bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–12–24
forty-four papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. S-acylation regulates SQSTM1/p62-mediated selective autophagy.
  2. Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.
  3. Membranes that make fat: roles of membrane lipids as acyl donors for triglyceride synthesis and organelle function.
  4. Targeting lipid metabolism in cancer metastasis.
  5. Three-dimensional assessments are necessary to determine the true spatial tissue composition of diseased tissues.
  6. A lipid membrane-centric role of the SQSTM1/p62 body during autophagosome formation.
  7. Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model.
  8. DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism.
  9. The lipid flippase Drs2 regulates anterograde transport of Atg9 during autophagy.
  10. Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.
  11. Stiffness-induced cancer-associated fibroblasts are responsible for immunosuppression in a platelet-derived growth factor ligand-dependent manner.
  12. Lysosomal microautophagy: an emerging dimension in mammalian autophagy.
  13. Heterogeneity of weight loss and transcriptomic signatures in pancreatic ductal adenocarcinoma.
  14. Engrailed-1 Promotes Pancreatic Cancer Metastasis.
  15. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.
  16. Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.
  17. Validity of the diagnostic criteria from the Asian Working Group for Cachexia in advanced cancer.
  18. Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer.
  19. Nonepithelial cancer dissemination: specificities and challenges.
  20. High Performance Adaptive Physics Refinement to Enable Large-Scale Tracking of Cancer Cell Trajectory.
  21. Nutrient signaling: Starvation flips a phosphoinositide switch on lysosomal catabolism.
  22. In vivo senescence imaging nanoprobe targets the associated reactive oxygen species.
  23. Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing.
  24. Therapy of Locally Advanced and Oligometastatic Pancreatic Adenocarcinoma.
  25. Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets.
  26. Bridging the Gap: Pancreas Tissue Slices From Organ and Tissue Donors for the Study of Diabetes Pathogenesis.
  27. Qualitative flow metabolic phenotype of pancreatic cancer. A new prognostic biomarker?
  28. Distinct secretomes in p16- and p21- positive senescent cells across tissues.
  29. Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy.
  30. GeneMAP: A discovery platform for metabolic gene function.
  31. Atg15 is a vacuolar phospholipase that disintegrates organelle membranes.
  32. The involvement of the hepatic artery is a risk factor for unresectability after neoadjuvant treatment in borderline pancreatic adenocarcinoma.
  33. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.
  34. The Information Theory of Aging.
  35. Autophagy supports PDGFRA-dependent brain tumor development by enhancing oncogenic signaling.
  36. Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection.
  37. Collective effects in flow-driven cell migration.
  38. The autophagy of stress granules.
  39. PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition.
  40. Microtubule-dependent apical polarization of basement membrane matrix mRNAs in mouse epithelial cells.
  41. Muscle immune cells protect mitochondrial organelles during exercise.
  42. Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
  43. APOBEC3 as a driver of genetic intratumor heterogeneity.
  44. Growing ecosystem of deep learning methods for modeling protein-protein interactions.
  1. Autophagy. 2023 Dec 20.
    S-acylation regulates SQSTM1/p62-mediated selective autophagy.
    Xue Huang, Lu Liu, Jia Yao, Changhai Lin, Tingxiu Xiang, Aimin Yang.
      Macroautophagy/autophagy is a highly conserved metabolic process that degrades intracellular components and recycles bioenergetic substrates. SQSTM1/p62 (sequestosome 1) is a classical autophagy receptor that participates in selective autophagy to eliminate abnormal intracellular components and recycle bioenergetic substrates. In autophagy, SQSTM1 recruits ubiquitinated substrates to form SQSTM1 droplets and delivers these cargoes to phagophores, the precursors to autophagosomes. Recently, we reported a previously unidentified SQSTM1 S-acylation, which is catalyzed by S-acyltransferase ZDHHC19 and reversed by LYPLA1/APT1. S-acylation of SQSTM1 enhances the affinity of SQSTM1 droplets with the phagophore membrane, thereby promoting efficient autophagic degradation of ubiquitinated substrates. Our study uncovers the role of the S-acylation-deacylation cycle in regulating SQSTM1-mediated selective autophagy.
    Keywords:  Autophagosome; SQSTM1; s-acylation; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2297623
  2. bioRxiv. 2023 Dec 04. pii: 2023.12.03.569791. [Epub ahead of print]
    Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.
    Urszula N Wasko, Jingjing Jiang, Alvaro Curiel-Garcia, Yingyun Wang, Bianca Lee, Margo Orlen, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Stephen A Sastra, Carmine F Palermo, Tanner Dalton, Marie C Hasselluhn, Amanda R Decker-Farrell, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Ruiping Zhao, Samantha B Kemp, Cynthia Clendenin, Rina Sor, Will Vostrejs, Amber A Amparo, Priya S Hibshman, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Basil Bakir, Michael A Badgley, John A Chabot, Michael D Kluger, Gulam A Manji, Elsa Quintana, Zhengping Wang, Jacqueline A M Smith, Matthew Holderfield, David Wildes, Andrew J Aguirre, Channing J Der, Robert H Vonderheide, Ben Z Stanger, Mallika Singh, Kenneth P Olive.
      Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS , we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo . Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.
    DOI:  https://doi.org/10.1101/2023.12.03.569791
  3. FEBS Lett. 2023 Dec 23.
    Membranes that make fat: roles of membrane lipids as acyl donors for triglyceride synthesis and organelle function.
    Antonio D Barbosa, Symeon Siniossoglou.
      Triglycerides constitute an inert storage form for fatty acids deposited in lipid droplets, and are mobilized to provide metabolic energy or membrane building blocks. The biosynthesis of triglycerides is highly conserved within eukaryotes and normally involves the sequential esterification of activated fatty acids with a glycerol backbone. Some eukaryotes, however, can also use cellular membrane lipids as direct fatty acid donors for triglyceride synthesis. The biological significance of a pathway that generates triglycerides at the expense of organelle membranes has remained elusive. Here we review current knowledge on how cells use membrane lipids as fatty acid donors for triglyceride synthesis, and discuss the hypothesis that a primary function of this pathway is to regulate membrane lipid remodelling and organelle function.
    Keywords:  Lipid droplet; endoplasmic reticulum; fat; membrane; nuclear membrane; phospholipid; triglyceride
    DOI:  https://doi.org/10.1002/1873-3468.14793
  4. Biochim Biophys Acta Rev Cancer. 2023 Dec 13. pii: S0304-419X(23)00200-7. [Epub ahead of print] 189051
    Targeting lipid metabolism in cancer metastasis.
    Gloria Pascual, Blanca Majem, Salvador Aznar-Benitah.
      This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
    Keywords:  Epigenetics; Lipid metabolism; Metastasis; Microenvironment; Therapies
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189051
  5. bioRxiv. 2023 Dec 06. pii: 2023.12.04.569986. [Epub ahead of print]
    Three-dimensional assessments are necessary to determine the true spatial tissue composition of diseased tissues.
    André Forjaz, Eduarda Vaz, Valentina Matos Romero, Saurabh Joshi, Alicia M Braxton, Ann C Jiang, Kohei Fujikura, Toby Cornish, Seung-Mo Hong, Ralph H Hruban, Pei-Hsun Wu, Laura D Wood, Ashley L Kiemen, Denis Wirtz.
