bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023‒04‒23
34 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.
  2. Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.
  3. Impact of context-dependent autophagy states on tumor progression.
  4. Learning the metabolic language of cancer.
  5. NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.
  6. An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.
  7. Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis.
  8. Goblet cell stress management.
  9. Rapid cancer cell perineural invasion utilizes amoeboid migration.
  10. Genomic mapping of metastatic organotropism in lung adenocarcinoma.
  11. Monitoring and assessment of lysosomal membrane damage in cultured cells using the high-content imager.
  12. Size distributions of intracellular condensates reflect competition between coalescence and nucleation.
  13. Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.
  14. Targeting IL-6 trans-signalling: past, present and future prospects.
  15. The proteomic landscape of genome-wide genetic perturbations.
  16. Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.
  17. Standardizing analysis of intra-tumoral heterogeneity with computational pathology.
  18. Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation.
  19. Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program.
  20. Oncogenic CDK13 mutations impede nuclear RNA surveillance.
  21. Mechanical basis and topological routes to cell elimination.
  22. Challenges in Recruitment and Retention: Leveraging Health-Related Antecedents and Information Carrier Factors to Improve Patient Participation in Pancreatic Cancer Research-A Review Article.
  23. Genetic Analysis of the ATG16L1 c.898A>G (p.T300A) Variant in Acute and Chronic Pancreatitis.
  24. ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA.
  25. The diverse nature of intestinal fibroblasts in development, homeostasis, and disease.
  26. Lysosomal lipid peroxidation mediates immunogenic cell death.
  27. Proteomic discovery of chemical probes that perturb protein complexes in human cells.
  28. Ultrastructural Localization of Endogenous LC3 by On-Section Correlative Light-Electron Microscopy.
  29. Targeting autophagy and lipid metabolism in cancer stem cells.
  30. Predictive value of computed tomography on surgical resectability in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: Results from a prospective, multicentre phase 2 trial (NEOLAP-AIO-PAK-0113).
  31. A chronic wound model to investigate skin cellular senescence.
  32. Slow integrin-dependent migration organizes networks of tissue-resident mast cells.
  33. Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer.
  34. Multiparametric detection and outcome prediction of pancreatic cancer involving dual-energy CT, diffusion-weighted MRI, and radiomics.
  1. Nat Commun. 2023 04 17. 14(1): 2194
    Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.
    Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L Rose, Sanjana Srinivasan, Shan Jiang, Q Edward Chang, Ningping Feng, Jason P Gay, Qi Wang, Jing Wang, Philip L Lorenzi, Lucas J Veillon, Bo Wei, John N Weinstein, Angela K Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A Lyssiotis, Joseph R Marszalek, Giulio F Draetta, Haoqiang Ying.
      Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial supercomplex assembly and ROS production; accordingly, blocking de novo ether phospholipid biosynthesis sensitized PDAC cells to complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. These data identify ether phospholipids as a regulator of mitochondrial redox control that contributes to the sensitivity of PDAC cells to complex I inhibition.
    DOI:  https://doi.org/10.1038/s41467-023-37924-9
  2. Sci Adv. 2023 04 21. 9(16): eadf9284
    Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.
    Subhadip Mukhopadhyay, Joel Encarnación-Rosado, Elaine Y Lin, Albert S W Sohn, Huan Zhang, Joseph D Mancias, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis, while other tumor types assessed require macropinocytosis, with autophagy being dispensable. We observed that cancer-associated fibroblasts can provide bioavailable iron to PDAC cells, promoting resistance to autophagy ablation. To overcome this cross-talk, we used a low-iron diet and demonstrated that this augmented the response to autophagy inhibition therapy in PDAC-bearing mice. Our work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression.
    DOI:  https://doi.org/10.1126/sciadv.adf9284
  3. Nat Cancer. 2023 Apr 17.
    Impact of context-dependent autophagy states on tumor progression.
    Mohamad Assi, Alec C Kimmelman.
      Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.
    DOI:  https://doi.org/10.1038/s43018-023-00546-7
  4. Nature. 2023 Apr;616(7958): 670-671
    Learning the metabolic language of cancer.
    Minervo Perez, Jordan L Meier.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-01024-x
  5. Cell Rep. 2023 Apr 20. pii: S2211-1247(23)00383-2. [Epub ahead of print]42(5): 112372
    NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.
    Congxin Sun, Elena Seranova, Malkiel A Cohen, Miruna Chipara, Jennie Roberts, Dewi Astuti, Adina M Palhegyi, Animesh Acharjee, Lucia Sedlackova, Tetsushi Kataura, Elsje G Otten, Prashanta K Panda, Samuel Lara-Reyna, Miriam E Korsgen, Kevin J Kauffman, Alejandro Huerta-Uribe, Malgorzata Zatyka, Luiz F S E Silva, Jorge Torresi, Shupei Zhang, Georgina W Hughes, Carl Ward, Erich R Kuechler, David Cartwright, Sergey Trushin, Eugenia Trushina, Gaurav Sahay, Yosef Buganim, Gareth G Lavery, Joerg Gsponer, Daniel G Anderson, Eva-Maria Frickel, Tatiana R Rosenstock, Timothy Barrett, Oliver D K Maddocks, Daniel A Tennant, Haoyi Wang, Rudolf Jaenisch, Viktor I Korolchuk, Sovan Sarkar.
      Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5-/-) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5-/- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5-/- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5-/- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.
