bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒10‒23
38 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
  2. Principles and functions of metabolic compartmentalization.
  3. The role of lipids in cancer progression and metastasis.
  4. Neoplastic cell enrichment of tumor tissues using coring and laser microdissection for proteomic and genomic analyses of pancreatic ductal adenocarcinoma.
  5. Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia.
  6. Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.
  7. The limits of molecular signatures for pancreatic ductal adenocarcinoma subtyping.
  8. Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody.
  9. HIRA loss transforms FH-deficient cells.
  10. MTCH2 is a mitochondrial outer membrane protein insertase.
  11. Deciphering the roadmap of in vivo reprogramming toward pluripotency.
  12. Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise.
  13. Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
  14. Culture media composition influences patient-derived organoids ability to predict therapeutic response in gastrointestinal cancers.
  15. Membrane curvature as a signal to ensure robustness of diverse cellular processes.
  16. UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting.
  17. Deregulated transcription factors in cancer cell metabolisms and reprogramming.
  18. Fusobacterium nucleatum induces proliferation and migration in pancreatic cancer cells through host autocrine and paracrine signaling.
  19. The distinguishing electrical properties of cancer cells.
  20. Development of new tools to study membrane-anchored mammalian Atg8 proteins.
  21. Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.
  22. The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics.
  23. Lipids reroute mitochondria.
  24. A BDNF-TrkB autocrine loop enhances senescent cell viability.
  25. NBR1: The archetypal selective autophagy receptor.
  26. Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors.
  27. Fibroblast activation protein-based theranostics in pancreatic cancer.
  28. Caveolae couple mechanical stress to integrin recycling and activation.
  29. TSC22D4 interacts with Akt1 to regulate glucose metabolism.
  30. Body Mass Index Trajectories Across the Adult Life Course and Pancreatic Cancer Risk.
  31. Reimagining Cancer: Moving from the Cellular to the Tissue Level.
  32. Meeting report - Cell size and growth: from single cells to the tree of life.
  33. Primary tumor-derived systemic nANGPTL4 inhibits metastasis.
  34. Understanding emerging bioactive metabolites with putative roles in cancer biology.
  35. Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools.
  36. The global research and emerging trends in autophagy of pancreatic cancer: A bibliometric and visualized study.
  37. Lysosomal positioning regulates Rab10 phosphorylation at LRRK2+ lysosomes.
  38. Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.
  1. Nat Commun. 2022 Oct 20. 13(1): 6239
    Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
    Zhongchi Li, Vivien Low, Valbona Luga, Janet Sun, Ethan Earlie, Bobak Parang, Kripa Shobana Ganesh, Sungyun Cho, Jennifer Endress, Tanya Schild, Mengying Hu, David Lyden, Wenbing Jin, Chunjun Guo, Noah Dephoure, Lewis C Cantley, Ashley M Laughney, John Blenis.
      The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
    DOI:  https://doi.org/10.1038/s41467-022-33862-0
  2. Nat Metab. 2022 Oct;4(10): 1232-1244
    Principles and functions of metabolic compartmentalization.
    Liron Bar-Peled, Nora Kory.
      Metabolism has historically been studied at the levels of whole cells, whole tissues and whole organisms. As a result, our understanding of how compartmentalization-the spatial and temporal separation of pathways and components-shapes organismal metabolism remains limited. At its essence, metabolic compartmentalization fulfils three important functions or 'pillars': establishing unique chemical environments, providing protection from reactive metabolites and enabling the regulation of metabolic pathways. However, how these pillars are established, regulated and maintained at both the cellular and systemic levels remains unclear. Here we discuss how the three pillars are established, maintained and regulated within the cell and discuss the consequences of dysregulation of metabolic compartmentalization in human disease. Organelles are increasingly emerging as 'command-and-control centres' and the increased understanding of metabolic compartmentalization is revealing new aspects of metabolic homeostasis, with this knowledge being translated into therapies for the treatment of cancer and certain neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s42255-022-00645-2
  3. Cell Metab. 2022 Oct 14. pii: S1550-4131(22)00447-8. [Epub ahead of print]
    The role of lipids in cancer progression and metastasis.
    Miguel Martin-Perez, Uxue Urdiroz-Urricelqui, Claudia Bigas, Salvador Aznar Benitah.
      Lipids have essential biological functions in the body (e.g., providing energy storage, acting as a signaling molecule, and being a structural component of membranes); however, an excess of lipids can promote tumorigenesis, colonization, and metastatic capacity of tumor cells. To metastasize, a tumor cell goes through different stages that require lipid-related metabolic and structural adaptations. These adaptations include altering the lipid membrane composition for invading other niches and overcoming cell death mechanisms and promoting lipid catabolism and anabolism for energy and oxidative stress protective purposes. Cancer cells also harness lipid metabolism to modulate the activity of stromal and immune cells to their advantage and to resist therapy and promote relapse. All this is especially worrying given the high fat intake in Western diets. Thus, metabolic interventions aiming to reduce lipid availability to cancer cells or to exacerbate their metabolic vulnerabilities provide promising therapeutic opportunities to prevent cancer progression and treat metastasis.
    Keywords:  lipid metabolism; metastasis; metastatic-initiating cells; tumor storm
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.023
  4. Clin Proteomics. 2022 Oct 20. 19(1): 36
    Neoplastic cell enrichment of tumor tissues using coring and laser microdissection for proteomic and genomic analyses of pancreatic ductal adenocarcinoma.
    Qing Kay Li, Yingwei Hu, Lijun Chen, Michael Schnaubelt, Daniel Cui Zhou, Yize Li, Rita Jui-Hsien Lu, Mathangi Thiagarajan, Galen Hostetter, Chelsea J Newton, Scott D Jewell, Gil Omenn, Ana I Robles, Mehdi Mesri, Oliver F Bathe, Bing Zhang, Li Ding, Ralph H Hruban, Daniel W Chan, Hui Zhang.
      BACKGROUND: The identification of differentially expressed tumor-associated proteins and genomic alterations driving neoplasia is critical in the development of clinical assays to detect cancers and forms the foundation for understanding cancer biology. One of the challenges in the analysis of pancreatic ductal adenocarcinoma (PDAC) is the low neoplastic cellularity and heterogeneous composition of bulk tumors. To enrich neoplastic cells from bulk tumor tissue, coring, and laser microdissection (LMD) sampling techniques have been employed. In this study, we assessed the protein and KRAS mutation changes associated with samples obtained by these enrichment techniques and evaluated the fraction of neoplastic cells in PDAC for proteomic and genomic analyses.METHODS: Three fresh frozen PDAC tumors and their tumor-matched normal adjacent tissues (NATs) were obtained from three sampling techniques using bulk, coring, and LMD; and analyzed by TMT-based quantitative proteomics. The protein profiles and characterizations of differentially expressed proteins in three sampling groups were determined. These three PDACs and samples of five additional PDACs obtained by the same three sampling techniques were also subjected to genomic analysis to characterize KRAS mutations.