      Methods for partially resolved cellular profiling has enabled in-depth quantitative tissue mapping via thinly cut sections to study inter-patient and intra-patient differences in normal human anatomy and disease onset and progression. These methods often profile extremely limited spatial regions, which may impact the evaluation of heterogeneity due to tissue sub-sampling. Here, we applied CODA, a deep learning-based tissue mapping platform, to reconstruct the 3D microanatomy of surgically resected human pancreas biospecimens obtained from patients diagnosed with pancreatic cancer. To compare differences in the inter- and intra-tumoral heterogeneity, we assessed the bulk and spatially resolved tissue composition of a cohort of two-dimensional (2D) whole slide images (WSIs), and a cohort of 3D serially sectioned and reconstructed tissues of pancreata. Here, we show the strength of using 3D as the gold standard, by measuring the information loss and sampling problems when using WSIs and TMAs. We demonstrate that spatial correlation in microanatomical tissue content decays significantly within a span of just a few microns within tumors. As a corollary, hundreds of TMAs and tens of WSIs are required to estimate spatial bulk tumor composition with <10% error in any given pancreatic tumor. In sum, we demonstrate that 3D assessments are necessary to accurately assess tumor burden and tissue composition. These preliminary results show the importance of rate of sampling necessary to more reliably assess spatially resolved tissue composition.
    DOI:  https://doi.org/10.1101/2023.12.04.569986
  6. Autophagy. 2023 Dec 19.
    A lipid membrane-centric role of the SQSTM1/p62 body during autophagosome formation.
    Jinpei Zhang, Xintong He, Na Mi.
      The phase separated SQSTM1/p62 body drives the formation of autophagosomes during macroautophagy/autophagy. However, the underlying mechanism by which the SQSTM1/p62 body acts during this process remains less understood. Recently, we reported that the SQSTM1/p62 body can work as a nucleation center to recruit local membrane sources for the expanding phagophore. Proteomics analysis reveals membrane vesicle-related components as important constituents of the SQSTM1/p62 body. ATG9- and ATG16L1-positive vesicles are recruited by the SQSTM1/p62 body as initial membrane sources of phagophores. ATG2 promotes the lipid transfer and vesicle fusion to further expand the membrane architecture of the initial phagophore. The lipid composition and content within the SQSTM1/p62 body is significantly affected by ATG2. The SQSTM1/p62 body also regulates the proper positioning and abundance of ATG9-positive vesicles. Furthermore, by spatially gathering ULK1 and membrane-anchored class III phosphatidylinositol (PtdIns) 3-kinase complexes, the SQSTM1/p62 body acts a local reaction platform to generate PtdIns-3-phosphate (PtdIns3P) to accelerate autophagosome maturation. These findings highlight a lipid membrane gathering model of the multifaceted SQSTM1/p62 body when driving autophagosome formation.
    Keywords:  ATG2; ATG9; autophagy; lipid; membrane; p62
    DOI:  https://doi.org/10.1080/15548627.2023.2297622
  7. Clin Transl Med. 2023 Dec;13(12): e1513
    Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model.
    Md Hafiz Uddin, Mohammad Najeeb Al-Hallak, Husain Yar Khan, Amro Aboukameel, Yiwei Li, Sahar F Bannoura, Gregory Dyson, Seongho Kim, Yosef Mzannar, Ibrahim Azar, Tanya Odisho, Amr Mohamed, Yosef Landesman, Steve Kim, Rafic Beydoun, Ramzi M Mohammad, Philip A Philip, Anthony F Shields, Asfar S Azmi.
       BACKGROUND: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient-derived tumours, and had promising activity in a phase I study.
    METHODS: Here, we investigated the impact of selinexor-gemcitabine-nab-paclitaxel (Sel-GemPac) combination on LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx1-Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq).
    RESULTS: Sel-GemPac synergistically inhibited the growth of the KPC tumour-derived cell line. The Sel-GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub-maximum tolerated dose (sub-MTD) , Sel-GemPac enhanced the survival of treated mice compared to controls (p < .05). Immunohistochemical analysis of residual KPC tumours showed re-organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase-like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'-kinase-Akt (PI3K-AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel-GemPac-treated mice tumours including the CD44+ stem cell population.
    CONCLUSION: Taken together, these results demonstrate that the Sel-GemPac treatment caused broad perturbation of PDAC-supporting signalling networks in the KPC mouse model.
    HIGHLIGHTS: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac). Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mouse derived cell line and enhanced the survival of mice. Digital spatial profiling shows that Sel-GemPac causes broad perturbation of PDAC-supporting signalling in the KPC model.
    Keywords:  KPC mouse model; digital spatial profiling; gemcitabine; nab-paclitaxel; pancreatic cancer; selinexor; snRNAseq
    DOI:  https://doi.org/10.1002/ctm2.1513
  8. Cancer Res. 2023 Dec 20.
    DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism.
    Ray Pillai, Thales Papagiannakopoulos.
      A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a pro-drug of DON. This compound effectively targets tumor metabolism while minimizing side effects. In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in pre-clinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, though tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib. In a related study, Recouvreux and colleagues found that DON is effective against pancreatic tumors, revealing that PDAC tumors upregulate asparagine synthesis in response to DON, making them susceptible to asparaginase treatment. Both studies underscore the potential of inhibiting glutamine metabolism and adaptive pathways as a promising strategy against PDAC. These findings pave the way for upcoming clinical trials utilizing DRP-104 and similar glutamine antagonists in the battle against solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3954
  9. Autophagy Rep. 2022 Aug 09. 1(1): 345-367
    The lipid flippase Drs2 regulates anterograde transport of Atg9 during autophagy.
    Franziska Kriegenburg, Wouter Huiting, Fleur van Buuren-Broek, Emma Zwilling, Ralph Hardenberg, Muriel Mari, Claudine Kraft, Fulvio Reggiori.
      Macroautophagy/autophagy is a conserved catabolic pathway during which cellular material is sequestered within newly formed double-membrane vesicles called autophagosomes and delivered to the lytic compartment of eukaryotic cells for degradation. Autophagosome biogenesis depends on the core autophagy-related (Atg) machinery, and involves a massive supply and remodelling of membranes. To gain insight into the lipid remodelling mechanisms during autophagy, we have systematically investigated whether lipid flippases are required for this pathway in the yeast Saccharomyces cerevisiae. We found that the flippase Drs2, which transfers phosphatidylserine and phosphatidylethanolamine from the lumenal to the cytosolic leaflet of the limiting membrane at the trans-Golgi network, is required for normal progression of autophagy. We also show that Drs2 is important for the trafficking of the core Atg protein Atg9. Atg9 is a transmembrane protein important for autophagosome biogenesis and its anterograde transport from its post-Golgi reservoirs to the site of autophagosome formation is severely impaired in the absence of Drs2. Thus, our results identify a novel autophagy player and highlight that membrane asymmetry regulates early autophagy steps.
    Keywords:  Aminophospholipid; Atg protein; autophagosome; flippase; lipid asymmetry; phagophore; phagophore assembly site
    DOI:  https://doi.org/10.1080/27694127.2022.2104781
  10. Gut. 2023 Dec 13. pii: gutjnl-2023-331074. [Epub ahead of print]
    Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.
