handgrip Strength Predicts Survival in Patients With Pancreatic Cancer.

Julia Freckelton, Ashray Rajagopalan, Gregory T Moore, Daniel Croagh.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is a common cancer with a poor prognosis and is associated with a high prevalence of cachexia, a metabolic syndrome of muscle wasting due to complex mechanisms. In addition to loss of muscle mass, cancer patients also experience functional deterioration. The aim of this study is to determine whether there is an association between muscle mass and function and clinical outcomes, particularly survival.METHODS: We performed a prospective cohort study including all patients with PDAC at Monash Health from March 2016 to December 2017. We conducted body composition analysis for myopenia and handgrip strength testing. We constructed Kaplan-Meier curves to estimate whether myopenia and low hand grip strength were associated with poorer survival.
RESULTS: Myopenia was not associated with a significant difference in PDAC-specific survival (log-rank P = 0.60). However, low handgrip strength was associated with significantly worse PDAC-specific survival compared with other patients (log-rank hazard ratio, 1.88; 95% confidence interval, 1.15-3.09; P = 0.004).
CONCLUSIONS: The relationship between survival in PDAC and handgrip strength, but not anatomical muscle mass, suggests that functional testing of strength may be important in prognostication of patients with PDAC, alongside existing tools such as the Eastern Cooperative Oncology Group performance status.

DOI: https://doi.org/10.1097/MPA.0000000000002319
Cold Spring Harb Perspect Med. 2024 Mar 19. pii: a041533. [Epub ahead of print]

Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond.

Esther W Lim, Christian M Metallo.

One-carbon (1C) metabolism is a network of biochemical reactions distributed across organelles that delivers folate-activated 1C units to support macromolecule synthesis, methylation, and reductive homeostasis. Fluxes through these pathways are up-regulated in highly proliferative cancer cells, and anti-folates, which target enzymes within the 1C pathway, have long been used in the treatment of cancer. In this work, we review fundamental aspects of 1C metabolism and place it in context with other biosynthetic and redox pathways, such that 1C metabolism acts to bridge pathways across compartments. We further discuss the importance of stable-isotope-tracing techniques combined with mass spectrometry analysis to study 1C metabolism and conclude by highlighting therapeutic approaches that could exploit cancer cells' dependency on 1C metabolism.

DOI: https://doi.org/10.1101/cshperspect.a041533
Mol Cell. 2024 Mar 12. pii: S1097-2765(24)00180-1. [Epub ahead of print]

FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis.

Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Natasha Mahealani Flores, Annie Truc Trinh, Tourkian Chasan, Julia Thompson, Pawel Karol Mazur, Or Gozani.

  eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

Keywords:  FAM86A; KRAS; cancer; eEF2; elongation; lung; lysine methylation; mRNA translation; protein synthesis

DOI:  https://doi.org/10.1016/j.molcel.2024.02.037
Biophys Rev (Melville). 2023 Mar;4(1): 011310

Vascular regulation of disseminated tumor cells during metastatic spread.

Victoria Sturgess, Udochi F Azubuike, Kandice Tanner.

Cancer cells can travel to other organs via interconnected vascular systems to form new lesions in a process known as metastatic spread. Unfortunately, metastasis remains the leading cause of patient lethality. In recent years, it has been demonstrated that physical cues are just as important as chemical and genetic perturbations in driving changes in gene expression, cell motility, and survival. In this concise review, we focus on the physical cues that cancer cells experience as they migrate through the lymphatic and blood vascular networks. We also present an overview of steps that may facilitate organ specific metastasis.

DOI: https://doi.org/10.1063/5.0106675
Exp Dermatol. 2024 Mar;33(3): e15054

Tissue fibrosis associated depletion of lipid-filled cells.

Anna Jussila, Brian Zhang, Sakin Kirti, Radhika Atit.