    RESULTS: The neoplastic cellularity of eight PDACs ranged from less than 10% to over 80% based on morphological review. Distinctive proteomic patterns and abundances of certain tumor-associated proteins were revealed when comparing the tumors and NATs by different sampling techniques. Coring and bulk tissues had comparable proteome profiles, while LMD samples had the most distinct proteome composition compared to bulk tissues. Further genomic analysis of bulk, cored, or LMD samples demonstrated that KRAS mutations were significantly enriched in LMD samples while coring was less effective in enriching for KRAS mutations when bulk tissues contained a relatively low neoplastic cellularity.
    CONCLUSIONS: In addition to bulk tissues, samples from LMD and coring techniques can be used for proteogenomic studies. The greatest enrichment of neoplastic cellularity is obtained with the LMD technique.
    Keywords:  Bulk tissue; Clinical Proteomic Tumor Analysis Consortium (CPTAC); Laser microdissection (LMD); Liquid chromatography–mass spectrometry; TMT-labeling; Tissue coring; Tissue sampling techniques
    DOI:  https://doi.org/10.1186/s12014-022-09373-x
  5. Mol Metab. 2022 Oct 13. pii: S2212-8778(22)00181-8. [Epub ahead of print] 101612
    Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia.
    Mengistu Lemecha, Jaya Chalise, Yuki Takamuku, Guoxiang Zhang, Takahiro Yamakawa, Garrett Larson, Keiichi Itakura.
      OBJECTIVE: Adipose tissue is the largest endocrine organ. When activated by cancer cells, adipocytes secrete adipocytokines and release fatty acids, which are then transferred to cancer cells and used for structural and biochemical support. How this metabolic symbiosis between cancer cells and adipocytes affects skeletal muscle and thermogenesis during cancer cachexia is unknown. Cancer cachexia is a multiorgan syndrome and how the communication between tissues is established has yet to be determined. We investigated adipose tissue secretory factors and explored their role in crosstalk of adipocytes, muscle, and tumor during pancreatic cancer cachexia.METHODS: We used a pancreatic cancer cachexia mouse model generated by syngenic implantation of pancreatic ductal adenocarcinoma (PDAC) cells (KPC) intraperitoneally into C57BL/6 mice and Lcn2-knockout mice. For in vitro studies, adipocytes (3T3-L1 and primary adipocytes), cachectic cancer cells (Panc0203), non-cachectic cancer cells (Du145 cells), and skeletal muscle cells (C2C12 myoblasts) were used.
    RESULTS: To identify molecules involved in the crosstalk of adipose tissue with muscle and tumors, we treated 3T3-L1 adipocytes with conditioned medium (CM) from cancer cells. Upon screening the secretomes from PDAC-induced adipocytes, several adipocytokines were identified, including lipocalin 2 (Lcn2). We investigated Lcn2 as a potential mediator of cachexia induced by adipocytes in response to PDAC. During tumor progression, mice exhibited a decline in body weight gain, which was accompanied by loss of adipose and muscle tissues. Tumor-harboring mice developed drastic hypothermia because of a dramatic loss of fat in brown adipose tissue (BAT) and suppression of the thermogenesis pathway. We inhibited Lcn2 with an anti-Lcn2 antibody neutralization or genomic ablation in mice. Lcn2 deficiency significantly improved body temperature in tumor-bearing mice, which was supported by the increased expression of Ucp1 and β3-adrenergic receptor in BAT. In addition, Lcn2 inhibition abrogated the loss of fat and muscle in tumor-bearing mice. In contrast to tumor-bearing WT mice, the corresponding Lcn2-knockout mice showed reduced ATGL expression in iWAT and decreased the expression of muscle atrophy molecular markers MuRF-1 and Fbx32.
    CONCLUSIONS: This study showed that Lcn2 is causally involved in the dysregulation of adipose tissue-muscle-tumor crosstalk during pancreatic cancer cachexia. Therapeutic targets that suppress Lcn2 may minimize the progression of cachexia.
    Keywords:  BAT; Cachexia; Hypothermia; Lcn2; PDAC; Thermogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2022.101612
  6. Oncogene. 2022 Oct 21.
    Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma.
    Imayavaramban Lakshmanan, Saravanakumar Marimuthu, Sanjib Chaudhary, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Sakthivel Muniyan, Ramakanth Chirravuri-Venkata, Pranita Atri, Sanchita Rauth, Rama Krishna Nimmakayala, Jawed Akhtar Siddiqui, Shailendra K Gautam, Ashu Shah, Gopalakrishnan Natarajan, Seema Parte, Namita Bhyravbhatla, Kavita Mallya, Dhanya Haridas, Geoffrey A Talmon, Lynette M Smith, Sushil Kumar, Apar Kishor Ganti, Maneesh Jain, Moorthy P Ponnusamy, Surinder K Batra.
      MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with KrasG12D and Trp53R172H mutations remains unknown. Deletion of Muc16 with activating mutations KrasG12D/+ and Trp53R172H/+ in mice significantly decreased progression and prolonged overall survival in KrasG12D/+; Trp53R172H/+; Pdx-1-Cre; Muc16-/- (KPCM) and KrasG12D/+; Pdx-1-Cre; Muc16-/- (KCM), as compared to KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) and KrasG12D/+; Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis-associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate compared to KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.
    DOI:  https://doi.org/10.1038/s41388-022-02493-6
  7. NAR Cancer. 2022 Dec;4(4): zcac030
    The limits of molecular signatures for pancreatic ductal adenocarcinoma subtyping.
    Manuela Lautizi, Jan Baumbach, Wilko Weichert, Katja Steiger, Markus List, Nicole Pfarr, Tim Kacprowski.
      Molecular signatures have been suggested as biomarkers to classify pancreatic ductal adenocarcinoma (PDAC) into two, three, four or five subtypes. Since the robustness of existing signatures is controversial, we performed a systematic evaluation of four established signatures for PDAC stratification across nine publicly available datasets. Clustering revealed inconsistency of subtypes across independent datasets and in some cases a different number of PDAC subgroups than in the original study, casting doubt on the actual number of existing subtypes. Next, we built sixteen classification models to investigate the ability of the signatures for tumor subtype prediction. The overall classification performance ranged from ∼35% to ∼90% accuracy, suggesting instability of the signatures. Notably, permuted subtypes and random gene sets achieved very similar performance. Cellular decomposition and functional pathway enrichment analysis revealed strong tissue-specificity of the predicted classes. Our study highlights severe limitations and inconsistencies that can be attributed to technical biases in sample preparation and tumor purity, suggesting that PDAC molecular signatures do not generalize across datasets. How stromal heterogeneity and immune compartment interplay in the diverging development of PDAC is still unclear. Therefore, a more mechanistic or a cross-platform multi-omic approach seems necessary to extract more robust and clinically exploitable insights.
    DOI:  https://doi.org/10.1093/narcan/zcac030
  8. Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2209563119
    Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody.