    Roni Ben-Ami, Qiao-Li Wang, Jinming Zhang, Julianna G Supplee, Johannes F Fahrmann, Roni Lehmann-Werman, Lauren K Brais, Jonathan Nowak, Chen Yuan, Maureen Loftus, Ana Babic, Ehsan Irajizad, Tal Davidi, Aviad Zick, Ayala Hubert, Daniel Neiman, Sheina Piyanzin, Ofer Gal-Rosenberg, Amit Horn, Ruth Shemer, Benjamin Glaser, Natalia Boos, Kunal Jajoo, Linda Lee, Thomas E Clancy, Douglas A Rubinson, Kimmie Ng, John A Chabot, Fay Kastrinos, Michael Kluger, Andrew J Aguirre, Pasi A Jänne, Nabeel Bardeesy, Ben Stanger, Mark H O'Hara, Jacob Till, Anirban Maitra, Erica L Carpenter, Andrea J Bullock, Jeanine Genkinger, Samir M Hanash, Cloud P Paweletz, Yuval Dor, Brian M Wolpin.
       OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.
    DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.
    RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).
    CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.
    Keywords:  METHYLATION; PANCREATIC CANCER; TUMOUR MARKERS
    DOI:  https://doi.org/10.1136/gutjnl-2023-331074
  11. PNAS Nexus. 2023 Dec;2(12): pgad405
    Stiffness-induced cancer-associated fibroblasts are responsible for immunosuppression in a platelet-derived growth factor ligand-dependent manner.
    Pia Gamradt, Kevin Thierry, Melissa Masmoudi, Zhichong Wu, Hector Hernandez-Vargas, Sophie Bachy, Tiffanie Antonio, Berkan Savas, Zainab Hussain, Richard Tomasini, Pascale Milani, Philippe Bertolino, Ana Hennino.
      Pancreatic ductal adenocarcinoma (PDAC) is associated with a vast stromal reaction that arises mainly from cancer-associated fibroblasts (CAFs) and promotes both immune escape and tumor growth. Here, we used a mouse model with deletion of the activin A receptor ALK4 in the context of the KrasG12D mutation, which strongly drives collagen deposition that leads to tissue stiffness. By ligand-receptor analysis of single-cell RNA-sequencing data, we identified that, in stiff conditions, neoplastic ductal cells instructed CAFs through sustained platelet-derived growth factor (PDGF) signaling. Tumor-associated tissue rigidity resulted in the emergence of stiffness-induced CAFs (siCAFs) in vitro and in vivo. Similar results were confirmed in human data. siCAFs were able to strongly inhibit CD8+ T-cell responses in vitro and in vivo, promoting local immunosuppression. More importantly, targeting PDGF signaling led to diminished siCAF and reduced tumor growth. Our data show for the first time that early paracrine signaling leads to profound changes in tissue mechanics, impacting immune responses and tumor progression. Our study highlights that PDGF ligand neutralization can normalize the tissue architecture independent of the genetic background, indicating that finely tuned stromal therapy may open new therapeutic avenues in pancreatic cancer.
    Keywords:  PDGFR/PDGF signaling; cancer-associated fibroblasts (CAFs); pancreatic adenocarcinoma (PDAC); tissue remodeling
    DOI:  https://doi.org/10.1093/pnasnexus/pgad405
  12. Trends Cell Biol. 2023 Dec 15. pii: S0962-8924(23)00238-6. [Epub ahead of print]
    Lysosomal microautophagy: an emerging dimension in mammalian autophagy.
    Yoshihiko Kuchitsu, Tomohiko Taguchi.
      Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There are three types of autophagy, i.e., macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. In macroautophagy, a portion of the cytoplasm is wrapped by the autophagosome, which then fuses with lysosomes and delivers the engulfed cytoplasm for degradation. In CMA, the translocation of cytosolic substrates to the lysosomal lumen is directly across the limiting membrane of lysosomes. In microautophagy, lytic organelles, including endosomes or lysosomes, take up a portion of the cytoplasm directly. Although macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become evident that microautophagy plays a variety of cellular roles from yeast to mammals. Here we review the very recent updates of microautophagy. In particular, we focus on the feature of the degradative substrates and the molecular machinery that mediates microautophagy.
    Keywords:  ESCRT complex; K63-linked ubiquitination; lysosome; microautophagy; vacuole
    DOI:  https://doi.org/10.1016/j.tcb.2023.11.005
  13. J Cachexia Sarcopenia Muscle. 2023 Dec 20.
    Heterogeneity of weight loss and transcriptomic signatures in pancreatic ductal adenocarcinoma.
    Andrea N Riner, Kelly M Herremans, Vignesh Vudatha, Song Han, Xufeng Qu, Jinze Liu, Nitai Mukhopadhyay, Devon C Freudenberger, Thomas J George, Sarah M Judge, Andrew R Judge, Steven J Hughes, Jose G Trevino.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss.
    METHODS: Treatment naïve patients with PDAC who underwent pancreatectomy at a single institution between 2012 and 2020 were identified retrospectively. Patients with pancreatic head or distal tumours were matched by sex, age, N and T stage. Serologic and anthropometric variables were obtained at the time of diagnosis. Skeletal muscle index (SMI), muscle radiation attenuation (MRA) and adiposity were measured. The primary outcome was presence of significant weight loss [>5% body weight (BW) loss in past 6 months]. Signed rank tests, Cochran Mantel Haenszel tests and Kaplan-Meier survival analysis are presented. RNA-seq of tumours was performed to explore enriched pathways related to cachexia and weight loss.
    RESULTS: Pancreatic head tumours (n = 24) were associated with higher prevalence (70.8% vs. 41.7%, P = 0.081) and degree of weight loss (7.9% vs. 2.5%, P = 0.014) compared to distal tumours (n = 24). BMI (P = 0.642), SMI (P = 0.738) and MRA (P = 0.478) were similar between groups. Combining BW loss, SMI and MRA into a composite score, patients with pancreatic head cancers met more criteria associated with poor prognosis (P = 0.142). Serum albumin (3.9 vs. 4.4 g/dL, P = 0.002) was lower and bilirubin (4.5 vs. 0.4 mg/dL, P < 0.001) were higher with pancreatic head tumours. Survival differed by tumour location (P = 0.014) with numerically higher median overall survival with distal tumours (11.1 vs. 21.8 months; P = 0.066). Transcriptomic analysis revealed inactivation of appetite stimulation, weight regulation and nutrient digestion/metabolism pathways in pancreatic head tumours.
    CONCLUSIONS: Resectable pancreatic head PDAC is associated with higher prevalence of significant weight loss and more poor prognosis features. Pancreaticobiliary obstruction and hypoalbuminemia in patients with head tumours suggests compounding effects of nutrient malabsorption and systemic inflammation on molecular drivers of cachexia, possibly contributing to shorter survival. Therefore, PDAC-associated cachexia is a heterogenous syndrome, which may be influenced by the primary tumour location. Select patients with resectable pancreatic head tumours may benefit from nutritional rehabilitation to improve outcomes.
    Keywords:  Adipose tissue; Malabsorption; Nutrition; Pancreaticobiliary obstruction; Skeletal muscle; Weight loss
    DOI:  https://doi.org/10.1002/jcsm.13390
  14. Adv Sci (Weinh). 2023 Dec 18. e2308537
    Engrailed-1 Promotes Pancreatic Cancer Metastasis.
    Jihao Xu, Jae-Seok Roe, EunJung Lee, Claudia Tonelli, Keely Y Ji, Omar W Younis, Tim D D Somervile, Melissa Yao, Joseph P Milazzo, Herve Tiriac, Anna M Kolarzyk, Esak Lee, Jean L Grem, Audrey J Lazenby, James A Grunkemeyer, Michael A Hollingsworth, Paul M Grandgenett, Alexander D Borowsky, Youngkyu Park, Christopher R Vakoc, David A Tuveson, Chang-Il Hwang.
      Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.