  Fibrosis is primarily described as the deposition of excessive extracellular matrix, but in many tissues it also involves a loss of lipid or lipid-filled cells. Lipid-filled cells are critical to tissue function and integrity in many tissues including the skin and lungs. Thus, loss or depletion of lipid-filled cells during fibrogenesis, has implications for tissue function. In some contexts, lipid-filled cells can impact ECM composition and stability, highlighting their importance in fibrotic transformation. Recent papers in fibrosis address this newly recognized fibrotic lipodystrophy phenomenon. Even in disparate tissues, common mechanisms are emerging to explain fibrotic lipodystrophy. These findings have implications for fibrosis in tissues composed of fibroblast and lipid-filled cell populations such as skin, lung, and liver. In this review, we will discuss the roles of lipid-containing cells, their reduction/loss during fibrotic transformation, and the mechanisms of that loss in the skin and lungs.

Keywords:  Wnt signalling; dermal adipocytes; lipodystrophy; skin fibrosis

DOI:  https://doi.org/10.1111/exd.15054
J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):

The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.

Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.

Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.

DOI: https://doi.org/10.1083/jcb.202302069
Nat Metab. 2024 Mar 18.

Lac-Phe mediates the effects of metformin on food intake and body weight.

Shuke Xiao, Veronica L Li, Xuchao Lyu, Xudong Chen, Wei Wei, Fahim Abbasi, Joshua W Knowles, Alan Sheng-Hwa Tung, Shuliang Deng, Gaurav Tiwari, Xu Shi, Shuning Zheng, Laurie Farrell, Zsu-Zsu Chen, Kent D Taylor, Xiuqing Guo, Mark O Goodarzi, Alexis C Wood, Yii-Der Ida Chen, Leslie A Lange, Stephen S Rich, Jerome I Rotter, Clary B Clish, Usman A Tahir, Robert E Gerszten, Mark D Benson, Jonathan Z Long.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

DOI: https://doi.org/10.1038/s42255-024-00999-9
Pancreas. 2024 Apr 01. 53(4): e350-e356

Pancreatic Cysts Greater Than 1 cm Are Associated With an Increased Risk for Developing Pancreatic Cancer in Individuals From Pancreatic-Cancer Prone Kindreds Undergoing Surveillance.

Muaz Aijazi, Kenneth E Fasanella, Kevin McGrath, Lynette M Smith, Aatur D Singhi, Randall E Brand.

BACKGROUND: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance.METHODS: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging.
RESULTS: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion.
CONCLUSIONS: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion.

DOI: https://doi.org/10.1097/MPA.0000000000002312
Nat Chem Biol. 2024 Mar 20.

Sulfide oxidation promotes hypoxic angiogenesis and neovascularization.

Roshan Kumar, Victor Vitvitsky, Apichaya Sethaudom, Rashi Singhal, Sumeet Solanki, Sydney Alibeckoff, Harrison L Hiraki, Hannah N Bell, Anthony Andren, Brendon M Baker, Costas A Lyssiotis, Yatrik M Shah, Ruma Banerjee.

Angiogenic programming in the vascular endothelium is a tightly regulated process for maintaining tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Here, we report that hypoxic upregulation of ·NO in endothelial cells reprograms the transsulfuration pathway to increase biogenesis of hydrogen sulfide (H2S), a proangiogenic metabolite. However, decreased H2S oxidation due to sulfide quinone oxidoreductase (SQOR) deficiency synergizes with hypoxia, inducing a reductive shift and limiting endothelial proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body (WBCreSqorfl/fl) and endothelial-specific (VE-cadherinCre-ERT2Sqorfl/fl) Sqor-knockout mice exhibit lower mass and angiogenesis than control mice. WBCreSqorfl/fl mice also exhibit decreased muscle angiogenesis following femoral artery ligation compared to control mice. Collectively, our data reveal the molecular intersections between H2S, O2 and ·NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization.

DOI: https://doi.org/10.1038/s41589-024-01583-8
Cold Spring Harb Perspect Med. 2024 Mar 19. pii: a041536. [Epub ahead of print]

Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.

Daniel Peled, Ruth Casey, Eyal Gottlieb.