    Douglas S Micalizzi, Dante Che, Benjamin T Nicholson, Jon F Edd, Niyati Desai, Evan R Lang, Mehmet Toner, Shyamala Maheswaran, David T Ting, Daniel A Haber.
      The successful application of antibody-based therapeutics in either primary or metastatic cancer depends upon the selection of rare cell surface epitopes that distinguish cancer cells from surrounding normal epithelial cells. By contrast, as circulating tumor cells (CTCs) transit through the bloodstream, they are surrounded by hematopoietic cells with dramatically distinct cell surface proteins, greatly expanding the number of targetable epitopes. Here, we show that an antibody (23C6) against cadherin proteins effectively suppresses blood-borne metastasis in mouse isogenic and xenograft models of triple negative breast and pancreatic cancers. The 23C6 antibody is remarkable in that it recognizes both the epithelial E-cadherin (CDH1) and mesenchymal OB-cadherin (CDH11), thus overcoming considerable heterogeneity across tumor cells. Despite its efficacy against single cells in circulation, the antibody does not suppress primary tumor formation, nor does it elicit detectable toxicity in normal epithelial organs, where cadherins may be engaged within intercellular junctions and hence inaccessible for antibody binding. Antibody-mediated suppression of metastasis is comparable in matched immunocompetent and immunodeficient mouse models. Together, these studies raise the possibility of antibody targeting CTCs within the vasculature, thereby suppressing blood-borne metastasis.
    Keywords:  antibody therapeutics; breast cancer; cadherins; cancer metastasis; circulating tumor cells
    DOI:  https://doi.org/10.1073/pnas.2209563119
  9. Sci Adv. 2022 Oct 21. 8(42): eabq8297
    HIRA loss transforms FH-deficient cells.
    Lorea Valcarcel-Jimenez, Connor Rogerson, Cissy Yong, Christina Schmidt, Ming Yang, Monica Cremades-Rodelgo, Victoria Harle, Victoria Offord, Kim Wong, Ariane Mora, Alyson Speed, Veronica Caraffini, Maxine Gia Binh Tran, Eamonn R Maher, Grant D Stewart, Sakari Vanharanta, David J Adams, Christian Frezza.
      Fumarate hydratase (FH) is a mitochondrial enzyme that catalyzes the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. Germline mutations of FH lead to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a cancer syndrome characterized by a highly aggressive form of renal cancer. Although HLRCC tumors metastasize rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas. How Fh1-deficient cells overcome these tumor-suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR-Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.
    DOI:  https://doi.org/10.1126/sciadv.abq8297
  10. Science. 2022 Oct 21. 378(6617): 317-322
    MTCH2 is a mitochondrial outer membrane protein insertase.
    Alina Guna, Taylor A Stevens, Alison J Inglis, Joseph M Replogle, Theodore K Esantsi, Gayathri Muthukumar, Kelly C L Shaffer, Maxine L Wang, Angela N Pogson, Jeff J Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S Weissman, Rebecca M Voorhees.
      In the mitochondrial outer membrane, α-helical transmembrane proteins play critical roles in cytoplasmic-mitochondrial communication. Using genome-wide CRISPR screens, we identified mitochondrial carrier homolog 2 (MTCH2), and its paralog MTCH1, and showed that it is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane β-barrel proteins. Purified MTCH2 was sufficient to mediate insertion into reconstituted proteoliposomes. Functional and mutational studies suggested that MTCH2 has evolved from a solute carrier transporter. MTCH2 uses membrane-embedded hydrophilic residues to function as a gatekeeper for the outer membrane, controlling mislocalization of TAs into the endoplasmic reticulum and modulating the sensitivity of leukemia cells to apoptosis. Our identification of MTCH2 as an insertase provides a mechanistic explanation for the diverse phenotypes and disease states associated with MTCH2 dysfunction.
    DOI:  https://doi.org/10.1126/science.add1856
  11. Stem Cell Reports. 2022 Oct 07. pii: S2213-6711(22)00458-1. [Epub ahead of print]
    Deciphering the roadmap of in vivo reprogramming toward pluripotency.
    Dafni Chondronasiou, Jaime Martínez de Villarreal, Elena Melendez, Cian J Lynch, Natalia Del Pozo, Marta Kovatcheva, Mònica Aguilera, Neus Prats, Francisco X Real, Manuel Serrano.
      Differentiated cells can be converted into pluripotent stem cells by expressing the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM) in a process known as reprogramming. Here, using single-cell RNA sequencing of pancreas undergoing reprogramming, we identify markers along the trajectory from acinar cell identity to pluripotency. These markers allow direct in situ visualization of cells undergoing dedifferentiation and acquiring features of early and advanced intermediate reprogramming. We also find that a fraction of cells do not dedifferentiate upon OSKM expression and are characterized by stress markers of the REG3 and AP-1 families. Importantly, most markers of intermediate reprogramming in the pancreas are also observed in stomach, colon, and cultured fibroblasts expressing OSKM. Among them is LY6A, a protein characteristic of progenitor cells and generally upregulated during tissue repair. Our roadmap defines intermediate reprogramming states that could be functionally relevant for tissue regeneration and rejuvenation.
    Keywords:  KRT14; LY6A; OSKM; dedifferentiation; pancreas; pancreatic intraepithelial neoplasia; pancreatitis; pluripotency; reprogramming; single cell sequencing
    DOI:  https://doi.org/10.1016/j.stemcr.2022.09.009
  12. J Physiol. 2022 Oct 17.
    Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise.
    Ben T Murphy, John J Mackrill, Ken D O'Halloran.
      Cancer cachexia is defined as a multi-factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50-80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focussing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition, and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia, and subsequently explores the available respiratory- and exercise-focussed literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise-induced support of muscle via antioxidant and anti-inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function, and muscle glucose uptake provide avenues for interventional studies. Currently available pre-clinical mouse models including novel transgenic animals provide a platform for the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer. Abstract figure legend Cancer cachexia is characterised by profound loss of skeletal muscle mass. Exercise has the potential to counteract several factors that contribute to muscle wasting. Atrophy and dysfunction of the ventilatory muscles can result in respiratory compromise and ultimately failure. There is a scarcity of research investigating structure and function of the respiratory musculature in cancer. Pre-clinical and clinical studies focussed on mechanisms of exercise-induced support of muscle are required to drive the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer. This article is protected by copyright. All rights reserved.
    Keywords:  cachexia; cancer; exercise; respiratory system
    DOI:  https://doi.org/10.1113/JP283569
  13. EMBO Rep. 2022 Oct 18. e55191
    Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.
    Chao-Chieh Lin, Jin Yan, Meghan D Kapur, Kristi L Norris, Cheng-Wei Hsieh, De Huang, Nicolas Vitale, Kah-Leong Lim, Ziqiang Guan, Xiao-Fan Wang, Jen-Tsan Chi, Wei-Yuan Yang, Tso-Pang Yao.
      Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin-1. The production of DAG requires mitochondrial ubiquitination and ubiquitin-binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi-derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin-1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell-permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria.