    Keywords:  ERK signaling; Engrailed-1; apoptosis; cancer progression; cancer therapeutics; developmental transcription factor; epigenetic reprogramming; metastasis; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/advs.202308537
  15. Cell Metab. 2023 Dec 08. pii: S1550-4131(23)00421-7. [Epub ahead of print]
    ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.
    Charandeep Singh, Byungchang Jin, Nirajan Shrestha, Andrew L Markhard, Apekshya Panda, Sarah E Calvo, Amy Deik, Xingxiu Pan, Austin L Zuckerman, Amel Ben Saad, Kathleen E Corey, Julia Sjoquist, Stephanie Osganian, Roya AminiTabrizi, Eugene P Rhee, Hardik Shah, Olga Goldberger, Alan C Mullen, Valentin Cracan, Clary B Clish, Vamsi K Mootha, Russell P Goodman.
      Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
    Keywords:  ChREBP; FGF21; GCK; GCKR; MLIXPL; NAD(+); NADH; fatty liver disease; gastric bypass surgery; metabolism; reductive stress; trigylcerides
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.010
  16. bioRxiv. 2023 Dec 04. pii: 2023.12.01.569633. [Epub ahead of print]
    Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.
    Ashley L Kiemen, Pei-Hsun Wu, Alicia M Braxton, Toby C Cornish, Ralph H Hruban, Laura Wood, Denis Wirtz, David Zwicker.
      Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence reveals that pancreatic intraepithelial neoplasms (PanINs), the microscopic precursor lesions in the pancreatic ducts that can give rise to invasive pancreatic cancer, are significantly larger and more prevalent than previously believed. Better understanding of the growth law dynamics of PanINs may improve our ability to understand how a miniscule fraction of these lesions makes the transition to invasive cancer. Here, using artificial intelligence (AI)-based three-dimensional (3D) tissue mapping method, we measured the volumes of >1,000 PanIN and found that lesion size is distributed according to a power law with a fitted exponent of -1.7 over > 3 orders of magnitude. Our data also suggest that PanIN growth is not very sensitive to the pancreatic microenvironment or an individual's age, family history, and lifestyle, and is rather shaped by general growth behavior. We analyze several models of PanIN growth and fit the predicted size distributions to the observed data. The best fitting models suggest that both intraductal spread of PanIN lesions and fusing of multiple lesions into large, highly branched structures drive PanIN growth patterns. This work lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, genomic, and transcriptomic features to understand pancreas tumorigenesis, and demonstrates the utility of combining experimental measurement of human tissues with dynamic modeling for understanding cancer tumorigenesis.
    DOI:  https://doi.org/10.1101/2023.12.01.569633
  17. J Cachexia Sarcopenia Muscle. 2023 Dec 19.
    Validity of the diagnostic criteria from the Asian Working Group for Cachexia in advanced cancer.
    Tatsuma Sakaguchi, Keisuke Maeda, Tomoko Takeuchi, Ai Mizuno, Ryoko Kato, Yuria Ishida, Junko Ueshima, Akio Shimizu, Koji Amano, Naoharu Mori.
       BACKGROUND: Recently, the Asian Working Group for Cachexia (AWGC) published a consensus statement on diagnostic criteria for cachexia in Asians. We aimed to validate the criteria in adult patients in Japan with advanced cancer.
    METHODS: We conducted a single-institution retrospective cohort study between April 2021 and October 2022. The AWGC criteria include chronic comorbidities and either a weight loss of >2% over 3-6 months or a body mass index (BMI) of <21 kg/m2 . In addition, any of the following items were required: anorexia as a subjective symptom, decreased grip strength as an objective measurement and an elevated C-reactive protein (CRP) level as a biomarker. We used the cut-off value of grip strength of 28/18 kg for male/female individuals and CRP level of 5 mg/L.
    RESULTS: Of the 449 consecutive patients, 85 of those who could not be evaluated because of end-of-life or refractory symptoms (n = 41) or missing data (n = 44) were excluded from the primary analysis. The prevalence of the AWGC-defined cachexia was 76% (n = 277), and the median survival time (MST) for all patients was 215 (95% confidence interval [CI] 145-270) days. The prevalence of the following criteria was significantly higher in patients with cachexia than in those without cachexia: a BMI of <21 kg/m2 (65% vs. 15%, P < 0.001), a weight loss of >2% in 6 months (87% vs. 14%, P < 0.001), anorexia (75% vs. 47%, P < 0.001), a grip strength of <28 kg in male individuals (63% vs. 28%, P < 0.001) and CRP level of >5 mg/L (85% vs. 56%, P < 0.001). Overall survival was significantly shorter in patients with cachexia than in those without cachexia (MST 157 days, 95% CI 108-226 days vs. MST 423 days, 95% CI 245 days to not available, P = 0.0023). The Cox proportional hazards analysis showed that best supportive care (hazard ratio [HR] 2.91, P ≤ 0.001), lung cancer (HR 1.67, P = 0.0046), an Eastern Cooperative Oncology Group Performance Status score of ≥3 (HR 1.58, P = 0.016), AWGC-defined cachexia (HR 1.56, P = 0.015), an age of ≥70 years (HR 1.53, P = 0.0070), oedema (HR 1.31, P = 0.022) and head/neck cancer (HR 0.44, P = 0.023) were found to be the significant predictors for mortality.
    CONCLUSIONS: We demonstrated that AWGC-defined cachexia has a significant prognostic value in advanced cancer.
    Keywords:  The Asian Working Group for Cachexia; cancer cachexia; diagnostic criteria; prognosis
    DOI:  https://doi.org/10.1002/jcsm.13408
  18. J Hematol Oncol. 2023 Dec 18. 16(1): 123
    Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer.
    Le-Wei Zheng, Cui-Cui Liu, Ke-Da Yu.
      Liquid-liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches.
    Keywords:  Biomolecular condensate; Cancer; Liquid–liquid phase separation; Membrane-less organelle; Novel therapeutics
    DOI:  https://doi.org/10.1186/s13045-023-01522-5
  19. Trends Cancer. 2023 Dec 21. pii: S2405-8033(23)00237-6. [Epub ahead of print]
    Nonepithelial cancer dissemination: specificities and challenges.
    Serena Diazzi, Julien Ablain.
      Epithelial cancers have served as a paradigm to study tumor dissemination but recent data have highlighted significant differences with nonepithelial cancers. Here, we review the current knowledge on nonepithelial tumor dissemination, drawing examples from the latest developments in melanoma, glioma, and sarcoma research. We underscore the importance of the reactivation of developmental processes during cancer progression and describe the nongenetic mechanisms driving nonepithelial tumor spread. We also outline therapeutic opportunities and ongoing clinical approaches to fight disseminating cancers. Finally, we discuss remaining challenges and emerging questions in the field. Defining the core principles underlying nonepithelial cancer dissemination may uncover actionable vulnerabilities of metastatic tumors and help improve the prognosis of patients with cancer.
    Keywords:  development; nonepithelial cancer; plasticity; therapy; tumor dissemination; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.006
  20. Proc IEEE Int Conf Clust Comput. 2022 Sep;2022 230-242
    High Performance Adaptive Physics Refinement to Enable Large-Scale Tracking of Cancer Cell Trajectory.
    Daniel F Puleri, Sayan Roychowdhury, Peter Balogh, John Gounley, Erik W Draeger, Jeff Ames, Adebayo Adebiyi, Simbarashe Chidyagwai, Benjamín Hernández, Seyong Lee, Shirley V Moore, Jeffrey S Vetter, Amanda Randles.