With the foundation pre-laid, research in the new millennium has readily excavated and expanded upon the architectural framework laid out by Otto Warburg's seminal work in a new wave of "westward expansion," ever widening our understanding of cancer metabolism beyond the telescopic vision seen over a century ago. On this path, the unique circuitry of the cancer metabolic program has been elucidated, illuminating mutations of conserved cellular pathways implicated in tumorigenesis. Paramount among these are mutations in tricarboxylic acid cycle enzymes, succinate dehydrogenase, and fumarate hydratase, leading to deleterious accumulations in metabolic intermediates, "oncometabolites," the pilots of the disease process. In this work, we seek to reflect on the advancements in the field in recent years, updating knowledge on the exact biochemical mechanisms at the helm of the tumor, providing rationale for clinical trials currently underway, and anticipating directions for the future on this expansive frontier.

DOI: https://doi.org/10.1101/cshperspect.a041536
Ann Surg. 2024 Mar 20.

Trends Over Time in Recurrence Patterns and Survival Outcomes after Neoadjuvant Therapy and Surgery for Pancreatic Cancer.

Samuel H Cass, Ching-Wei D Tzeng, Laura R Prakash, Jessica Maxwell, Rebecca A Snyder, Michael P Kim, Ryan W Huey, Brandon G Smaglo, Shubham Pant, Eugene J Koay, Robert A Wolff, Jeffery E Lee, Matthew H G Katz, Naruhiko Ikoma.

OBJECTIVE: We aimed to determine if advances in neoadjuvant therapy affected recurrence patterns and survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC).BACKGROUND: Data are limited on how modern multimodality therapy affects PDAC recurrence and post-recurrence survival.
METHODS: Patients who received neoadjuvant therapy followed by curative-intent pancreatectomy for PDAC during 1998-2018 were identified. Treatments, recurrence sites and timing, and survival were compared between patients who completed neoadjuvant therapy and pancreatectomy in 1998-2004, 2005-2011, and 2012-2018.
RESULTS: The study included 727 patients (203, 251, and 273 in the 1998-2004, 2005-2011, and 2012-2018 cohorts, respectively). Use of neoadjuvant induction chemotherapy increased over time, and regimens changed over time, with >80% of patients treated in 2012-2018 receiving FOLFIRINOX or gemcitabine with nab-paclitaxel. Overall, recurrence sites and incidence (67.5%, 66.1%, and 65.9%) remained stable, and 85% of recurrences occurred within 2 years of surgery. However, compared to earlier cohorts, the 2012-2018 cohort had lower conditional risk of recurrence in postoperative year 1 and higher risk in postoperative year 2. Overall survival increased over time (median, 30.6, 33.6, and 48.7 mo, P < 0.005), driven by improved post-recurrence overall survival (median, 7.8, 12.5, and 12.6 mo; 3-year rate, 7%, 10%, and 20%; P < 0.005).
CONCLUSIONS: We observed changes in neoadjuvant therapy regimens over time and an associated shift in the conditional risk of recurrence from postoperative year 1 to postoperative year 2, although recurrence remained common. Overall survival and post-recurrence survival remarkably improved over time, reflecting improved multimodality regimens for recurrent disease.

DOI: https://doi.org/10.1097/SLA.0000000000006269
Front Immunol. 2024 ;15 1360629

High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment.

Hassan Sadozai, Animesh Acharjee, Hateem Z Kayani, Thomas Gruber, Reginald M Gorczynski, Bernard Burke.

  Introduction: Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression.Methods: We used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions.
Results: First, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (HypoxiaHI vs. HypoxiaLOW) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to HypoxiaLOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in HypoxiaHI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines.
Discussion: In summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs.

Keywords:  galectins; hypoxia; immune checkpoint; pancreatic ductal adenocarcinoma (PDAC); tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2024.1360629
Biol Imaging. 2024 ;4 e1

Three-dimensional topology-based analysis segments volumetric and spatiotemporal fluorescence microscopy.

Luca Panconi, Amy Tansell, Alexander J Collins, Maria Makarova, Dylan M Owen.