    Keywords:  Lipin-1; PLD2; Parkin; diacylglycerol; mitophagy
    DOI:  https://doi.org/10.15252/embr.202255191
  14. JCI Insight. 2022 Oct 18. pii: e158060. [Epub ahead of print]
    Culture media composition influences patient-derived organoids ability to predict therapeutic response in gastrointestinal cancers.
    Tara L Hogenson, Hao Xie, William J Phillips, Merih D Toruner, Jenny J Li, Isaac P Horn, Devin J Kennedy, Luciana L Almada, David L Marks, Ryan M Carr, Murat Toruner, Ashley N Sigafoos, Amanda N Koenig-Kappes, Rachel Lo Olson, Ezequiel J Tolosa, Cheng Zhang, Hu Li, Jason D Doles, Jonathan Bleeker, Michael T Barrett, James H Boyum, Benjamin R Kipp, Amit Mahipal, Joleen M Hubbard, Temperance J Scheffler Hanson, Gloria M Petersen, Surendra Dasari, Ann L Oberg, Mark J Truty, Rondell P Graham, Michael J Levy, Mojun Zhu, Daniel D Billadeau, Alex A Adjei, Nelson Dusetti, Juan L Iovanna, Tanios S Bekaii-Saab, Wen Wee Ma, Martin E Fernandez-Zapico.
      BACKGROUND: A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response to gastrointestinal (GI) cancers.METHODS: We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments.
    RESULTS: We reported an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed significant difference in response to standard of care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDOs cultures.
    CONCLUSION: While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.
    TRIAL REGISTRATION: Not applicable.
    FUNDING: This work was supported by the Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, CA265050, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, a University of Minnesota-Mayo Clinic Partnership grant, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).
    Keywords:  Colorectal cancer; Drug therapy; Liver cancer; Oncology; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.158060
  15. Trends Cell Biol. 2022 Oct 13. pii: S0962-8924(22)00214-8. [Epub ahead of print]
    Membrane curvature as a signal to ensure robustness of diverse cellular processes.
    Robert C Cail, David G Drubin.
      An increasing corpus of research has demonstrated that membrane shape, generated either by the external environment of the cell or by intrinsic mechanisms such as cytokinesis and vesicle or organelle formation, is an important parameter in the control of diverse cellular processes. In this review we discuss recent findings that demonstrate how membrane curvature (from nanometer to micron length-scales) alters protein function. We describe an expanding toolkit for experimentally modulating membrane curvature to reveal effects on protein function, and discuss how membrane curvature - far from being a passive consequence of the physical environment and the internal protein activity of a cell - is an important signal that controls protein affinity and enzymatic activity to ensure robust forward progression of key processes within the cell.
    Keywords:  cell–substrate interactions; membrane dynamics; peripheral membrane proteins; protein scaffolds
    DOI:  https://doi.org/10.1016/j.tcb.2022.09.004
  16. Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2200215119
    UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting.
    Song Gao, Guohua Zhang, Zicheng Zhang, James Z Zhu, Li Li, Yong Zhou, George G Rodney, Reem S Abo-Zahrah, Lindsey Anderson, Jose M Garcia, Yong Tae Kwon, Yi-Ping Li.
      Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.
    Keywords:  MHC-IIb; MHC-IIx; UBR2; cancer cachexia; ubiquitylation
    DOI:  https://doi.org/10.1073/pnas.2200215119
  17. Semin Cancer Biol. 2022 Oct 13. pii: S1044-579X(22)00205-X. [Epub ahead of print]
    Deregulated transcription factors in cancer cell metabolisms and reprogramming.
    Rajni Kant, Rajesh Kumar Manne, Mohammad Anas, Vasudevarao Penugurti, Tingjin Chen, Bo-Syong Pan, Che-Chia Hsu, Hui-Kuan Lin.
      Metabolic reprogramming is an important cancer hallmark that plays a key role in cancer malignancies and therapy resistance. Cancer cells reprogram the metabolic pathways to generate not only energy and building blocks but also produce numerous key signaling metabolites to impact signaling and epigenetic/transcriptional regulation for cancer cell proliferation and survival. A deeper understanding of the mechanisms by which metabolic reprogramming is regulated in cancer may provide potential new strategies for cancer targeting. Recent studies suggest that deregulated transcription factors have been observed in various human cancers and significantly impact metabolism and signaling in cancer. In this review, we highlight the key transcription factors that are involved in metabolic control, dissect the crosstalk between signaling and transcription factors in metabolic reprogramming, and offer therapeutic strategies targeting deregulated transcription factors for cancer treatment.
    Keywords:  Cancer treatment; Cell metabolism; Metabolic Reprogramming; Transcription Factors; signaling metabolites
    DOI:  https://doi.org/10.1016/j.semcancer.2022.10.001
  18. Sci Signal. 2022 Oct 18. 15(756): eabn4948
    Fusobacterium nucleatum induces proliferation and migration in pancreatic cancer cells through host autocrine and paracrine signaling.
    Barath Udayasuryan, Raffae N Ahmad, Tam T D Nguyen, Ariana Umaña, LaDeidra Monét Roberts, Polina Sobol, Stephen D Jones, Jennifer M Munson, Daniel J Slade, Scott S Verbridge.
      The tumor microbiome is increasingly implicated in cancer progression and resistance to chemotherapy. In pancreatic ductal adenocarcinoma (PDAC), high intratumoral loads of Fusobacterium nucleatum correlate with shorter survival in patients. Here, we investigated the potential mechanisms underlying this association. We found that F. nucleatum infection induced both normal pancreatic epithelial cells and PDAC cells to secrete increased amounts of the cytokines GM-CSF, CXCL1, IL-8, and MIP-3α. These cytokines increased proliferation, migration, and invasive cell motility in both infected and noninfected PDAC cells but not in noncancerous pancreatic epithelial cells, suggesting autocrine and paracrine signaling to PDAC cells. This phenomenon occurred in response to Fusobacterium infection regardless of the strain and in the absence of immune and other stromal cells. Blocking GM-CSF signaling markedly limited proliferative gains after infection. Thus, F. nucleatum infection in the pancreas elicits cytokine secretion from both normal and cancerous cells that promotes phenotypes in PDAC cells associated with tumor progression. The findings support the importance of exploring host-microbe interactions in pancreatic cancer to guide future therapeutic interventions.
    DOI:  https://doi.org/10.1126/scisignal.abn4948
  19. Phys Life Rev. 2022 Oct 04. pii: S1571-0645(22)00063-X. [Epub ahead of print]43 139-188
    The distinguishing electrical properties of cancer cells.
    Elisabetta Di Gregorio, Simone Israel, Michael Staelens, Gabriella Tankel, Karthik Shankar, Jack A Tuszyński.