      The ability to track simulated cancer cells through the circulatory system, important for developing a mechanistic understanding of metastatic spread, pushes the limits of today's supercomputers by requiring the simulation of large fluid volumes at cellular-scale resolution. To overcome this challenge, we introduce a new adaptive physics refinement (APR) method that captures cellular-scale interaction across large domains and leverages a hybrid CPU-GPU approach to maximize performance. Through algorithmic advances that integrate multi-physics and multi-resolution models, we establish a finely resolved window with explicitly modeled cells coupled to a coarsely resolved bulk fluid domain. In this work we present multiple validations of the APR framework by comparing against fully resolved fluid-structure interaction methods and employ techniques, such as latency hiding and maximizing memory bandwidth, to effectively utilize heterogeneous node architectures. Collectively, these computational developments and performance optimizations provide a robust and scalable framework to enable system-level simulations of cancer cell transport.
    Keywords:  cancer metastasis; deformable cells; heterogeneous architectures; immersed boundary; multiphysics
    DOI:  https://doi.org/10.1109/cluster51413.2022.00036
  21. Curr Biol. 2023 Dec 18. pii: S0960-9822(23)01489-6. [Epub ahead of print]33(24): R1289-R1291
    Nutrient signaling: Starvation flips a phosphoinositide switch on lysosomal catabolism.
    Michal J Nagiec, John Blenis.
      Lysosomes are highly dynamic organelles that rapidly respond to changes in cellular nutrient status. A new study identifies a phosphoinositide switch that dictates lysosome function during nutrient starvation.
    DOI:  https://doi.org/10.1016/j.cub.2023.10.066
  22. Nanoscale. 2023 Dec 22.
    In vivo senescence imaging nanoprobe targets the associated reactive oxygen species.
    Seung Koo Lee, Myung Shin Han, Ching-Hsuan Tung.
      Cellular senescence, a cell-cycle arrest state upon stress or damage, can adversely impact aging and cancers. We have designed a novel near infrared fluorogenic nanoprobe, named D3, which can only be turned on by highly elevated levels of reactive oxygen species (ROS), critical players for the induction and maintenance of senescence, for real-time senescence sensing and imaging. In contrast to glowing senescent cells, non-senescent cells whose ROS levels are too low to activate the D3 signal remain optically silent. Upon systemic injection into senescent tumor-bearing mice, the D3 nanoprobe quickly accumulates in tumors, and its fluorescence signal is turned on specifically by senescence-associated ROS in the senescent tumors. The fluorescence signal at senescent tumors was 3-fold higher than that of non-senescent tumors. This groundbreaking design introduces a novel activation mechanism and a powerful imaging nanoprobe to identify and assess cellular senescence in living organisms.
    DOI:  https://doi.org/10.1039/d3nr04083f
  23. Nat Commun. 2023 Dec 18. 14(1): 8405
    Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing.
    Jack Holcombe, Helen Weavers.
      Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.
    DOI:  https://doi.org/10.1038/s41467-023-44098-x
  24. Cancers (Basel). 2023 Dec 18. pii: 5881. [Epub ahead of print]15(24):
    Therapy of Locally Advanced and Oligometastatic Pancreatic Adenocarcinoma.
    Isabell Luisa Wahler, Alexander Damanakis, Nils Große Hokamp, Christiane Bruns, Thomas Schmidt.
      Pancreatic adenocarcinoma is a lethal disease, and surgical resection remains the only curative treatment option. Unfortunately, upon primary diagnosis, only 15-20% of all patients with pancreatic ductal adenocarcinoma (PDAC) have localized disease that is eligible for operation. The remainder of patients either have borderline resectable or locally advanced disease or present with distant metastasis. In this review, we present a comprehensive overview regarding the current strategies and future directions in the multimodal therapy of locally advanced and oligometastasized pancreatic adenocarcinoma and discuss the benefit of surgery following neoadjuvant therapy in these patients.
    Keywords:  neoadjuvant chemotherapy; oligometastasis; pancreatic adenocarcinoma
    DOI:  https://doi.org/10.3390/cancers15245881
  25. PNAS Nexus. 2023 Dec;2(12): pgad420
    Regulation of lipolysis by 14-3-3 proteins on human adipocyte lipid droplets.
    Qin Yang, Zinger Yang Loureiro, Anand Desai, Tiffany DeSouza, Kaida Li, Hui Wang, Sarah M Nicoloro, Javier Solivan-Rivera, Silvia Corvera.
      Adipocyte lipid droplets (LDs) play a crucial role in systemic lipid metabolism by storing and releasing lipids to meet the organism's energy needs. Hormonal signals such as catecholamines and insulin act on adipocyte LDs, and impaired responsiveness to these signals can lead to uncontrolled lipolysis, lipotoxicity, and metabolic disease. To investigate the mechanisms that control LD function in human adipocytes, we applied proximity labeling mediated by enhanced ascorbate peroxidase (APEX2) to identify the interactome of PLIN1 in adipocytes differentiated from human mesenchymal progenitor cells. We identified 70 proteins that interact specifically with PLIN1, including PNPLA2 and LIPE, which are the primary effectors of regulated triglyceride hydrolysis, and 4 members of the 14-3-3 protein family (YWHAB, YWHAE, YWHAZ, and YWHAG), which are known to regulate diverse signaling pathways. Functional studies showed that YWHAB is required for maximum cyclic adenosine monophosphate (cAMP)-stimulated lipolysis, as its CRISPR-Cas9-mediated knockout mitigates lipolysis through a mechanism independent of insulin signaling. These findings reveal a new regulatory mechanism operating in human adipocytes that can impact lipolysis and potentially systemic metabolism.
    Keywords:  14-3-3 proteins; insulin; lipid droplet; lipolysis; proximity labeling
    DOI:  https://doi.org/10.1093/pnasnexus/pgad420
  26. Diabetes. 2024 Jan 01. 73(1): 11-22
    Bridging the Gap: Pancreas Tissue Slices From Organ and Tissue Donors for the Study of Diabetes Pathogenesis.
    Christian M Cohrs, Chunguang Chen, Mark A Atkinson, Denise M Drotar, Stephan Speier.
      Over the last two decades, increased availability of human pancreatic tissues has allowed for major expansions in our understanding of islet biology in health and disease. Indeed, studies of fixed and frozen pancreatic tissues, as well as efforts using viable isolated islets obtained from organ donors, have provided significant insights toward our understanding of diabetes. However, the procedures associated with islet isolation result in distressed cells that have been removed from any surrounding influence. The pancreas tissue slice technology was developed as an in situ approach to overcome certain limitations associated with studies on isolated islets or fixed tissue. In this Perspective, we discuss the value of this novel platform and review how pancreas tissue slices, within a short time, have been integrated in numerous studies of rodent and human islet research. We show that pancreas tissue slices allow for investigations in a less perturbed organ tissue environment, ranging from cellular processes, over peri-islet modulations, to tissue interactions. Finally, we discuss the considerations and limitations of this technology in its future applications. We believe the pancreas tissue slices will help bridge the gap between studies on isolated islets and cells to the systemic conditions by providing new insight into physiological and pathophysiological processes at the organ level.
    ARTICLE HIGHLIGHTS: Human pancreas tissue slices represent a novel platform to study human islet biology in close to physiological conditions. Complementary to established technologies, such as isolated islets, single cells, and histological sections, pancreas tissue slices help bridge our understanding of islet physiology and pathophysiology from single cell to intact organ. Diverse sources of viable human pancreas tissue, each with distinct characteristics to be considered, are available to use in tissue slices for the study of diabetes pathogenesis.