  Image analysis techniques provide objective and reproducible statistics for interpreting microscopy data. At higher dimensions, three-dimensional (3D) volumetric and spatiotemporal data highlight additional properties and behaviors beyond the static 2D focal plane. However, increased dimensionality carries increased complexity, and existing techniques for general segmentation of 3D data are either primitive, or highly specialized to specific biological structures. Borrowing from the principles of 2D topological data analysis (TDA), we formulate a 3D segmentation algorithm that implements persistent homology to identify variations in image intensity. From this, we derive two separate variants applicable to spatial and spatiotemporal data, respectively. We demonstrate that this analysis yields both sensitive and specific results on simulated data and can distinguish prominent biological structures in fluorescence microscopy images, regardless of their shape. Furthermore, we highlight the efficacy of temporal TDA in tracking cell lineage and the frequency of cell and organelle replication.

Keywords:  R; cell segmentation; cell tracking; fluorescence microscopy; topological data analysis

DOI:  https://doi.org/10.1017/S2633903X23000260
Aging (Albany NY). 2024 Mar 20. 16

CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.

Alcir L Dafre, Saadia Zahid, Jessica Jorge Probst, Antonio Currais, Jingting Yu, David Schubert, Pamela Maher.

  BACKGROUND: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice.METHODS: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism.
RESULTS: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121.
CONCLUSIONS: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.

Keywords:  diabetes; geroneuroprotection; ketogenic diet; metabolic disorders; obesity

DOI:  https://doi.org/10.18632/aging.205673
Autophagy. 2024 Mar 21.

The activation mechanism of Atg15, a vacuolar phospholipase required for the disintegration of organelle membranes.

Yasunori Watanabe, Kuninori Suzuki.

  The disintegration of cytoplasm-to-vacuole targeting (Cvt) bodies and autophagic bodies in vacuoles is essential to the Cvt pathway and macroautophagy in yeast. Atg15 is a vacuolar lipase required for the degradation of both Cvt and autophagic bodies. However, the molecular mechanism of their degradation by Atg15 remains poorly understood. In a recent study, we showed that recombinant Chaetomium thermophilum Atg15 (CtAtg15) possesses phospholipase activity, and that this activity is significantly elevated by proteolytic cleavage at a site away from the active center. The proteolytic cleavage of CtAtg15 causes a conformational change around the active center, resulting in the active open state. Interestingly, activated CtAtg15 can degrade not only Cvt and autophagic bodies but also organelle membranes. On the basis of these results, we propose an activation mechanism by which Atg15, as an "organellase," functions only in vacuoles.

Keywords:  Atg15; autophagic body; organelle membrane; phospholipase; vacuolar proteases; yeast

DOI:  https://doi.org/10.1080/15548627.2024.2333165
Elife. 2024 Mar 22. pii: RP92078. [Epub ahead of print]12

Caveolin-1 protects endothelial cells from extensive expansion of transcellular tunnel by stiffening the plasma membrane.

Camille Morel, Eline Lemerle, Feng-Ching Tsai, Thomas Obadia, Nishit Srivastava, Maud Marechal, Audrey Salles, Marvin Albert, Caroline Stefani, Yvonne Benito, François Vandenesch, Christophe Lamaze, Stéphane Vassilopoulos, Matthieu Piel, Patricia Bassereau, David Gonzalez-Rodriguez, Cecile Leduc, Emmanuel Lemichez.

  Large transcellular pores elicited by bacterial mono-ADP-ribosyltransferase (mART) exotoxins inhibiting the small RhoA GTPase compromise the endothelial barrier. Recent advances in biophysical modeling point toward membrane tension and bending rigidity as the minimal set of mechanical parameters determining the nucleation and maximal size of transendothelial cell macroaperture (TEM) tunnels induced by bacterial RhoA-targeting mART exotoxins. We report that cellular depletion of caveolin-1, the membrane-embedded building block of caveolae, and depletion of cavin-1, the master regulator of caveolae invaginations, increase the number of TEMs per cell. The enhanced occurrence of TEM nucleation events correlates with a reduction in cell height due to the increase in cell spreading and decrease in cell volume, which, together with the disruption of RhoA-driven F-actin meshwork, favor membrane apposition for TEM nucleation. Strikingly, caveolin-1 specifically controls the opening speed of TEMs, leading to their dramatic 5.4-fold larger widening. Consistent with the increase in TEM density and width in siCAV1 cells, we record a higher lethality in CAV1 KO mice subjected to a catalytically active mART exotoxin targeting RhoA during staphylococcal bloodstream infection. Combined theoretical modeling with independent biophysical measurements of plasma membrane bending rigidity points toward a specific contribution of caveolin-1 to membrane stiffening in addition to the role of cavin-1/caveolin-1-dependent caveolae in the control of membrane tension homeostasis.