      In recent decades, medical research has been primarily focused on the inherited aspect of cancers, despite the reality that only 5-10% of tumours discovered are derived from genetic causes. Cancer is a broad term, and therefore it is inaccurate to address it as a purely genetic disease. Understanding cancer cells' behaviour is the first step in countering them. Behind the scenes, there is a complicated network of environmental factors, DNA errors, metabolic shifts, and electrostatic alterations that build over time and lead to the illness's development. This latter aspect has been analyzed in previous studies, but how the different electrical changes integrate and affect each other is rarely examined. Every cell in the human body possesses electrical properties that are essential for proper behaviour both within and outside of the cell itself. It is not yet clear whether these changes correlate with cell mutation in cancer cells, or only with their subsequent development. Either way, these aspects merit further investigation, especially with regards to their causes and consequences. Trying to block changes at various levels of occurrence or assisting in their prevention could be the key to stopping cells from becoming cancerous. Therefore, a comprehensive understanding of the current knowledge regarding the electrical landscape of cells is much needed. We review four essential electrical characteristics of cells, providing a deep understanding of the electrostatic changes in cancer cells compared to their normal counterparts. In particular, we provide an overview of intracellular and extracellular pH modifications, differences in ionic concentrations in the cytoplasm, transmembrane potential variations, and changes within mitochondria. New therapies targeting or exploiting the electrical properties of cells are developed and tested every year, such as pH-dependent carriers and tumour-treating fields. A brief section regarding the state-of-the-art of these therapies can be found at the end of this review. Finally, we highlight how these alterations integrate and potentially yield indications of cells' malignancy or metastatic index.
    Keywords:  Electromagnetic fields; Electrophysiology; Ion channel expression; Ionic conductivity; Mitochondrial membrane potential; Oncology
    DOI:  https://doi.org/10.1016/j.plrev.2022.09.003
  20. Autophagy. 2022 Oct 17. 1-20
    Development of new tools to study membrane-anchored mammalian Atg8 proteins.
    Sang-Won Park, Pureum Jeon, Akinori Yamasaki, Hye Eun Lee, Haneul Choi, Ji Young Mun, Yong-Woo Jun, Ju-Hui Park, Seung-Hwan Lee, Soo-Kyeong Lee, You-Kyung Lee, Hyun Kyu Song, Michael Lazarou, Dong-Hyong Cho, Masaaki Komatsu, Nobuo N Noda, Deok-Jin Jang, Jin-A Lee.
      ABBREVIATIONS: A:C autophagic membrane:cytosol; ALS amyotrophic lateral sclerosis; ATG4 autophagy related 4; Atg8 autophagy related 8; BafA1 bafilomycin A1; BNIP3L/Nix BCL2 interacting protein 3 like; CALCOCO2/NDP52 calcium binding and coiled-coil domain 2; EBSS Earle's balanced salt solution; GABARAP GABA type A receptor-associated protein; GST glutathione S transferase; HKO hexa knockout; Kd dissociation constant; LIR LC3-interacting region; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; NLS nuclear localization signal/sequence; PE phosphatidylethanolamine; SpHfl1 Schizosaccharomyces pombeorganic solute transmembrane transporter; SQSTM1/p62 SQSTM1/p62; TARDBP/TDP-43 TAR DNA binding protein; TKO triple knockout.
    Keywords:  Autophagy; GABARAP; LIR motif; RavZ protein; mammalian ATG8; selective mATG8–PE delipidation
    DOI:  https://doi.org/10.1080/15548627.2022.2132040
  21. Nat Biomed Eng. 2022 Oct;6(10): 1148-1166
    Brachytherapy via a depot of biopolymer-bound 131I synergizes with nanoparticle paclitaxel in therapy-resistant pancreatic tumours.
    Jeffrey L Schaal, Jayanta Bhattacharyya, Jeremy Brownstein, Kyle C Strickland, Garrett Kelly, Soumen Saha, Joshua Milligan, Samagya Banskota, Xinghai Li, Wenge Liu, David G Kirsch, Michael R Zalutsky, Ashutosh Chilkoti.
      Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (131I-ELP) when combined with systemically delivered nanoparticle albumin-bound paclitaxel. This combination therapy induced complete tumour regressions in diverse subcutaneous and orthotopic mouse models of locoregional pancreatic tumours. 131I-ELP brachytherapy was effective independently of the paclitaxel formulation and dose, but external beam radiotherapy (EBRT) only achieved tumour-growth inhibition when co-administered with nanoparticle paclitaxel. Histological analyses revealed that 131I-ELP brachytherapy led to changes in the expression of intercellular collagen and junctional proteins within the tumour microenvironment. These changes, which differed from those of EBRT-treated tumours, correlated with the improved delivery and accumulation of paclitaxel nanoparticles within the tumour. Our findings support the further translational development of 131I-ELP depots for the synergistic treatment of localized pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41551-022-00949-4
  22. Nat Commun. 2022 Oct 21. 13(1): 6283
    The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics.
    Matthew Yoke Wui Ng, Chara Charsou, Ana Lapao, Sakshi Singh, Laura Trachsel-Moncho, Sebastian W Schultz, Sigve Nakken, Michael J Munson, Anne Simonsen.
      During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.
    DOI:  https://doi.org/10.1038/s41467-022-33933-2
  23. Nat Metab. 2022 Oct;4(10): 1218
    Lipids reroute mitochondria.
    Michael Attwaters.
      
    DOI:  https://doi.org/10.1038/s42255-022-00662-1
  24. Nat Commun. 2022 Oct 20. 13(1): 6228
    A BDNF-TrkB autocrine loop enhances senescent cell viability.
    Carlos Anerillas, Allison B Herman, Rachel Munk, Amanda Garrido, Kwan-Wood Gabriel Lam, Matthew J Payea, Martina Rossi, Dimitrios Tsitsipatis, Jennifer L Martindale, Yulan Piao, Krystyna Mazan-Mamczarz, Jinshui Fan, Chang-Yi Cui, Supriyo De, Kotb Abdelmohsen, Rafael de Cabo, Myriam Gorospe.
      Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions aim at selectively eliminating senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors capable of triggering apoptosis of several senescent, but not proliferating, human cells. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF signaling suggested an autocrine function for TrkB and BDNF, which activated ERK5 and elevated BCL2L2 levels, favoring senescent cell survival. Treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. We propose that the activation of TrkB by SASP factor BDNF promotes cell survival and could be exploited therapeutically to reduce the senescent-cell burden.
    DOI:  https://doi.org/10.1038/s41467-022-33709-8
  25. J Cell Biol. 2022 11 07. pii: e202208092. [Epub ahead of print]221(11):
    NBR1: The archetypal selective autophagy receptor.
    Nikoline Lander Rasmussen, Athanasios Kournoutis, Trond Lamark, Terje Johansen.