    DOI:  https://doi.org/10.2337/dbi20-0018
  27. HPB (Oxford). 2023 Nov 25. pii: S1365-182X(23)01999-8. [Epub ahead of print]
    Qualitative flow metabolic phenotype of pancreatic cancer. A new prognostic biomarker?
    Deniece Riviere, Erik Aarntzen, Erwin van Geenen, David Chang, Lioe-Fee de Geus-Oei, Lodewijk Brosens, Kees van Laarhoven, Martin Gotthardt, John Hermans.
       BACKGROUND: Retrospective analysis to investigate the relationship between the flow-metabolic phenotype and overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) and its potential clinical utility.
    METHODS: Patients with histopathologically proven PDAC between 2005 and 2014 using tumor attenuation on routine pre-operative CECT as a surrogate for the vascularity and [18F]FDG-uptake as a surrogate for metabolic activity on [18F]FDG-PET.
    RESULTS: In total, 93 patients (50 male, 43 female, median age 63) were included. Hypoattenuating PDAC with high [18F]FDG-uptake has the poorest prognosis (median OS 7 ± 1 months), compared to hypoattenuating PDAC with low [18F]FDG-uptake (median OS 11 ± 3 months; p = 0.176), iso- or hyperattenuating PDAC with high [18F]FDG-uptake (median OS 15 ± 5 months; p = 0.004) and iso- or hyperattenuating PDAC with low [18F]FDG-uptake (median OS 23 ± 4 months; p = 0.035). In multivariate analysis, surgery combined with tumor differentiation, tumor stage, systemic therapy and flow metabolic phenotype remained independent predictors for overall survival.
    DISCUSSION: The novel qualitative flow-metabolic phenotype of PDAC using a combination of CECT and [18F]FDG-PET features, predicted significantly worse survival for hypoattenuating-high uptake pancreatic cancers compared to the other phenotypes.
    DOI:  https://doi.org/10.1016/j.hpb.2023.11.010
  28. bioRxiv. 2023 Dec 05. pii: 2023.12.05.569858. [Epub ahead of print]
    Distinct secretomes in p16- and p21- positive senescent cells across tissues.
    Dominik Saul, Diana Jurk, Madison L Doolittle, Robyn Laura Kosinsky, David G Monroe, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Sundeep Khosla, João F Passos.
      Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21 Cip1 and p16 Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing (scRNA-seq) datasets spanning both murine and human tissues during aging. Our analysis revealed that p21 Cip1 and p16 Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21 Cip1 or p16 Ink4a expression. Our study underscores the extraordinary diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent. However, a few SASP factors consistently contribute to a shared "core" SASP. These findings highlight the need for a more nuanced investigation of senescence across a wide array of biological contexts.
    DOI:  https://doi.org/10.1101/2023.12.05.569858
  29. Cancer Med. 2023 Dec 22.
    Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy.
    Saryleine de Ortiz de Choudens, Alexis Visotcky, Anjishnu Banerjee, Mohammed Aldakkak, Susan Tsai, Douglas B Evans, Kathleen K Christians, Callisia N Clarke, Ben George, Aditya Shreenivas, Mandana Kamgar, Sakti Chakrabarti, Kulwinder S Dua, Abdul Haq Khan, Srivats Madhavan, Beth A Erickson, William A Hall.
       PURPOSE/OBJECTIVES: Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC.
    MATERIALS/METHODS: Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients.
    RESULTS: 121 patients were included with a median age of 62 years (37-86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving <18 months and ≥18 months regarding the presence of lung only metastases (36% vs. 16%, p = 0.04), number of organs with metastases (≥2 vs. 1, p = 0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p = 0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p = 0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19-9 (p < 0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p = 0.03). In those patients that normalized their CA 19-9, median overall survival was 16 months.
    CONCLUSIONS: In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions.
    Keywords:  neoplasm metastasis; oligometastasis; pancreatic neoplasms
    DOI:  https://doi.org/10.1002/cam4.6582
  30. bioRxiv. 2023 Dec 08. pii: 2023.12.07.570588. [Epub ahead of print]
    GeneMAP: A discovery platform for metabolic gene function.
    Artem Khan, Gokhan Unlu, Phillip Lin, Yuyang Liu, Ece Kilic, Timothy C Kenny, Kıvanç Birsoy, Eric R Gamazon.
      Organisms maintain metabolic homeostasis through the combined functions of small molecule transporters and enzymes. While many of the metabolic components have been well-established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Associations Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions, even pinpointing genes that are distant from the variants implicated by GWAS. In particular, our work identified SLC25A48 as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite, betaine. Rare variant testing and polygenic risk score analyses have elucidated choline-relevant phenomic consequences of SLC25A48 dysfunction. Altogether, our study proposes SLC25A48 as a mitochondrial choline transporter and provides a discovery platform for metabolic gene function.
    DOI:  https://doi.org/10.1101/2023.12.07.570588
  31. Cell Rep. 2023 Dec 15. pii: S2211-1247(23)01579-6. [Epub ahead of print] 113567
    Atg15 is a vacuolar phospholipase that disintegrates organelle membranes.
    Yasunori Watanabe, Yurina Iwasaki, Kyoka Sasaki, Chie Motono, Kenichiro Imai, Kuninori Suzuki.
      Atg15 (autophagy-related 15) is a vacuolar phospholipase essential for the degradation of cytoplasm-to-vacuole targeting (Cvt) bodies and autophagic bodies, hereinafter referred to as intravacuolar/intralysosomal autophagic compartments (IACs), but it remains unknown if Atg15 directly disrupts IAC membranes. Here, we show that the recombinant Chaetomium thermophilum Atg15 lipase domain (CtAtg15(73-475)) possesses phospholipase activity. The activity of CtAtg15(73-475) was markedly elevated by limited digestion. We inserted the human rhinovirus 3C protease recognition sequence and found that cleavage between S159 and V160 was important to activate CtAtg15(73-475). Our molecular dynamics simulation suggested that the cleavage facilitated conformational change around the active center of CtAtg15, resulting in an exposed state. We confirmed that CtAtg15 could disintegrate S. cerevisiae IAC in vivo. Further, both mitochondria and IAC of S. cerevisiae were disintegrated by CtAtg15. This study suggests Atg15 plays a role in disrupting any organelle membranes delivered to vacuoles by autophagy.
    Keywords:  CP: Cell biology; autophagosome; autophagy; autophagy-related 15; cytoplasm-to-vacuole targeting; molecular dynamics simulation; organelle membrane; phospholipase; phospholipid; vacuole; yeast
    DOI:  https://doi.org/10.1016/j.celrep.2023.113567
  32. Surg Oncol. 2023 Dec 11. pii: S0960-7404(23)00127-5. [Epub ahead of print]52 102027
    The involvement of the hepatic artery is a risk factor for unresectability after neoadjuvant treatment in borderline pancreatic adenocarcinoma.
    Luis Secanella, Juli Busquets, Núria Peláez, María Sorribas, Berta Laquente, Sandra Ruiz-Osuna, Juan Fabregat.
       INTRODUCTION: Borderline Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) benefits from neoadjuvant treatment (NAT) with the intent of surgical salvage in the absence of disease progression during chemotherapy (CT) or chemoradiotherapy (CRT). Scarce literature exists about prognostic factors of resectability at the time of diagnosis or during neoadjuvant treatment, especially regarding vascular relationships.