    Keywords:  CP: Cell biology; CP: Metabolism; NAD; NADases; NAM; NMN; NR; autophagy; cell death; cell survival, human embryonic stem cell-derived neurons; mitochondria; nicotinamide; nicotinamide adenine dinucleotide; nicotinamide mononucleotide; nicotinamide riboside
    DOI:  https://doi.org/10.1016/j.celrep.2023.112372
  6. Sci Adv. 2023 04 21. 9(16): eadf8966
    An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.
    Samantha G Scharenberg, Wentao Dong, Ali Ghoochani, Kwamina Nyame, Roni Levin-Konigsberg, Aswini R Krishnan, Eshaan S Rawat, Kaitlyn Spees, Michael C Bassik, Monther Abu-Remaileh.
      Lysosomes degrade macromolecules and recycle their nutrient content to support cell function and survival. However, the machineries involved in lysosomal recycling of many nutrients remain to be discovered, with a notable example being choline, an essential metabolite liberated via lipid degradation. Here, we engineered metabolic dependency on lysosome-derived choline in pancreatic cancer cells to perform an endolysosome-focused CRISPR-Cas9 screen for genes mediating lysosomal choline recycling. We identified the orphan lysosomal transmembrane protein SPNS1 as critical for cell survival under choline limitation. SPNS1 loss leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). Mechanistically, we reveal that SPNS1 is a proton gradient-dependent transporter of LPC species from the lysosome for their re-esterification into phosphatidylcholine in the cytosol. Last, we establish that LPC efflux by SPNS1 is required for cell survival under choline limitation. Collectively, our work defines a lysosomal phospholipid salvage pathway that is essential under nutrient limitation and, more broadly, provides a robust platform to deorphan lysosomal gene function.
    DOI:  https://doi.org/10.1126/sciadv.adf8966
  7. Mol Cell. 2023 Apr 20. pii: S1097-2765(23)00213-7. [Epub ahead of print]83(8): 1340-1349.e7
    Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis.
    Cong-Hui Yao, Joon Seok Park, Kiran Kurmi, Song-Hua Hu, Giulia Notarangelo, Joseph Crowley, Heidi Jacobson, Sheng Hui, Arlene H Sharpe, Marcia C Haigis.
      The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is ∼4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.
    Keywords:  GPD; NAD; glycerol; glycerol-3-phosphate dehydrogenase; glycerol-3-phosphate shuttle; kidney cancer; lipids; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.023
  8. Sci Signal. 2023 Apr 18. 16(781): eadi2176
    Goblet cell stress management.
    Annalisa M VanHook.
      Autophagy augments the mucus-secreting capacity of goblet cells by reducing ER stress.
    DOI:  https://doi.org/10.1126/scisignal.adi2176
  9. Proc Natl Acad Sci U S A. 2023 Apr 25. 120(17): e2210735120
    Rapid cancer cell perineural invasion utilizes amoeboid migration.
    Andrea R Marcadis, Elizabeth Kao, Qi Wang, Chun-Hao Chen, Laxmi Gusain, Ann Powers, Richard L Bakst, Sylvie Deborde, Richard J Wong.
      The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.
    Keywords:  amoeboid; invasion; migration; perineural
    DOI:  https://doi.org/10.1073/pnas.2210735120
  10. Cancer Cell. 2023 Apr 08. pii: S1535-6108(23)00091-0. [Epub ahead of print]
    Genomic mapping of metastatic organotropism in lung adenocarcinoma.
    Harry B Lengel, Brooke Mastrogiacomo, James G Connolly, Kay See Tan, Yuan Liu, Cameron N Fick, Elizabeth G Dunne, Di He, Manendra B Lankadasari, Baby Anusha Satravada, Yichao Sun, Ritika Kundra, Chris Fong, Shaleigh Smith, Gregory J Riely, Charles M Rudin, Daniel R Gomez, David B Solit, Michael F Berger, Bob T Li, Marty W Mayo, Irina Matei, David C Lyden, Prasad S Adusumilli, Nikolaus Schultz, Francisco Sanchez-Vega, David R Jones.
      We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.
    DOI:  https://doi.org/10.1016/j.ccell.2023.03.018
  11. STAR Protoc. 2023 Apr 18. pii: S2666-1667(23)00194-6. [Epub ahead of print]4(2): 102236
    Monitoring and assessment of lysosomal membrane damage in cultured cells using the high-content imager.
    Keisuke Tabata, Marika Saeki, Tamotsu Yoshimori, Maho Hamasaki.
      Autophagy is an intracellular self-degradation process in which part of the cytoplasm, aggregates, or damaged organelles are degraded in lysosomes. Lysophagy is a specific form of selective autophagy responsible for clearing damaged lysosomes. Here, we present a protocol for inducing lysosomal damage in cultured cells and assessing lysosomal damage using a high-content imager and software program. We describe steps for induction of lysosomal damage, image acquisition with spinning disk confocal microscopy, and image analysis using Pathfinder. We then detail data analysis of the clearance of damaged lysosomes. For complete details on the use and execution of this protocol, please refer to Teranishi et al. (2022).1.
    Keywords:  Cell Biology; Cell Culture; High-throughput Screening; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2023.102236
  12. Nat Phys. 2023 ;19(4): 586-596
    Size distributions of intracellular condensates reflect competition between coalescence and nucleation.