      NBR1 was discovered as an autophagy receptor not long after the first described vertebrate autophagy receptor p62/SQSTM1. Since then, p62 has currently been mentioned in >10,000 papers on PubMed, while NBR1 is mentioned in <350 papers. Nonetheless, evolutionary analysis reveals that NBR1, and likely also selective autophagy, was present already in the last eukaryotic common ancestor (LECA), while p62 appears first in the early Metazoan lineage. Furthermore, yeast-selective autophagy receptors Atg19 and Atg34 represent NBR1 homologs. NBR1 is the main autophagy receptor in plants that do not contain p62, while most animal taxa contain both NBR1 and p62. Mechanistic studies are starting to shed light on the collaboration between mammalian NBR1 and p62 in the autophagic degradation of protein aggregates (aggrephagy). Several domains of NBR1 are involved in cargo recognition, and the list of known substrates for NBR1-mediated selective autophagy is increasing. Lastly, roles of NBR1 in human diseases such as proteinopathies and cancer are emerging.
    DOI:  https://doi.org/10.1083/jcb.202208092
  26. Elife. 2022 Oct 18. pii: e78915. [Epub ahead of print]11
    Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors.
    Alba Timón-Gómez, Alexandra L Scharr, Nicholas Y Wong, Erwin Ni, Arijit Roy, Min Liu, Julisia Chau, Jack L Lampert, Homza Hireed, Noah S Kim, Masood Jan, Alexander R Gupta, Ryan W Day, James M Gardner, Richard J A Wilson, Antoni Barrientos, Andy J Chang.
      Mammalian carotid body arterial chemoreceptors function as an early warning system for hypoxia, triggering acute life-saving arousal and cardiorespiratory reflexes. To serve this role, carotid body glomus cells are highly sensitive to decreases in oxygen availability. While the mitochondria and plasma membrane signaling proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we identify HIGD1C, a novel hypoxia-inducible gene domain factor isoform, as an electron transport chain Complex IV-interacting protein that is almost exclusively expressed in the carotid body and is therefore not generally necessary for mitochondrial function. Importantly, HIGD1C is required for carotid body oxygen sensing and enhances Complex IV sensitivity to hypoxia. Thus, we propose that HIGD1C promotes exquisite oxygen sensing by the carotid body, illustrating how specialized mitochondria can be used as sentinels of metabolic stress to elicit essential adaptive behaviors.
    Keywords:  biochemistry; chemical biology; human; mouse; neuroscience; rat
    DOI:  https://doi.org/10.7554/eLife.78915
  27. Front Oncol. 2022 ;12 969731
    Fibroblast activation protein-based theranostics in pancreatic cancer.
    Chien-Shan Cheng, Pei-Wen Yang, Yun Sun, Shao-Li Song, Zhen Chen.
      Fibroblast activation protein-α (FAP) is a type II transmembrane serine protease that has specific endopeptidase activity. Given its well-established selective expression in the activated stromal fibroblasts of epithelial cancers, although not in quiescent fibroblasts, FAP has received substantial research attention as a diagnostic marker and therapeutic target. Pancreatic cancer is characterized by an abundant fibrotic or desmoplastic stroma, leading to rapid progression, therapeutic resistance, and poor clinical outcomes. Numerous studies have revealed that the abundant expression of FAP in cancer cells, circulating tumor cells, stromal cells, and cancer-associated fibroblasts (CAFs) of pancreatic adenocarcinoma is implicated in diverse cancer-related signaling pathways, contributing to cancer progression, invasion, migration, metastasis, immunosuppression, and resistance to treatment. In this article, we aim to systematically review the recent advances in research on FAP in pancreatic adenocarcinoma, including its utility as a diagnostic marker, therapeutic potential, and correlation with prognosis. We also describe the functional role of FAP-overexpressing stromal cells, particulary CAFs, in tumor immuno- and metabolic microenvironments, and summarize the mechanisms underlying the contribution of FAP-overexpressing CAFs in pancreatic cancer progression and treatment resistance. Furthermore, we discuss whether targeting FAP-overexpressing CAFs could represent a potential therapeutic strategy and describe the development of FAP-targeted probes for diagnostic imaging. Finally, we assess the emerging basic and clinical studies regarding the bench-to-bedside translation of FAP in pancreatic cancer.
    Keywords:  FAPI imaging; cancer theranostics; cancer-associated fibroblasts; fibroblast activation protein-α; pancreatic adenocarcinoma
    DOI:  https://doi.org/10.3389/fonc.2022.969731
  28. Elife. 2022 Oct 20. pii: e82348. [Epub ahead of print]11
    Caveolae couple mechanical stress to integrin recycling and activation.
    Fidel-Nicolás Lolo, Dácil María Pavón, Araceli Grande, Alberto Elósegui Artola, Valeria Inés Segatori, Sara Sánchez, Xavier Trepat, Pere Roca-Cusachs, Miguel Ángel Del Pozo.
      Cells are subjected to multiple mechanical inputs throughout their lives. Their ability to detect these environmental cues is called mechanosensing, a process in which integrins play an important role. During cellular mechanosensing, plasma membrane (PM) tension is adjusted to mechanical stress through the buffering action of caveolae; however, little is known about the role of caveolae in early integrin mechanosensing regulation. Here, we show that Cav1KO fibroblasts increase adhesion to FN-coated beads when pulled with magnetic tweezers, as compared to wild type fibroblasts. This phenotype is Rho-independent and mainly derived from increased active b1-integrin content on the surface of Cav1KO fibroblasts. FRAP analysis and endocytosis/recycling assays revealed that active b1-integrin is mostly endocytosed through the CLIC/GEEC pathway and is more rapidly recycled to the PM in Cav1KO fibroblasts, in a Rab4 and PM tension-dependent manner. Moreover, the threshold for PM tension-driven b1-integrin activation is lower in Cav1KO MEFs than in wild type MEFs, through a mechanism dependent on talin activity. Our findings suggest that caveolae couple mechanical stress to integrin cycling and activation, thereby regulating the early steps of the cellular mechanosensing response.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.82348
  29. Sci Adv. 2022 Oct 21. 8(42): eabo5555
    TSC22D4 interacts with Akt1 to regulate glucose metabolism.
    Sevgican Demir, Gretchen Wolff, Annika Wieder, Adriano Maida, Lea Bühler, Maik Brune, Oksana Hautzinger, Annette Feuchtinger, Tanja Poth, Julia Szendroedi, Stephan Herzig, Bilgen Ekim Üstünel.
      Maladaptive insulin signaling is a key feature in the pathogenesis of severe metabolic disorders, including obesity and diabetes. Enhancing insulin sensitivity represents a major goal in the treatment of patients affected by diabetes. Here, we identify transforming growth factor-β1 stimulated clone 22 D4 (TSC22D4) as a novel interaction partner for protein kinase B/Akt1, a critical mediator of insulin/phosphatidylinositol 3-kinase signaling pathway. While energy deprivation and oxidative stress promote the TSC22D4-Akt1 interaction, refeeding mice or exposing cells to glucose and insulin impairs this interaction, which relies on an intrinsically disordered region (D2 domain) within TSC22D4. Functionally, the interaction with TSC22D4 reduces basal phosphorylation of Akt and its downstream targets during starvation, thereby promoting insulin sensitivity. Genetic, liver-specific reconstitution experiments in mice demonstrate that the interaction between TSC22D4 and Akt1 improves glucose handling and insulin sensitivity. Overall, our findings postulate a model whereby TSC22D4 acts as an environmental sensor and interacts with Akt1 to regulate insulin signaling and glucose metabolism.