    MATERIALS: We reviewed our prospective BR-PDAC cohort to determine resectability predictors. We collected data about clinical baseline characteristics, vessels' involvement, type of NAT, CA19-9 evolution, and radiological outcome. We performed a descriptive analysis and a logistic regression model to define resectability predictors; we finally compared overall survival (OS) and progression-free survival (PFS) for those predictors.
    RESULTS: One hundred patients started NAT, with a resection rate of 44 % (40 pancreaticoduodenectomies, 4 distal pancreatectomies). The most frequent vessel relationship was the abutment of the superior mesenteric artery (44 %), and 26 patients had ≥2 vessels involved. Prognostic factors of resectability were CA19-9 response >10 % (OR 3.07, p = 0.016) and Hepatic Artery involvement (OR 0.21, p = 0.026). Median overall survival was better for CA19-9 responders than for non-responders (20.9 months and 11.8 months respectively, p < 0.001), and similar to normalized CA19-9 (25.0 months, p = 0.48). There were no differences in terms of OS or PFS with the involvement of the HA (17.7 vs 17.1 months, p = 0.367; and 8.7 vs 12.0 months, p = 0.267).
    CONCLUSION: The involvement of the Hepatic Artery seems to confer a worse prognosis regarding resectability. A decrease of only >10 % of CA19-9 is a predictive factor for resectability and better overall and progression-free survival.
    Keywords:  Borderline pancreatic cancer; Ca19-9 antigen; Surgical oncology; Vascular involvement
    DOI:  https://doi.org/10.1016/j.suronc.2023.102027
  33. Cancer Cell. 2023 Dec 18. pii: S1535-6108(23)00402-6. [Epub ahead of print]
    Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.
    Sabina Kaczanowska, Tara Murty, Ahmad Alimadadi, Cristina F Contreras, Caroline Duault, Priyanka B Subrahmanyam, Warren Reynolds, Norma A Gutierrez, Reema Baskar, Catherine J Wu, Franziska Michor, Jennifer Altreuter, Yang Liu, Aashna Jhaveri, Vandon Duong, Hima Anbunathan, Claire Ong, Hua Zhang, Radim Moravec, Joyce Yu, Roshni Biswas, Stephen Van Nostrand, James Lindsay, Mina Pichavant, Elena Sotillo, Donna Bernstein, Amanda Carbonell, Joanne Derdak, Jacquelyn Klicka-Skeels, Julia E Segal, Eva Dombi, Stephanie A Harmon, Baris Turkbey, Bita Sahaf, Sean Bendall, Holden Maecker, Steven L Highfill, David Stroncek, John Glod, Melinda Merchant, Catherine C Hedrick, Crystal L Mackall, Sneha Ramakrishna, Rosandra N Kaplan.
      Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.
    Keywords:  CAR-T cells; cancer; chimeric antigen receptor; correlative studies; immune suppression; immunotherapy; monocytes; myeloid cells; osteosarcoma; pediatric oncology; solid tumor
    DOI:  https://doi.org/10.1016/j.ccell.2023.11.011
  34. Nat Aging. 2023 Dec;3(12): 1486-1499
    The Information Theory of Aging.
    Yuancheng Ryan Lu, Xiao Tian, David A Sinclair.
      Information storage and retrieval is essential for all life. In biology, information is primarily stored in two distinct ways: the genome, comprising nucleic acids, acts as a foundational blueprint and the epigenome, consisting of chemical modifications to DNA and histone proteins, regulates gene expression patterns and endows cells with specific identities and functions. Unlike the stable, digital nature of genetic information, epigenetic information is stored in a digital-analog format, susceptible to alterations induced by diverse environmental signals and cellular damage. The Information Theory of Aging (ITOA) states that the aging process is driven by the progressive loss of youthful epigenetic information, the retrieval of which via epigenetic reprogramming can improve the function of damaged and aged tissues by catalyzing age reversal.
    DOI:  https://doi.org/10.1038/s43587-023-00527-6
  35. Dev Cell. 2023 Dec 08. pii: S1534-5807(23)00621-4. [Epub ahead of print]
    Autophagy supports PDGFRA-dependent brain tumor development by enhancing oncogenic signaling.
    Joanne E Simpson, Morwenna T Muir, Martin Lee, Catherine Naughton, Nick Gilbert, Steven M Pollard, Noor Gammoh.
      Autophagy is a conserved cellular degradation process. While autophagy-related proteins were shown to influence the signaling and trafficking of some receptor tyrosine kinases, the relevance of this during cancer development is unclear. Here, we identify a role for autophagy in regulating platelet-derived growth factor receptor alpha (PDGFRA) signaling and levels. We find that PDGFRA can be targeted for autophagic degradation through the activity of the autophagy cargo receptor p62. As a result, short-term autophagy inhibition leads to elevated levels of PDGFRA but an unexpected defect in PDGFA-mediated signaling due to perturbed receptor trafficking. Defective PDGFRA signaling led to its reduced levels during prolonged autophagy inhibition, suggesting a mechanism of adaptation. Importantly, PDGFA-driven gliomagenesis in mice was disrupted when autophagy was inhibited in a manner dependent on Pten status, thus highlighting a genotype-specific role for autophagy during tumorigenesis. In summary, our data provide a mechanism by which cells require autophagy to drive tumor formation.
    Keywords:  PDGFRA; PTEN; RTK; autophagy; cancer; endocytosis; glioblastoma; signaling
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.023
  36. HPB (Oxford). 2023 Dec 10. pii: S1365-182X(23)02008-7. [Epub ahead of print]
    Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection.
    Zhi V Fong, George Severs, John Moir, Steve White, Motaz Qadan, Samuel Tingle.
       BACKGROUND: Repurposing existing drugs for use in oncology is more efficient, cost-effective and safe than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance. This study assessed the impact of calcium channel blockers (CCB) in pancreatic cancer.
    METHODS: Retrospective population study of patients undergoing resection (curative intent) of pancreatic ductal adenocarcinoma (SEER-Medicare, 2007-2017). Cox models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, the impact of CCB was assessed separately in patients receiving neoadjuvant chemotherapy.
    RESULTS: 6,223 patients were included, of whom 660 were prescribed CCB. In total, 591 received neoadjuvant chemotherapy; in this cohort CCB prescription was associated with improved overall survival when adjusting for multiple prognostic factors (aHR = 0.715, 0.514-0.996, P = 0.047). This effect was not observed in patients not receiving neoadjuvant chemotherapy (aHR = 1.082, 0.982-1.191, P = 0.112).
    CONCLUSION: CCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy, mirroring the chemosensitising effect in laboratory studies. This defines patients receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.
    DOI:  https://doi.org/10.1016/j.hpb.2023.12.001
  37. Phys Rev E. 2023 Nov;108(5-1): 054406
    Collective effects in flow-driven cell migration.
    Louis González, Andrew Mugler.
      Autologous chemotaxis is the process in which cells secrete and detect molecules to determine the direction of fluid flow. Experiments and theory suggest that autologous chemotaxis fails at high cell densities because molecules from other cells interfere with a given cell's signal. We investigate autologous chemotaxis using a three-dimensional Monte Carlo-based motility simulation that couples spatial and temporal gradient sensing with cell-cell repulsion. Surprisingly, we find that when temporal gradient sensing dominates, high-density clusters chemotax faster than individual cells. To explain this observation, we propose a mechanism by which temporal gradient sensing allows cells to form a collective sensory unit. We demonstrate using computational fluid mechanics that that this mechanism indeed allows a cluster of cells to outperform single cells in terms of the detected anisotropy of the signal, a finding that we demonstrate with analytic scaling arguments. Our work suggests that collective autologous chemotaxis at high cell densities is possible and requires only known, ubiquitous cell capabilities.