    Daniel S W Lee, Chang-Hyun Choi, David W Sanders, Lien Beckers, Joshua A Riback, Clifford P Brangwynne, Ned S Wingreen.
      Phase separation of biomolecules into condensates has emerged as a mechanism for intracellular organization and affects many intracellular processes, including reaction pathways through the clustering of enzymes and pathway intermediates. Precise and rapid spatiotemporal control of reactions by condensates requires tuning of their sizes. However, the physical processes that govern the distribution of condensate sizes remain unclear. Here we show that both native and synthetic condensates display an exponential size distribution, which is captured by Monte Carlo simulations of fast nucleation followed by coalescence. In contrast, pathological aggregates exhibit a power-law size distribution. These distinct behaviours reflect the relative importance of nucleation and coalescence kinetics. We demonstrate this by utilizing a combination of synthetic and native condensates to probe the underlying physical mechanisms determining condensate size. The appearance of exponential distributions for abrupt nucleation versus power-law distributions under continuous nucleation may reflect a general principle that determines condensate size distributions.
    Keywords:  Biophysics; Self-assembly
    DOI:  https://doi.org/10.1038/s41567-022-01917-0
  13. Cell Syst. 2023 Apr 19. pii: S2405-4712(23)00078-9. [Epub ahead of print]14(4): 252-257
    Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.
    Frederick R Adler, Alexander R A Anderson, Abhinav Bhushan, Paul Bogdan, Jose Javier Bravo-Cordero, Amy Brock, Yun Chen, Edna Cukierman, Kathleen E DelGiorno, Gerald V Denis, Meghan C Ferrall-Fairbanks, Zev Jordan Gartner, Ronald N Germain, Deborah M Gordon, Ginger Hunter, Mohit Kumar Jolly, Loukia Georgiou Karacosta, Karthikeyan Mythreye, Parag Katira, Rajan P Kulkarni, Matthew L Kutys, Arthur D Lander, Ashley M Laughney, Herbert Levine, Emil Lou, Pedro R Lowenstein, Kristyn S Masters, Dana Pe'er, Shelly R Peyton, Manu O Platt, Jeremy E Purvis, Gerald Quon, Jennifer K Richer, Nicole C Riddle, Analiz Rodriguez, Joshua C Snyder, Gregory Lee Szeto, Claire J Tomlin, Itai Yanai, Ioannis K Zervantonakis, Hannah Dueck.
      Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.
    DOI:  https://doi.org/10.1016/j.cels.2023.03.002
  14. Nat Rev Immunol. 2023 Apr 17.
    Targeting IL-6 trans-signalling: past, present and future prospects.
    Stefan Rose-John, Brendan J Jenkins, Christoph Garbers, Jens M Moll, Jürgen Scheller.
      Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling - known as cluster signalling - involves preformed complexes of membrane-bound IL-6-mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.
    DOI:  https://doi.org/10.1038/s41577-023-00856-y
  15. Cell. 2023 Apr 17. pii: S0092-8674(23)00300-8. [Epub ahead of print]
    The proteomic landscape of genome-wide genetic perturbations.
    Christoph B Messner, Vadim Demichev, Julia Muenzner, Simran K Aulakh, Natalie Barthel, Annika Röhl, Lucía Herrera-Domínguez, Anna-Sophia Egger, Stephan Kamrad, Jing Hou, Guihong Tan, Oliver Lemke, Enrica Calvani, Lukasz Szyrwiel, Michael Mülleder, Kathryn S Lilley, Charles Boone, Georg Kustatscher, Markus Ralser.
      Functional genomic strategies have become fundamental for annotating gene function and regulatory networks. Here, we combined functional genomics with proteomics by quantifying protein abundances in a genome-scale knockout library in Saccharomyces cerevisiae, using data-independent acquisition mass spectrometry. We find that global protein expression is driven by a complex interplay of (1) general biological properties, including translation rate, protein turnover, the formation of protein complexes, growth rate, and genome architecture, followed by (2) functional properties, such as the connectivity of a protein in genetic, metabolic, and physical interaction networks. Moreover, we show that functional proteomics complements current gene annotation strategies through the assessment of proteome profile similarity, protein covariation, and reverse proteome profiling. Thus, our study reveals principles that govern protein expression and provides a genome-spanning resource for functional annotation.
    Keywords:  Saccharomyces cerevisiae; data-independent acquisition; deletion; functional genomics; functional proteomics; gene annotation; high throughput; knockout; quantitative proteomics; systems biology
    DOI:  https://doi.org/10.1016/j.cell.2023.03.026
  16. Pancreas. 2022 Oct 01. 51(9): 1061-1073
    Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.
    Teresa L Mastracci, Minoti Apte, Laufey T Amundadottir, Alexandra Alvarsson, Steven Artandi, Melena D Bellin, Ernesto Bernal-Mizrachi, Alejandro Caicedo, Martha Campbell-Thompson, Zobeida Cruz-Monserrate, Abdelfattah El Ouaamari, Kyle J Gaulton, Andrea Geisz, Mark O Goodarzi, Manami Hara, Rebecca L Hull-Meichle, Alexander Kleger, Alison P Klein, Janel L Kopp, Rohit N Kulkarni, Mandar D Muzumdar, Anjaparavanda P Naren, Scott A Oakes, Søren S Olesen, Edward A Phelps, Alvin C Powers, Cherie L Stabler, Temel Tirkes, David C Whitcomb, Dhiraj Yadav, Jing Yong, Norann A Zaghloul, Maike Sander, Stephen J Pandol.