    DOI:  https://doi.org/10.1126/sciadv.abo5555
  30. JNCI Cancer Spectr. 2022 Oct 18. pii: pkac066. [Epub ahead of print]
    Body Mass Index Trajectories Across the Adult Life Course and Pancreatic Cancer Risk.
    Simran Arjani, Pedro F Saint-Maurice, Sachelly Julián-Serrano, Guido Eibl, Rachael Stolzenberg-Solomon.
      BACKGROUND: Body mass index (BMI) during adulthood has been associated with pancreatic ductal adenocarcinoma (PDAC), however patterns of body size across the adult life course have not been studied extensively. We comprehensively evaluated the association between adiposity across adulthood and PDAC.METHODS: We conducted a prospective analysis of 269,480 (162,735 males, 106,745 females) NIH-AARP Diet and Health Study participants, aged 50-71years (1995-1996) who self-reported height and weight history. Participants were followed through December 31, 2011. We examined associations between BMI (kg/m2) at ages 18, 35, 50, and 50-71 (baseline) years, their trajectories determined from latent-class trajectory modeling, and incident PDAC. Cox proportional hazard models were used to calculate multivariable adjusted hazards ratios (HR) and 95% confidence intervals (CI).
    RESULTS: During up to 15.2 years of follow-up, 3,092 (2,020 males, 1,072 females) incident PDAC cases were identified. BMI at all four ages were significantly associated with increased PDAC (per 5-unit increase, HRs = 1.09 to 1.13) with higher magnitude associations in males than females at ages ≥ 35 (P-interaction < 0.05). Four BMI trajectories were created. Compared to normal-weight-maintainers, normal-to-overweight, normal-to-obese class I, and overweight-to-severely obese trajectories had HRs (95% CI) of 1.15 (1.06-1.25), 1.39 (1.25-1.54), and 1.48 (1.18-1.87), respectively (P-interaction by sex = 0.07).
    CONCLUSIONS: High BMI and BMI trajectories that result in overweight or obesity during adulthood were positively associated with PDAC, with stronger associations among those with early onset adiposity and male sex. Avoidance of excess body weight throughout the life course may prevent PDAC.
    DOI:  https://doi.org/10.1093/jncics/pkac066
  31. Cancer Res. 2022 Oct 20. pii: CAN-22-1601. [Epub ahead of print]
    Reimagining Cancer: Moving from the Cellular to the Tissue Level.
    Romano Demicheli, William Jm Hrushesky.
      The current universally accepted explanation of cancer origin and behavior, the somatic mutation theory, is cell-centered and rooted in perturbation of gene function independent of the external environmental context. However, tumors consist of various epithelial and stromal cell populations temporally and spatially organized into an integrated neoplastic community, and they can have properties similar to normal tissues. Accordingly, we review specific normal cellular and tissue traits and behaviors with adaptive temporal and spatial self-organization that result in ordered patterns and structures. A few recent theories have described these tissue-level cancer behaviors, invoking a conceptual shift from the cellular level and highlighting the need for methodological approaches based on the analysis of complex systems. We propose extending the analytical approach of regulatory networks to the tissue level and introduce the concept of "cancer attractors." These concepts require re-evaluation of cancer imaging and investigational approaches and challenge the traditional reductionist approach of cancer molecular biology.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1601
  32. J Cell Sci. 2022 10 15. pii: jcs260634. [Epub ahead of print]135(20):
    Meeting report - Cell size and growth: from single cells to the tree of life.
    Dimitra Chatzitheodoridou, Marco D'Ario, Ian Jones, Liliana Piñeros, Diana Serbanescu, Frank O'Donnell, Clotilde Cadart, Matthew P Swaffer.
      In April 2022, The Company of Biologists hosted their first post-pandemic in-person Workshop at Buxted Park Country House in the Sussex countryside. The Workshop, entitled 'Cell size and growth: from single cells to the tree of life', gathered a small group of early-career and senior researchers with expertise in cell size spanning a broad range of organisms, including bacteria, yeast, animal cells, embryos and plants, and working in fields from cell biology to ecology and evolutionary biology. The programme made ample room for fruitful discussions and provided a much-needed opportunity to discuss the most recent findings relating to the regulation of cell size and growth, identify the emerging challenges for the field, and build a community after the pandemic.
    DOI:  https://doi.org/10.1242/jcs.260634
  33. J Exp Med. 2023 Jan 02. pii: e20202595. [Epub ahead of print]220(1):
    Primary tumor-derived systemic nANGPTL4 inhibits metastasis.
    Corinne Hübers, Ashik Ahmed Abdul Pari, Denise Grieshober, Martin Petkov, Alexander Schmidt, Tatjana Messmer, Christian Moritz Heyer, Sebastian Schölch, Stephanie S Kapel, Nicolas Gengenbacher, Mahak Singhal, Benjamin Schieb, Claudine Fricke, Rainer Will, Kim Remans, Jochen Sven Utikal, Christoph Reissfelder, Matthias Schlesner, Kairbaan M Hodivala-Dilke, Sander Kersten, Sergij Goerdt, Hellmut G Augustin, Moritz Felcht.
      Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
    DOI:  https://doi.org/10.1084/jem.20202595
  34. Front Oncol. 2022 ;12 1014748
    Understanding emerging bioactive metabolites with putative roles in cancer biology.
    Olivier Philips, Mukhayyo Sultonova, Beau Blackmore, J Patrick Murphy.
      Dysregulated metabolism in cancers is, by now, well established. Although metabolic adaptations provide cancers with the ability to synthesize the precursors required for rapid biosynthesis, some metabolites have direct functional, or bioactive, effects in human cells. Here we summarize recently identified metabolites that have bioactive roles either as post-translational modifications (PTMs) on proteins or in, yet unknown ways. We propose that these metabolites could play a bioactive role in promoting or inhibiting cancer cell phenotypes in a manner that is mostly unexplored. To study these potentially important bioactive roles, we discuss several novel metabolomic and proteomic approaches aimed at defining novel PTMs and metabolite-protein interactions. Understanding metabolite PTMs and protein interactors of bioactive metabolites may provide entirely new therapeutic targets for cancer.
    Keywords:  bioactive metabolite; cancer metabolism; cancer therapeutics; metabolite-protein interaction profiling; post-translational modification
    DOI:  https://doi.org/10.3389/fonc.2022.1014748
  35. Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2202736119
    Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools.
    Aidan T Pezacki, Carson D Matier, Xingxing Gu, Eric Kummelstedt, Sarah E Bond, Laura Torrente, Kelly L Jordan-Sciutto, Gina M DeNicola, Timothy A Su, Donita C Brady, Christopher J Chang.