Keywords:  bacterial toxin; caveolin-1; cell biology; human; mouse; physics of living systems; plasma membrane mechanics; transendothelial cell macroaperture

DOI:  https://doi.org/10.7554/eLife.92078
bioRxiv. 2024 Mar 07. pii: 2024.03.06.583589. [Epub ahead of print]

Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.

Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.

Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in the cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Nevertheless, the signaling consequences of primary mitochondrial malfunction and of primary lysosomal defects are not similar, despite in both cases there are impairments of mitochondria and of lysosomes. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects, to identify what are the global cellular consequences that are associated with malfunction of mitochondria or lysosomes. We used these data to determine what are the pathways that are affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. This pathway is transcriptionally up-regulated in cellular and mouse models of lysosomal defects and is transcriptionally down-regulated in cellular and mouse models of mitochondrial defects. We identified a role for post-transcriptional regulation of the transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, the retention of Ca 2+ in the lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo , using models of mitochondria-associated diseases in C. elegans , that normalization of lysosomal Ca 2+ levels results in partial rescue of the developmental arrest induced by the respiratory chain deficiency.

DOI: https://doi.org/10.1101/2024.03.06.583589
Nat Med. 2024 Mar;30(3): 850-862

Towards a general-purpose foundation model for computational pathology.

Richard J Chen, Tong Ding, Ming Y Lu, Drew F K Williamson, Guillaume Jaume, Andrew H Song, Bowen Chen, Andrew Zhang, Daniel Shao, Muhammad Shaban, Mane Williams, Lukas Oldenburg, Luca L Weishaupt, Judy J Wang, Anurag Vaidya, Long Phi Le, Georg Gerber, Sharifa Sahai, Walt Williams, Faisal Mahmood.

Quantitative evaluation of tissue images is crucial for computational pathology (CPath) tasks, requiring the objective characterization of histopathological entities from whole-slide images (WSIs). The high resolution of WSIs and the variability of morphological features present significant challenges, complicating the large-scale annotation of data for high-performance applications. To address this challenge, current efforts have proposed the use of pretrained image encoders through transfer learning from natural image datasets or self-supervised learning on publicly available histopathology datasets, but have not been extensively developed and evaluated across diverse tissue types at scale. We introduce UNI, a general-purpose self-supervised model for pathology, pretrained using more than 100 million images from over 100,000 diagnostic H&E-stained WSIs (>77 TB of data) across 20 major tissue types. The model was evaluated on 34 representative CPath tasks of varying diagnostic difficulty. In addition to outperforming previous state-of-the-art models, we demonstrate new modeling capabilities in CPath such as resolution-agnostic tissue classification, slide classification using few-shot class prototypes, and disease subtyping generalization in classifying up to 108 cancer types in the OncoTree classification system. UNI advances unsupervised representation learning at scale in CPath in terms of both pretraining data and downstream evaluation, enabling data-efficient artificial intelligence models that can generalize and transfer to a wide range of diagnostically challenging tasks and clinical workflows in anatomic pathology.

DOI: https://doi.org/10.1038/s41591-024-02857-3
Endocr Rev. 2024 Mar 19. pii: bnae010. [Epub ahead of print]

Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction.

Masayoshi Suda, Karl H Paul, Utkarsh Tripathi, Tohru Minamino, Tamara Tchkonia, James L Kirkland.

  Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type II diabetes mellitus (T2DM). Drugs that selectively induce senescent cell removal, "senolytics", and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, "senomorphics", appear to delay the onset or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. Over thirty clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.

Keywords:  SASP; cellular senescence; diabetes; endocrine diseases; osteoporosis; senolytics; senomorphics

DOI:  https://doi.org/10.1210/endrev/bnae010
Nutrition. 2024 Feb 18. pii: S0899-9007(24)00049-2. [Epub ahead of print]122 112399

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.