      ABSTRACT: The "Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases" Workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report summarizes the workshop proceedings. The goal of the workshop was to forge connections and identify gaps in knowledge that could guide future research directions. Presentations were segregated into 6 major themes, including (a) Pancreas Anatomy and Physiology; (b) Diabetes in the Setting of Exocrine Disease; (c) Metabolic Influences on the Exocrine Pancreas; (d) Genetic Drivers of Pancreatic Diseases; (e) Tools for Integrated Pancreatic Analysis; and (f) Implications of Exocrine-Endocrine Crosstalk. For each theme, there were multiple presentations followed by panel discussions on specific topics relevant to each area of research; these are summarized herein. Significantly, the discussions resulted in the identification of research gaps and opportunities for the field to address. In general, it was concluded that as a pancreas research community, we must more thoughtfully integrate our current knowledge of the normal physiology as well as the disease mechanisms that underlie endocrine and exocrine disorders so that there is a better understanding of the interplay between these compartments.
    DOI:  https://doi.org/10.1097/MPA.0000000000002170
  17. Genes Chromosomes Cancer. 2023 Apr 17.
    Standardizing analysis of intra-tumoral heterogeneity with computational pathology.
    Ameesha Paliwal, Kevin Faust, Azhar Alshoumer, Phedias Diamandis.
      Many malignant cancers like glioblastoma are highly adaptive diseases that dynamically change their regional biology to survive and thrive under diverse microenvironmental and therapeutic pressures. While the concept of intra-tumoral heterogeneity has become a major paradigm in cancer research and care, systematic approaches to assess and document bio-variation in cancer are still in their infancy. Here we discuss existing approaches and challenges to documenting intra-tumoral heterogeneity and emerging computational approaches that leverage artificial intelligence to begin to overcome these limitations. We propose how these emerging techniques can be coupled with a diversity of molecular tools to address intra-tumoral heterogeneity more systematically in research and in practice, especially across larger specimens and longitudinal analyses. Systematic documentation and characterization of heterogeneity across entire tumor specimens and their longitudinal evolution has the potential to improve our understanding and treatment of cancer.
    Keywords:  artificial intelligence; computer vision; deep learning; molecular profiling; tumor heterogeneity
    DOI:  https://doi.org/10.1002/gcc.23146
  18. Cell Metab. 2023 Apr 12. pii: S1550-4131(23)00124-9. [Epub ahead of print]
    Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation.
    Weiyi Chen, Oliver Mehlkop, Alexandra Scharn, Hendrik Nolte, Paul Klemm, Sinika Henschke, Lukas Steuernagel, Tamara Sotelo-Hitschfeld, Ecem Kaya, Claudia Maria Wunderlich, Thomas Langer, Natalia L Kononenko, Patrick Giavalisco, Jens Claus Brüning.
      Autophagy represents a key regulator of aging and metabolism in sensing energy deprivation. We find that fasting in mice activates autophagy in the liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators, and promotes ketogenesis. AgRP neuron-dependent induction of liver autophagy relies on NPY release in the paraventricular nucleus of the hypothalamus (PVH) via presynaptic inhibition of NPY1R-expressing neurons to activate PVHCRH neurons. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and rewiring of metabolism. AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of liver autophagy in control of metabolic adaptation during nutrient deprivation.
    Keywords:  AgRP neurons; CRH neurons; HPA axis; NPY1R; autophagy; corticosterone; hypothalamus; liver metabolism; non-cell autonomous; short-term fasting
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.019
  19. Cancer Discov. 2023 Apr 17. OF1-OF20
    Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program.
    Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M Whitley, Vinod Pant, Shunbin Xiong, Vrutant Shah, Jerome Lin, Encarnacion Perez, Marta L Fiorotto, Iqbal Mahmud, Abhinav K Jain, Philip L Lorenzi, Nicholas E Navin, Ellen R Richie, Guillermina Lozano.
      Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies.SIGNIFICANCE: New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li-Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are "basal" p53 activities.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0872
  20. Science. 2023 Apr 21. 380(6642): eabn7625
    Oncogenic CDK13 mutations impede nuclear RNA surveillance.
    Megan L Insco, Brian J Abraham, Sara J Dubbury, Ines H Kaltheuner, Sofia Dust, Constance Wu, Kevin Y Chen, David Liu, Stanislav Bellaousov, Anna M Cox, Benjamin J E Martin, Tongwu Zhang, Calvin G Ludwig, Tania Fabo, Rodsy Modhurima, Dakarai E Esgdaille, Telmo Henriques, Kevin M Brown, Stephen J Chanock, Matthias Geyer, Karen Adelman, Phillip A Sharp, Richard A Young, Paul L Boutz, Leonard I Zon.
      RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 (CDK13) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.
    DOI:  https://doi.org/10.1126/science.abn7625
  21. Elife. 2023 Apr 18. pii: e82435. [Epub ahead of print]12
    Mechanical basis and topological routes to cell elimination.
    Siavash Monfared, Guruswami Ravichandran, José Andrade, Amin Doostmohammadi.