      Copper is an essential metal nutrient for life that often relies on redox cycling between Cu(I) and Cu(II) oxidation states to fulfill its physiological roles, but alterations in cellular redox status can lead to imbalances in copper homeostasis that contribute to cancer and other metalloplasias with metal-dependent disease vulnerabilities. Copper-responsive fluorescent probes offer powerful tools to study labile copper pools, but most of these reagents target Cu(I), with limited methods for monitoring Cu(II) owing to its potent fluorescence quenching properties. Here, we report an activity-based sensing strategy for turn-on, oxidation state-specific detection of Cu(II) through metal-directed acyl imidazole chemistry. Cu(II) binding to a metal and oxidation state-specific receptor that accommodates the harder Lewis acidity of Cu(II) relative to Cu(I) activates the pendant dye for reaction with proximal biological nucleophiles and concomitant metal ion release, thus avoiding fluorescence quenching. Copper-directed acyl imidazole 649 for Cu(II) (CD649.2) provides foundational information on the existence and regulation of labile Cu(II) pools, including identifying divalent metal transporter 1 (DMT1) as a Cu(II) importer, labile Cu(II) increases in response to oxidative stress induced by depleting total glutathione levels, and reciprocal increases in labile Cu(II) accompanied by decreases in labile Cu(I) induced by oncogenic mutations that promote oxidative stress.
    Keywords:  activity-based sensing; cancer metabolism; fluorescent copper probe; oxidative stress; transition metal signaling
    DOI:  https://doi.org/10.1073/pnas.2202736119
  36. Front Oncol. 2022 ;12 987026
    The global research and emerging trends in autophagy of pancreatic cancer: A bibliometric and visualized study.
    Mingyang Song, Qin Lu, Min Xu, Yajie Li, Yawen Zhao, Chen Gong, Xilong Ou.
      Objective: To present the global research features and hotspots, and forecast the emerging trends by conducting a bibliometric analysis based on literature related to autophagy of pancreatic cancer from 2011 to 2022.Methods: The literature data regarding autophagy of pancreatic cancer were retrieved and downloaded from the Web of Science Core Collection (WOSCC) from Clarivate Analytics on June 10th, 2022. VOSviewer (version 1.6.18) was used to perform the bibliometric analysis.
    Results: A total of 616 studies written by 3993 authors, covered 45 countries and 871 organizations, published in 263 journals and co-cited 28152 references from 2719 journals. China (n=260, 42.2%) and the United States (n=211, 34.3%) were the most frequent publishers and collaborated closely. However, publications from China had a low average number of citations (25.35 times per paper). The output of University of Texas MD Anderson Cancer Center ranked the first with 26 papers (accounting for 4.2% of the total publications). Cancers (n=23, 3.7%; Impact Factor = 6.639) published most papers in this field and was very pleasure to accept related researches. Daolin Tang and Rui Kang published the most papers (n=18, respectively). The research hotspots mainly focused on the mechanisms of autophagy in tumor onset and progression, the role of autophagy in tumor apoptosis, and autophagy-related drugs in treating pancreatic cancer (especially combined therapy). The emerging topics were chemotherapy resistance mediated by autophagy, tumor microenvironment related to autophagy, autophagy-depended epithelial-mesenchymal transition (EMT), mitophagy, and the role of autophagy in tumor invasion.
    Conclusion: Attention has been increasing in autophagy of pancreatic cancer over the past 12 years. Our results undoubtedly provide scholars with new clues and ideas in this field.
    Keywords:  apoptosis; autophagy; bibliometric study; chemotherapy resistance; gemcitabine; pancreatic cancer
    DOI:  https://doi.org/10.3389/fonc.2022.987026
  37. Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2205492119
    Lysosomal positioning regulates Rab10 phosphorylation at LRRK2+ lysosomes.
    Jillian H Kluss, Alexandra Beilina, Chad D Williamson, Patrick A Lewis, Mark R Cookson, Luis Bonet-Ponce.
      Genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus contributes to an enhanced risk of familial and sporadic Parkinson's disease. Previous data have demonstrated that recruitment to various membranes of the endolysosomal system results in LRRK2 activation. However, the mechanism(s) underlying LRRK2 activation at endolysosomal membranes and the cellular consequences of these events are still poorly understood. Here, we directed LRRK2 to lysosomes and early endosomes, triggering both LRRK2 autophosphorylation and phosphorylation of the direct LRRK2 substrates Rab10 and Rab12. However, when directed to the lysosomal membrane, pRab10 was restricted to perinuclear lysosomes, whereas pRab12 was visualized on both peripheral and perinuclear LRRK2+ lysosomes, suggesting that lysosomal positioning provides additional regulation of LRRK2-dependent Rab phosphorylation. Anterograde transport of lysosomes to the cell periphery by increasing the expression of ARL8B and SKIP or by knockdown of JIP4 blocked the recruitment and phosphorylation of Rab10 by LRRK2. The absence of pRab10 from the lysosomal membrane prevented the formation of a lysosomal tubulation and sorting process we previously named LYTL. Conversely, overexpression of RILP resulted in lysosomal clustering within the perinuclear area and increased LRRK2-dependent Rab10 recruitment and phosphorylation. The regulation of Rab10 phosphorylation in the perinuclear area depends on counteracting phosphatases, as the knockdown of phosphatase PPM1H significantly increased pRab10 signal and lysosomal tubulation in the perinuclear region. Our findings suggest that LRRK2 can be activated at multiple cellular membranes, including lysosomes, and that lysosomal positioning further provides the regulation of some Rab substrates likely via differential phosphatase activity or effector protein presence in nearby cellular compartments.
    Keywords:  JIP4; LLOMe; LYTL; Parkinson's disease; kinase
    DOI:  https://doi.org/10.1073/pnas.2205492119
  38. Cancer Cell. 2022 Oct 10. pii: S1535-6108(22)00444-5. [Epub ahead of print]
    Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.
    Deshka S Foster, Michael Januszyk, Daniel Delitto, Kathryn E Yost, Michelle Griffin, Jason Guo, Nicholas Guardino, Andrea E Delitto, Malini Chinta, Austin R Burcham, Alan T Nguyen, Khristian E Bauer-Rowe, Ashley L Titan, Ankit Salhotra, R Ellen Jones, Oscar da Silva, Hunter G Lindsay, Charlotte E Berry, Kellen Chen, Dominic Henn, Shamik Mascharak, Heather E Talbott, Alexia Kim, Fatemeh Nosrati, Dharshan Sivaraj, R Chase Ransom, Michael Matthews, Anum Khan, Dhananjay Wagh, John Coller, Geoffrey C Gurtner, Derrick C Wan, Irene L Wapnir, Howard Y Chang, Jeffrey A Norton, Michael T Longaker.
      Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.
    Keywords:  ATAC-seq; CODEX; RNA-seq; cancer; fibroblasts; mechanotransduction; multi-omics; single cell; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.ccell.2022.09.015
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