Kai-Lun Zhang, Ming-Ming Zhou, Kun-Hua Wang, Min Weng, Fu-Xiang Zhou, Jiu-Wei Cui, Wei Li, Hu Ma, Zeng-Qing Guo, Su-Yi Li, Jun-Qiang Chen, Xiang-Hua Wu, Qing-Chuan Zhao, Ji-Peng Li, Hong-Xia Xu, Han-Ping Shi, Chun-Hua Song.

  OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia.METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality.
RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969).
CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

Keywords:  Cancer cachexia; Handgrip strength; Malnutrition; Neutrophil-to-lymphocyte ratio; Prognostic

DOI:  https://doi.org/10.1016/j.nut.2024.112399
Cancer Imaging. 2024 Mar 20. 24(1): 38

Dual-energy computed tomography in a multiparametric regression model for diagnosing lymph node metastases in pancreatic ductal adenocarcinoma.

Sheng Li, Dongping Jiang, Linling Jiang, Shumei Yan, Lizhi Liu, Guangying Ruan, Xuhui Zhou, Shuiqing Zhuo.

  OBJECTIVE: To investigate the diagnostic value of dual-energy computed tomography (DECT) quantitative parameters in the identification of regional lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC).METHODS: This retrospective diagnostic study assessed 145 patients with pathologically confirmed pancreatic ductal adenocarcinoma from August 2016-October 2020. Quantitative parameters for targeted lymph nodes were measured using DECT, and all parameters were compared between benign and metastatic lymph nodes to determine their diagnostic value. A logistic regression model was constructed; the receiver operator characteristics curve was plotted; the area under the curve (AUC) was calculated to evaluate the diagnostic efficacy of each energy DECT parameter; and the DeLong test was used to compare AUC differences. Model evaluation was used for correlation analysis of each DECT parameter.
RESULTS: Statistical differences in benign and metastatic lymph nodes were found for several parameters. Venous phase iodine density had the highest diagnostic efficacy as a single parameter, with AUC 0.949 [95% confidence interval (CI):0.915-0.972, threshold: 3.95], sensitivity 79.80%, specificity 96.00%, and accuracy 87.44%. Regression models with multiple parameters had the highest diagnostic efficacy, with AUC 0.992 (95% CI: 0.967-0.999), sensitivity 95.96%, specificity 96%, and accuracy 94.97%, which was higher than that for a single DECT parameter, and the difference was statistically significant.
CONCLUSION: Among all DECT parameters for regional lymph node metastasis in PDAC, venous phase iodine density has the highest diagnostic efficacy as a single parameter, which is convenient for use in clinical settings, whereas a multiparametric regression model has higher diagnostic value compared with the single-parameter model.

Keywords:  Computed tomography; Dual-energy; Iodine density; Lymph node metastases; Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1186/s40644-024-00687-7
EMBO J. 2024 Mar 15.

MemPrep, a new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress.

John Reinhard, Leonhard Starke, Christian Klose, Per Haberkant, Henrik Hammarén, Frank Stein, Ofir Klein, Charlotte Berhorst, Heike Stumpf, James P Sáenz, Jochen Hub, Maya Schuldiner, Robert Ernst.

  Biological membranes have a stunning ability to adapt their composition in response to physiological stress and metabolic challenges. Little is known how such perturbations affect individual organelles in eukaryotic cells. Pioneering work has provided insights into the subcellular distribution of lipids in the yeast Saccharomyces cerevisiae, but the composition of the endoplasmic reticulum (ER) membrane, which also crucially regulates lipid metabolism and the unfolded protein response, remains insufficiently characterized. Here, we describe a method for purifying organelle membranes from yeast, MemPrep. We demonstrate the purity of our ER membrane preparations by proteomics, and document the general utility of MemPrep by isolating vacuolar membranes. Quantitative lipidomics establishes the lipid composition of the ER and the vacuolar membrane. Our findings provide a baseline for studying membrane protein biogenesis and have important implications for understanding the role of lipids in regulating the unfolded protein response (UPR). The combined preparative and analytical MemPrep approach uncovers dynamic remodeling of ER membranes in stressed cells and establishes distinct molecular fingerprints of lipid bilayer stress.