      Cell layers eliminate unwanted cells through the extrusion process, which underlines healthy versus flawed tissue behaviors. Although several biochemical pathways have been identified, the underlying mechanical basis including the forces involved in cellular extrusion remains largely unexplored. Utilizing a phase-field model of a three-dimensional cell layer, we study the interplay of cell extrusion with cell-cell and cell-substrate interactions in a flat monolayer. Independent tuning of cell-cell versus cell-substrate adhesion forces reveals that extrusion events can be distinctly linked to defects in nematic and hexatic orders associated with cellular arrangements. Specifically, we show that by increasing relative cell-cell adhesion forces the cell monolayer can switch between the collective tendency towards fivefold, hexatic, disclinations relative to half-integer, nematic, defects for extruding a cell. We unify our findings by accessing three-dimensional mechanical stress fields to show that an extrusion event acts as a mechanism to relieve localized stress concentration.
    Keywords:  biophysics; cell extrusion; collective cell migration; defects in liquid crystals; epithelial cells; mechanobiology; physics of living systems
    DOI:  https://doi.org/10.7554/eLife.82435
  22. Pancreas. 2022 Oct 01. 51(9): 1074-1082
    Challenges in Recruitment and Retention: Leveraging Health-Related Antecedents and Information Carrier Factors to Improve Patient Participation in Pancreatic Cancer Research-A Review Article.
    Tara B Coffin, Barbara J Kenner.
      ABSTRACT: Advancements in pancreatic ductal adenocarcinoma (PDAC) prevention, diagnosis, and treatment rely on representative and robust clinical trial participation. Given the severity of PDAC, along with the lack of effective early detection approaches, the need for accessible screening tools and new treatments is dire. Unfortunately, enrollment barriers often result in low participant accrual rates for PDAC studies and illustrate the challenging terrain researchers are facing. Research participation along with access to preventative care has been further impacted by the coronavirus disease 2019 pandemic. In this review, we use the Comprehensive Model for Information Seeking to discuss underexplored factors that influence patient participation in clinical studies. Adequate staffing, flexible scheduling, effective patient and physician communication, and culturally responsive messaging, along with the use of telehealth, can support enrollment objectives. Clinical research studies are a key component of health care, informing medical advancements, and improving outcomes. By leveraging health-related antecedents and information carrier factors, researchers can more effectively address barriers to participation and implement potential evidence-based mitigating strategies. While this work focuses on the PDAC research context, the lessons delineated here are applicable to the wider cancer research setting.
    DOI:  https://doi.org/10.1097/MPA.0000000000002162
  23. Pancreas. 2022 Oct 01. 51(9): 1231-1234
    Genetic Analysis of the ATG16L1 c.898A>G (p.T300A) Variant in Acute and Chronic Pancreatitis.
    Claudia Neubauer, Maren Ewers, Hans-Ulrich Schulz, Frank Ulrich Weiß, Felix Lämmerhirt, Markus M Lerch, Peter Bugert, Olfert Landt, Hana Algül, Jonas Rosendahl, Heiko Witt.
      OBJECTIVES: Human and animal studies suggest an important role of autophagy in the pathogenesis of pancreatitis. ATG16L1 (autophagy-related 16 like 1) is part of a protein complex that is involved in the formation of autophagosomes. The c.898A > G (p.T300A) variant of ATG16L1 is associated with Crohn disease. In this study, we analyzed ATG16L1 c.898A > G (p.T300A) for an association with pancreatitis.METHODS: We genotyped 777 patients and 551 control subjects of German origin by melting curve analysis using fluorescence resonance energy transfer probes. The patient group included 429 patients with nonalcoholic chronic pancreatitis (CP), 141 patients with alcoholic CP, and 207 patients with acute pancreatitis (AP). We classified AP by severity according to the Atlanta symposium 1992.
    RESULTS: Allele and genotype frequencies of ATG16L1 c.898A > G (p.T300A) did not differ significantly between patients and controls (G allele frequencies: nonalcoholic CP, 49.9%; alcoholic CP, 48.2%; AP, 49.5%; controls, 52.7%). We found no significant association with the severity of AP either.
    CONCLUSIONS: Our data do not support a role of ATG16L1 c.898A > G (p.T300A) in the pathogenesis of AP or CP or an influence on the severity of AP.
    DOI:  https://doi.org/10.1097/MPA.0000000000002177
  24. Genome Med. 2023 Apr 20. 15(1): 27
    ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA.
    Ariana Huebner, James R M Black, Francesca Sarno, Roberto Pazo, Ignacio Juez, Laura Medina, Rocio Garcia-Carbonero, Carmen Guillén, Jaime Feliú, Carolina Alonso, Carlota Arenillas, Ana Belén Moreno-Cárdenas, Helena Verdaguer, Teresa Macarulla, Manuel Hidalgo, Nicholas McGranahan, Rodrigo A Toledo.
      BACKGROUND: Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution.METHODS: To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity.
    RESULTS: SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour.
    CONCLUSIONS: This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.
    Keywords:  Cell-free DNA; Circulating tumour DNA; Copy number; Intra-tumour heterogeneity; Pancreatic cancer; Tumour evolution; cfDNA; ctDNA
    DOI:  https://doi.org/10.1186/s13073-023-01171-w
  25. Trends Cell Biol. 2023 Apr 18. pii: S0962-8924(23)00048-X. [Epub ahead of print]
    The diverse nature of intestinal fibroblasts in development, homeostasis, and disease.
    Michael David Brügger, Konrad Basler.