    DOI:  https://doi.org/10.1103/PhysRevE.108.054406
  38. FEBS Lett. 2023 Dec 15.
    The autophagy of stress granules.
    Laura Ryan, David C Rubinsztein.
      Our understanding of stress granule (SG) biology has deepened considerably in recent years, and with this, increased understanding of links has been made between SGs and numerous neurodegenerative diseases. One of the proposed mechanisms by which SGs and any associated protein aggregates may become pathological is based upon defects in their autophagic clearance, and so the precise processes governing the degradation of SGs are important to understand. Mutations and disease-associated variants implicated in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and frontotemporal lobar dementia compromise autophagy, whilst autophagy-inhibiting drugs or knockdown of essential autophagy proteins result in the persistence of SGs. In this review, we will consider the current knowledge regarding the autophagy of SG.
    Keywords:  P62; amyotrophic lateral sclerosis; autophagy; granulophagy; neurodegeneration; proteostasis; stress granules; valosin-containing protein
    DOI:  https://doi.org/10.1002/1873-3468.14787
  39. Cell Rep Med. 2023 Dec 19. pii: S2666-3791(23)00543-8. [Epub ahead of print]4(12): 101326
    PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition.
    Yang Li, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Travis D Kerr, Deepa Bisht, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L Mendillo, Yiling Lu, Collene R Jeter, Guang Peng, Jinsong Liu, Shannon N Westin, Anil K Sood, Michael T Lewis, Jishnu Das, S Stephen Yi, Mark T Bedford, Daniel J McGrail, Nidhi Sahni.
      Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.
    Keywords:  DNA replication stress; PARP inhibitors; PRMT inhibitors; arginine methylation; breast cancer; ovarian cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101326
  40. Cells Dev. 2023 Dec 14. pii: S2667-2901(23)00074-8. [Epub ahead of print]177 203898
    Microtubule-dependent apical polarization of basement membrane matrix mRNAs in mouse epithelial cells.
    Shaohe Wang, Kazue Matsumoto, Madison M Mehlferber, Guofeng Zhang, Maria A Aronova, Kenneth M Yamada.
      The basement membrane (BM) demarcating epithelial tissues undergoes rapid expansion to accommodate tissue growth and morphogenesis during embryonic development. To facilitate the secretion of bulky BM proteins, their mRNAs are polarized basally in the follicle epithelial cells of the Drosophila egg chamber to position their sites of production close to their deposition. In contrast, we observed the apical rather than basal polarization of all major BM mRNAs in the outer epithelial cells adjacent to the BM of mouse embryonic salivary glands using single-molecule RNA fluorescence in situ hybridization (smFISH). Moreover, electron microscopy and immunofluorescence revealed apical polarization of both the endoplasmic reticulum (ER) and Golgi apparatus, indicating that the site of BM component production was opposite to the site of deposition. At the apical side, BM mRNAs colocalized with ER, suggesting they may be co-translationally tethered. After microtubule inhibition, the BM mRNAs and ER became uniformly distributed rather than apically polarized, but they remained unchanged after inhibiting myosin II, ROCK, or F-actin, or after enzymatic disruption of the BM. Because Rab6 is generally required for Golgi-to-plasma membrane trafficking of BM components, we used lentivirus to express an mScarlet-tagged Rab6a in salivary gland epithelial cultures to visualize vesicle trafficking dynamics. We observed extensive bidirectional vesicle movements between Golgi at the apical side and the basal plasma membrane adjacent to the BM. Moreover, we showed that these vesicle movements depend on the microtubule motor kinesin-1 because very few vesicles remained motile after treatment with kinesore to compete for cargo-binding sites on kinesin-1. Overall, our work highlights the diverse strategies that different organisms use to secrete bulky matrix proteins: while Drosophila follicle epithelial cells strategically place their sites of BM protein production close to their deposition, mouse embryonic epithelial cells place their sites of production at the opposite end. Instead of spatial proximity, they use the microtubule cytoskeleton to mediate this organization as well as for the apical-to-basal transport of BM proteins.
    Keywords:  Apical polarization; Basement membrane; Collagen IV; Kinesin; Microtubule
    DOI:  https://doi.org/10.1016/j.cdev.2023.203898
  41. Nature. 2024 Jan;625(7993): 35-36
    Muscle immune cells protect mitochondrial organelles during exercise.
    Gerald Coulis, S Armando Villalta.
      
    Keywords:  Cell biology; Immunology; Physiology
    DOI:  https://doi.org/10.1038/d41586-023-03972-w
  42. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00445-X. [Epub ahead of print]
    Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
    Aida Rashidi, Leah K Billingham, Andrew Zolp, Tzu-Yi Chia, Caylee Silvers, Joshua L Katz, Cheol H Park, Suzi Delay, Lauren Boland, Yuheng Geng, Steven M Markwell, Crismita Dmello, Victor A Arrieta, Kaylee Zilinger, Irene M Jacob, Aurora Lopez-Rosas, David Hou, Brandyn Castro, Alicia M Steffens, Kathleen McCortney, Jordain P Walshon, Mariah S Flowers, Hanchen Lin, Hanxiang Wang, Junfei Zhao, Adam Sonabend, Peng Zhang, Atique U Ahmed, Daniel J Brat, Dieter H Heiland, Catalina Lee-Chang, Maciej S Lesniak, Navdeep S Chandel, Jason Miska.
      Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
    Keywords:  creatine metabolism; glioblastoma; myeloid cells; pseudopalisading necrosis
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.013
  43. Mol Cell Oncol. 2023 ;10(1): 2014734
    APOBEC3 as a driver of genetic intratumor heterogeneity.
    Subramanian Venkatesan, Mihaela Angelova, Jirina Bartkova, Samuel F Bakhoum, Jiri Bartek, Nnennaya Kanu, Charles Swanton.
      Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution.
    Keywords:  APOBEC; breast cancer; chromosomal instability; intratumor heterogeneity; non-small cell lung cancer
    DOI:  https://doi.org/10.1080/23723556.2021.2014734
  44. Protein Eng Des Sel. 2023 Dec 15. pii: gzad023. [Epub ahead of print]
    Growing ecosystem of deep learning methods for modeling protein-protein interactions.
    Julia R Rogers, Gergö Nikolényi, Mohammed AlQuraishi.
      Numerous cellular functions rely on protein-protein interactions. Efforts to comprehensively characterize them remain challenged however by the diversity of molecular recognition mechanisms employed within the proteome. Deep learning has emerged as a promising approach for tackling this problem by exploiting both experimental data and basic biophysical knowledge about protein interactions. Here, we review the growing ecosystem of deep learning methods for modeling protein interactions, highlighting the diversity of these biophysically-informed models and their respective trade-offs. We discuss recent successes in using representation learning to capture complex features pertinent to predicting protein interactions and interaction sites, geometric deep learning to reason over protein structures and predict complex structures, and generative modeling to design de novo protein assemblies. We also outline some of the outstanding challenges and promising new directions. Opportunities abound to discover novel interactions, elucidate their physical mechanisms, and engineer binders to modulate their functions using deep learning and, ultimately, unravel how protein interactions orchestrate complex cellular behaviors.
    Keywords:  binder design; deep learning; protein complex structure prediction; protein–protein interactions; representation learning
    DOI:  https://doi.org/10.1093/protein/gzad023
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