Keywords:  ER Stress; Lipid Bilayer Stress; MemPrep; Organelle Lipidomics; UPR

DOI:  https://doi.org/10.1038/s44318-024-00063-y
Physiology (Bethesda). 2024 Mar 19.

Cell membrane tension gradients, membrane flows and cellular processes.

Qi Yan, Carolina Gomis Perez, Erdem Karatekin.

  Cell membrane tension affects and is affected by many fundamental cellular processes, yet it is poorly understood. Recent experiments show that membrane tension can propagate at vastly different speeds in different cell types, reflecting physiological adaptations. Here we briefly review the current knowledge about membrane tension gradients, membrane flows, and their physiological context.

Keywords:  cell membrane dynamics; cell membrane flow; cell membrane tension; cell membrane-cytoskeleton interactions

DOI:  https://doi.org/10.1152/physiol.00007.2024
Cell Rep Med. 2024 Mar 19. pii: S2666-3791(24)00117-4. [Epub ahead of print]5(3): 101471

Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse.

Mengnuo Chen, Sara Mainardi, Cor Lieftink, Arno Velds, Iris de Rink, Chen Yang, Hendrik J Kuiken, Ben Morris, Finn Edwards, Fleur Jochems, Olaf van Tellingen, Manon Boeije, Natalie Proost, Robin A Jansen, Shifan Qin, Haojie Jin, J C Koen van der Mijn, Arnout Schepers, Subramanian Venkatesan, Wenxin Qin, Roderick L Beijersbergen, Liqin Wang, René Bernards.

Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within a tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the tumor following drug withdrawal. Using a cancer cell line with an engineered suicide switch to kill proliferating cells, we perform both genetic screens and compound screens to identify the inhibition of bromodomain and extraterminal domain (BET) proteins as a selective vulnerability of DTPs. BET inhibitors are especially detrimental to DTPs that have reentered the cell cycle (DTEPs) in a broad spectrum of cancer types. Mechanistically, BET inhibition induces lethal levels of ROS through the suppression of redox-regulating genes highly expressed in DTPs, including GPX2, ALDH3A1, and MGST1. In vivo BET inhibitor treatment delays tumor relapse in both melanoma and lung cancer. Our study suggests that combining standard of care therapy with BET inhibitors to eliminate residual persister cells is a promising therapeutic strategy.

DOI: https://doi.org/10.1016/j.xcrm.2024.101471
Commun Biol. 2024 Mar 20. 7(1): 346

Common mouse models of chronic kidney disease are not associated with cachexia.

Benjamin Lair, Marlène Lac, Lucas Frassin, Manon Brunet, Marie Buléon, Guylène Feuillet, Claire Maslo, Marie Marquès, Laurent Monbrun, Virginie Bourlier, Emilie Montastier, Nathalie Viguerie, Geneviève Tavernier, Claire Laurens, Cedric Moro.

The 5/6 nephrectomy and adenine-induced nephropathy mouse models have been extensively used to study Chronic Kidney Disease (CKD)-related cachexia. One common caveat of these CKD models is the cross-sectional nature of comparisons made versus controls. We here performed a comprehensive longitudinal assessment of body composition and energy metabolism in both models. The most striking finding is that weight loss is largely driven by reduced food intake which promotes rapid loss of lean and fat mass. However, in both models, mice catch up weight and lean mass a few days after the surgery or when they are switched back to standard chow diet. Muscle force and mass are fully recovered and no sign of cachexia is observed. Our data demonstrate that the time-course of kidney failure and weight loss are unrelated in these common CKD models. These data highlight the need to reconsider the relative contribution of direct and indirect mechanisms to muscle wasting observed in CKD.

DOI: https://doi.org/10.1038/s42003-024-06021-y
bioRxiv. 2024 Mar 05. pii: 2024.03.01.583001. [Epub ahead of print]

A Panoramic View of Cell Population Dynamics in Mammalian Aging.

Zehao Zhang, Chloe Schaefer, Weirong Jiang, Ziyu Lu, Jasper Lee, Andras Sziraki, Abdulraouf Abdulraouf, Brittney Wick, Maximilian Haeussler, Zhuoyan Li, Gesmira Molla, Rahul Satija, Wei Zhou, Junyue Cao.