      Only in recent years have we begun to appreciate the involvement of fibroblasts in intestinal development, tissue homeostasis, and disease. These insights followed the advent of single-cell transcriptomics that allowed researchers to explore the heterogeneity of intestinal fibroblasts in unprecedented detail. Since researchers often defined cell types and their associated function based on the biological process they studied, there are a plethora of partially overlapping markers for different intestinal fibroblast populations. This ambiguity complicates putting different research findings into context. Here, we provide a census on the function and identity of intestinal fibroblasts in mouse and human. We propose a simplified framework consisting of three colonic and four small intestinal fibroblast populations to aid navigating the diversity of intestinal fibroblasts.
    Keywords:  colorectal cancer; inflammatory disease; intestinal development; intestinal fibroblasts; intestinal homeostasis; single-cell transcriptomic analysis
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.007
  26. J Clin Invest. 2023 Apr 17. pii: e169240. [Epub ahead of print]133(8):
    Lysosomal lipid peroxidation mediates immunogenic cell death.
    Pravin Phadatare, Jayanta Debnath.
      Cancer cells rely on lysosome-dependent degradation to recycle nutrients that serve their energetic and biosynthetic needs. Despite great interest in repurposing the antimalarial hydroxychloroquine as a lysosomal inhibitor in clinical oncology trials, the mechanisms by which hydroxychloroquine and other lysosomal inhibitors induce tumor-cell cytotoxicity remain unclear. In this issue of the JCI, Bhardwaj et al. demonstrate that DC661, a dimeric form of chloroquine that inhibits palmitoyl-protein thioesterase 1 (PPT1), promoted lysosomal lipid peroxidation, resulting in lysosomal membrane permeabilization and tumor cell death. Remarkably, this lysosomal cell death pathway elicited cell-intrinsic immunogenicity and promoted T lymphocyte-mediated tumor cell clearance. The findings provide the mechanistic foundation for the potential combined use of immunotherapy and lysosomal inhibition in clinical trials.
    DOI:  https://doi.org/10.1172/JCI169240
  27. Mol Cell. 2023 Apr 18. pii: S1097-2765(23)00239-3. [Epub ahead of print]
    Proteomic discovery of chemical probes that perturb protein complexes in human cells.
    Michael R Lazear, Jarrett R Remsberg, Martin G Jaeger, Katherine Rothamel, Hsuan-Lin Her, Kristen E DeMeester, Evert Njomen, Simon J Hogg, Jahan Rahman, Landon R Whitby, Sang Joon Won, Michael A Schafroth, Daisuke Ogasawara, Minoru Yokoyama, Garrett L Lindsey, Haoxin Li, Jason Germain, Sabrina Barbas, Joan Vaughan, Thomas W Hanigan, Vincent F Vartabedian, Christopher J Reinhardt, Melissa M Dix, Seong Joo Koo, Inha Heo, John R Teijaro, Gabriel M Simon, Brahma Ghosh, Omar Abdel-Wahab, Kay Ahn, Alan Saghatelian, Bruno Melillo, Stuart L Schreiber, Gene W Yeo, Benjamin F Cravatt.
      Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such "binding-first" assays affect protein function, nonetheless, often remains unclear. Here, we describe a "function-first" proteomic strategy that uses size exclusion chromatography (SEC) to assess the global impact of electrophilic compounds on protein complexes in human cells. Integrating the SEC data with cysteine-directed activity-based protein profiling identifies changes in protein-protein interactions that are caused by site-specific liganding events, including the stereoselective engagement of cysteines in PSME1 and SF3B1 that disrupt the PA28 proteasome regulatory complex and stabilize a dynamic state of the spliceosome, respectively. Our findings thus show how multidimensional proteomic analysis of focused libraries of electrophilic compounds can expedite the discovery of chemical probes with site-specific functional effects on protein complexes in human cells.
    Keywords:  activity-based protein profiling; chemical probe; covalent; cysteine; proteasome; protein complexes; proteomics; size-exclusion chromatography; spliceosome
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.026
  28. J Vis Exp. 2023 Mar 31.
    Ultrastructural Localization of Endogenous LC3 by On-Section Correlative Light-Electron Microscopy.
    Jan van der Beek, Tineke Veenendaal, Cecilia de Heus, Suzanne van Dijk, Corlinda Ten Brink, Nalan Liv, Judith Klumperman.
      The visualization of autophagic organelles at the ultrastructural level by electron microscopy (EM) is essential to establish their identity and reveal details that are important for understanding the autophagic process. However, EM methods often lack molecular information, obstructing the correlation of ultrastructural information obtained by EM to fluorescence microscopy-based localization of specific autophagy proteins. Furthermore, the rarity of autophagosomes in unaltered cellular conditions hampers investigation by EM, which requires high magnification, and hence provides a limited field of view. In answer to both challenges, an on-section correlative light-electron microscopy (CLEM) method based on fluorescent labeling was applied to correlate a common autophagosomal marker, LC3, to EM ultrastructure. The method was used to rapidly screen cells in fluorescence microscopy for LC3 labeling in combination with other relevant markers. Subsequently, the underlying ultrastructural features of selected LC3-labeled spots were identified by CLEM. The method was applied to starved cells without adding inhibitors of lysosomal acidification. In these conditions, LC3 was found predominantly on autophagosomes and rarely in autolysosomes, in which LC3 is rapidly degraded. These data show both the feasibility and sensitivity of this approach, demonstrating that CLEM can be used to provide ultrastructural insights on LC3-mediated autophagy in native conditions-without drug treatments or genetic alterations. Overall, this method presents a valuable tool for ultrastructural localization studies of autophagy proteins and other scarce antigens by bridging light microscopy to EM data.