To elucidate the aging-associated cellular population dynamics throughout the body, here we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes. This comprehensive dataset allowed us to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Our panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Moreover, we investigated aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte-dependent. The breadth and depth of our 'cell-omics' methodology not only enhance our comprehension of cellular aging but also lay the groundwork for exploring the complex regulatory networks among varied cell types in the context of aging and aging-associated diseases.One Sentence Summary: PanSci, a single-cell transcriptome atlas of over 20 million cells throughout the mouse lifespan, unveils the temporal architecture of aging-associated cellular population dynamics, organ-specific immune cell shifts, and the lymphocyte's role in organismal aging.

DOI: https://doi.org/10.1101/2024.03.01.583001
Sci Rep. 2024 03 19. 14(1): 6582

Role of the fatty pancreatic infiltration in pancreatic oncogenesis.

Sonia Frendi, Chloé Martineau, Hélène Cazier, Rémy Nicolle, Anaïs Chassac, Miguel Albuquerque, Jérôme Raffenne, Julie Le Faouder, Valérie Paradis, Jérôme Cros, Anne Couvelard, Vinciane Rebours.

  Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.

Keywords:  Intra-lobular and extra-lobular fatty pancreatic infiltration; Lipidomic MALDI-TOF imaging mass spectrometry; Obesity; Pancreatic oncogenesis; Pancreatic precancerous lesions

DOI:  https://doi.org/10.1038/s41598-024-57294-6
ACS Chem Biol. 2024 Mar 20.

Lipid-Restricted Culture Media Reveal Unexpected Cancer Cell Sensitivities.

Ralston B Goldfarb, Matthew J Atala Pleshinger, David F Yan, Drew J Adams.

Cancer cell culture models frequently rely on fetal bovine serum as a source of protein and lipid factors that support cell survival and proliferation; however, serum-containing media imperfectly mimic the in vivo cancer environment. Recent studies suggest that typical serum-containing cell culture conditions can mask cancer dependencies, for example, on cholesterol biosynthesis enzymes, that exist in vivo and emerge when cells are cultured in media that provide more realistic levels of lipids. Here, we describe a high-throughput screen that identified fenretinide and ivermectin as small molecules whose cytotoxicity is greatly enhanced in lipid-restricted media formulations. The mechanism of action studies indicates that ivermectin-induced cell death involves oxidative stress, while fenretinide likely targets delta 4-desaturase, sphingolipid 1, a lipid desaturase necessary for ceramide synthesis, to induce cell death. Notably, both fenretinide and ivermectin have previously demonstrated in vivo anticancer efficacy despite their low cytotoxicity under typical cell culture conditions. These studies suggest ceramide synthesis as a targetable vulnerability of cancer cells cultured under lipid-restricted conditions and reveal a general screening strategy for identifying additional cancer dependencies masked by the superabundance of medium lipids.

DOI: https://doi.org/10.1021/acschembio.3c00699
Cold Spring Harb Perspect Med. 2024 Mar 19. pii: a041378. [Epub ahead of print]

Addressing Biological Questions with Preclinical Cancer Imaging.

Chris B Damoci, Joseph R Merrill, Yanping Sun, Scott K Lyons, Kenneth P Olive.

The broad application of noninvasive imaging has transformed preclinical cancer research, providing a powerful means to measure dynamic processes in living animals. While imaging technologies are routinely used to monitor tumor growth in model systems, their greatest potential lies in their ability to answer fundamental biological questions. Here we present the broad range of potential imaging applications according to the needs of a cancer biologist with a focus on some of the common biological processes that can be used to visualize and measure. Topics include imaging metastasis; biophysical properties such as perfusion, diffusion, oxygenation, and stiffness; imaging the immune system and tumor microenvironment; and imaging tumor metabolism. We also discuss the general ability of each approach and the level of training needed to both acquire and analyze images. The overall goal is to provide a practical guide for cancer biologists interested in answering biological questions with preclinical imaging technologies.

DOI: https://doi.org/10.1101/cshperspect.a041378