    DOI:  https://doi.org/10.3791/65067
  29. Biochem Pharmacol. 2023 Apr 13. pii: S0006-2952(23)00141-7. [Epub ahead of print]212 115550
    Targeting autophagy and lipid metabolism in cancer stem cells.
    Bandana Chakravarti, Jawed Akhtar Siddiqui, Rohit Anthony Sinha, Sana Raza.
      Cancer stem cells (CSCs) are a subset of cancer cells with self-renewal ability and tumor initiating properties. Unlike the other non-stem cancer cells, CSCs resist traditional therapy and remain a major cause of disease relapse. With the recent advances in metabolomics, various studies have demonstrated that CSCs have distinct metabolic properties. Metabolic reprogramming in CSCs contributes to self-renewal and maintenance of stemness. Accumulating evidence suggests that rewiring of energy metabolism is a key player that enables to meet energy demands, maintains stemness, and sustains cancer growth and invasion. CSCs use various mechanisms such as increased glycolysis, redox signaling, and autophagy modulation to overcome nutritional deficiency and sustain cell survival. The alterations in lipid metabolism acquired by the CSCs support biomass production through increased dependence on fatty acid synthesis and β-oxidation, and contribute to oncogenic signaling pathways. This review summarizes our current understanding of lipid metabolism in CSCs and how pharmacological regulation of autophagy and lipid metabolism influences CSC phenotype. Increased dependence on lipid metabolism appears as an attractive strategy to eliminate CSCs using therapeutic agents that specifically target CSCs based on their modulation of lipid metabolism.
    Keywords:  Autophagy; Cancer stem cells (CSCs); Heterogeneity; Lipid metabolism; Therapy
    DOI:  https://doi.org/10.1016/j.bcp.2023.115550
  30. Eur J Radiol. 2023 Apr 10. pii: S0720-048X(23)00148-1. [Epub ahead of print]163 110834
    Predictive value of computed tomography on surgical resectability in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: Results from a prospective, multicentre phase 2 trial (NEOLAP-AIO-PAK-0113).
    K V Guggenberger, T A Bley, S Held, R Keller, S Flemming, A Wiegering, C T Germer, B Kimmel, V Kunzmann, I Hartlapp, F Anger.
      PURPOSE: To assess the role of current imaging-based resectability criteria and the degree of radiological downsizing in locally advanced pancreatic adenocarcinoma (LAPC) after multiagent induction chemotherapy (ICT) in multicentre, open-label, randomized phase 2 trial.METHOD: LAPC patients were prospectively treated with multiagent ICT followed by surgical exploration within the NEOLAP trial. All patients underwent CT scan at baseline and after ICT to assess resectability status according to national comprehensive cancer network guidelines (NCCN) criteria and response evaluation criteria in solid tumors (RECIST) at the local study center and retrospectively in a central review. Imaging results were compared in terms of local and central staging, downsizing and pathological resection status.
    RESULTS: 83 patients were evaluable for central review of baseline and restaging imaging results. Downstaging by central review was rarely seen after multiagent ICT (7.7%), whereas tumor downsizing was documented frequently (any downsizing 90.4%, downsizing to partial response (PR) according to RECIST: 26.5%). Patients with any downsizing showed no significant different R0 resection rate (37.3%) as patients that fulfilled the criteria of PR (40.9%). The sensitivity of any downsizing for predicting R0 resection was 97% with a negative predictive value (NPV) of 0.88. ROC-analysis revealed that tumor downsizing was a predictor of R0 resection (AUC 0.647, p = 0.028) with a best cut-off value of 22.5% downsizing yielding a sensitivity of 65% and a specificity of 61%.
    CONCLUSIONS: Imaging-based tumor downsizing and not downstaging can guide the selection of patients with a realistic chance of R0-resection in LAPC after multi-agent ICT.
    Keywords:  Accuracy; Computed tomography; Neoadjuvant chemotherapy; Pancreatic adenocarcinoma; Predictive value; Preoperative staging
    DOI:  https://doi.org/10.1016/j.ejrad.2023.110834
  31. Aging (Albany NY). 2023 Apr 21. 15
    A chronic wound model to investigate skin cellular senescence.
    Saranya P Wyles, Parisa Dashti, Tamar Pirtskhalava, Burak Tekin, Christina Inman, Lilian Sales Gomez, Anthony B Lagnado, Larissa Prata, Diana Jurk, João F Passos, Tamar Tchkonia, James L Kirkland.
      Wound healing is an essential physiological process for restoring normal skin structure and function post-injury. The role of cellular senescence, an essentially irreversible cell cycle state in response to damaging stimuli, has emerged as a critical mechanism in wound remodeling. Transiently-induced senescence during tissue remodeling has been shown to be beneficial in the acute wound healing phase. In contrast, persistent senescence, as observed in chronic wounds, contributes to delayed closure. Herein we describe a chronic wound murine model and its cellular senescence profile, including the senescence-associated secretory phenotype.
    Keywords:  cellular senescence; chronic wound; re-epithelization; skin; wound healing
    DOI:  https://doi.org/10.18632/aging.204667
  32. Nat Immunol. 2023 Apr 20.
    Slow integrin-dependent migration organizes networks of tissue-resident mast cells.
    Lukas Kaltenbach, Paloma Martzloff, Sarah K Bambach, Nadim Aizarani, Michael Mihlan, Alina Gavrilov, Katharina M Glaser, Manuel Stecher, Roland Thünauer, Aude Thiriot, Klaus Heger, Katrin Kierdorf, Stephan Wienert, Ulrich H von Andrian, Marc Schmidt-Supprian, Claus Nerlov, Frederick Klauschen, Axel Roers, Marc Bajénoff, Dominic Grün, Tim Lämmermann.
      Immune cell locomotion is associated with amoeboid migration, a flexible mode of movement, which depends on rapid cycles of actin polymerization and actomyosin contraction1. Many immune cells do not necessarily require integrins, the major family of adhesion receptors in mammals, to move productively through three-dimensional tissue spaces2,3. Instead, they can use alternative strategies to transmit their actin-driven forces to the substrate, explaining their migratory adaptation to changing external environments4-6. However, whether these generalized concepts apply to all immune cells is unclear. Here, we show that the movement of mast cells (immune cells with important roles during allergy and anaphylaxis) differs fundamentally from the widely applied paradigm of interstitial immune cell migration. We identify a crucial role for integrin-dependent adhesion in controlling mast cell movement and localization to anatomical niches rich in KIT ligand, the major mast cell growth and survival factor. Our findings show that substrate-dependent haptokinesis is an important mechanism for the tissue organization of resident immune cells.
    DOI:  https://doi.org/10.1038/s41590-023-01493-2
  33. Cancer Lett. 2023 Apr 14. pii: S0304-3835(23)00136-2. [Epub ahead of print] 216185
    Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer.
    Dipakkumar R Prajapati, Caitlin Molczyk, Abhilasha Purohit, Sugandha Saxena, Reegan Sturgeon, Bhavana J Dave, Sushil Kumar, Surinder K Batra, Rakesh K Singh.
      Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.
    Keywords:  Angiogenesis; CXCR2 antagonist; Metastasis; Neutrophils; Pancreatic cancer; Tumor growth
    DOI:  https://doi.org/10.1016/j.canlet.2023.216185
  34. Cancer Imaging. 2023 Apr 18. 23(1): 38
    Multiparametric detection and outcome prediction of pancreatic cancer involving dual-energy CT, diffusion-weighted MRI, and radiomics.
    Vitali Koch, Nils Weitzer, Daniel Pinto Dos Santos, Leon D Gruenewald, Scherwin Mahmoudi, Simon S Martin, Katrin Eichler, Simon Bernatz, Tatjana Gruber-Rouh, Christian Booz, Renate M Hammerstingl, Teodora Biciusca, Nicolas Rosbach, Aynur Gökduman, Tommaso D'Angelo, Fabian Finkelmeier, Ibrahim Yel, Leona S Alizadeh, Christof M Sommer, Duygu Cengiz, Thomas J Vogl, Moritz H Albrecht.
      BACKGROUND: The advent of next-generation computed tomography (CT)- and magnetic resonance imaging (MRI) opened many new perspectives in the evaluation of tumor characteristics. An increasing body of evidence suggests the incorporation of quantitative imaging biomarkers into clinical decision-making to provide mineable tissue information. The present study sought to evaluate the diagnostic and predictive value of a multiparametric approach involving radiomics texture analysis, dual-energy CT-derived iodine concentration (DECT-IC), and diffusion-weighted MRI (DWI) in participants with histologically proven pancreatic cancer.METHODS: In this study, a total of 143 participants (63 years ± 13, 48 females) who underwent third-generation dual-source DECT and DWI between November 2014 and October 2022 were included. Among these, 83 received a final diagnosis of pancreatic cancer, 20 had pancreatitis, and 40 had no evidence of pancreatic pathologies. Data comparisons were performed using chi-square statistic tests, one-way ANOVA, or two-tailed Student's t-test. For the assessment of the association of texture features with overall survival, receiver operating characteristics analysis and Cox regression tests were used.
    RESULTS: Malignant pancreatic tissue differed significantly from normal or inflamed tissue regarding radiomics features (overall P < .001, respectively) and iodine uptake (overall P < .001, respectively). The performance for the distinction of malignant from normal or inflamed pancreatic tissue ranged between an AUC of ≥ 0.995 (95% CI, 0.955-1.0; P < .001) for radiomics features, ≥ 0.852 (95% CI, 0.767-0.914; P < .001) for DECT-IC, and ≥ 0.690 (95% CI, 0.587-0.780; P = .01) for DWI, respectively. During a follow-up of 14 ± 12 months (range, 10-44 months), the multiparametric approach showed a moderate prognostic power to predict all-cause mortality (c-index = 0.778 [95% CI, 0.697-0.864], P = .01).
    CONCLUSIONS: Our reported multiparametric approach allowed for accurate discrimination of pancreatic cancer and revealed great potential to provide independent prognostic information on all-cause mortality.
    Keywords:  Diffusion magnetic resonance imaging; Dual-energy computed tomography; Multidetector computed tomography; Pancreatic cancer; Survival
    DOI:  https://doi.org/10.1186/s40644-023-00549-8
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