bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒08‒28
thirty papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
  2. Autophagy, Acute Pancreatitis and the Metamorphoses of a Trypsinogen-Activating Organelle.
  3. Oncofetal reprogramming in tumour development and progression.
  4. BECN1F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner.
  5. LEAP: a novel LC3C-dependent pathway connects autophagy, endocytic trafficking and signaling.
  6. Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.
  7. Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis.
  8. Reclassifying tumour cell cycle activity in terms of its tissue of origin.
  9. EATING YOUR OWN FAT TO STAY FIT: LIPOPHAGY SUSTAINS LYMPHANGIOGENESIS.
  10. Increasing cell size remodels the proteome and promotes senescence.
  11. Single Cell Analysis of Cultivated Fibroblasts from Chronic Pancreatitis and Pancreatic Cancer Patients.
  12. Regulation of tumor metabolism by post translational modifications on metabolic enzymes.
  13. FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk.
  14. The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.
  15. Fine-needle biopsies with 19-gauge needle are effective combination modalities of EUS-tissue acquisition for genomic profiling of unresectable pancreatic cancer.
  16. RASA2 ablation in T cells boosts antigen sensitivity and long-term function.
  17. Myofibroblastic CAF Density, Not Activated Stroma Index, Indicates Prognosis after Neoadjuvant Therapy of Pancreatic Carcinoma.
  18. Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.
  19. Advances in measuring cancer cell metabolism with subcellular resolution.
  20. Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis.
  21. A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes.
  22. MTPpilot: An Interactive Software for Visualization of Next-Generation Sequencing Results in Molecular Tumor Boards.
  23. Old plasma dilution reduces human biological age: a clinical study.
  24. SPICE-Met: profiling and imaging energy metabolism at the single-cell level using a fluorescent reporter mouse.
  25. EPIC: an evaluation of the psychological impact of early-phase clinical trials in cancer patients.
  26. ADAM17-mediated EGFR ligand shedding directs macrophage promoted cancer cell invasion.
  27. Automated biophysical classification of apoptotic pancreatic cancer cell subpopulations by using machine learning approaches with impedance cytometry.
  28. Intraductal pressure in experimental models of acute and chronic pancreatitis in mice.
  29. Science-Driven Nutritional Interventions for the Prevention and Treatment of Cancer.
  30. Correlation of transcriptional subtypes with a validated CT radiomics score in resectable pancreatic ductal adenocarcinoma.
  1. Front Mol Biosci. 2022 ;9 930223
    Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
    Debora Gentile, Marianna Esposito, Paolo Grumati.
      Autophagy is an evolutionary conserved catabolic pathway that uses a unique double-membrane vesicle, called autophagosome, to sequester cytosolic components, deliver them to lysosomes and recycle amino-acids. Essentially, autophagy acts as a cellular cleaning system that maintains metabolic balance under basal conditions and helps to ensure nutrient viability under stress conditions. It is also an important quality control mechanism that removes misfolded or aggregated proteins and mediates the turnover of damaged and obsolete organelles. In this regard, the idea that autophagy is a non-selective bulk process is outdated. It is now widely accepted that forms of selective autophagy are responsible for metabolic rewiring in response to cellular demand. Given its importance, autophagy plays an essential role during tumorigenesis as it sustains malignant cellular growth by acting as a coping-mechanisms for intracellular and environmental stress that occurs during malignant transformation. Cancer development is accompanied by the formation of a peculiar tumor microenvironment that is mainly characterized by hypoxia (oxygen < 2%) and low nutrient availability. Such conditions challenge cancer cells that must adapt their metabolism to survive. Here we review the regulation of autophagy and selective autophagy by hypoxia and the crosstalk with other stress response mechanisms, such as UPR. Finally, we discuss the emerging role of ER-phagy in sustaining cellular remodeling and quality control during stress conditions that drive tumorigenesis.
    Keywords:  ER stress; ER-phagy; UPR; autophagy; cancer; endoplasmic reticulum; hypoxia
    DOI:  https://doi.org/10.3389/fmolb.2022.930223
  2. Cells. 2022 Aug 12. pii: 2514. [Epub ahead of print]11(16):
    Autophagy, Acute Pancreatitis and the Metamorphoses of a Trypsinogen-Activating Organelle.
    Svetlana Voronina, Michael Chvanov, Francesca De Faveri, Ulrike Mayer, Tom Wileman, David Criddle, Alexei Tepikin.
      Recent studies have highlighted the importance of autophagy and particularly non-canonical autophagy in the development and progression of acute pancreatitis (a frequent disease with considerable morbidity and significant mortality). An important early event in the development of acute pancreatitis is the intrapancreatic activation of trypsinogen, (i.e., formation of trypsin) leading to the autodigestion of the organ. Another prominent phenomenon associated with the initiation of this disease is vacuolisation and specifically the formation of giant endocytic vacuoles in pancreatic acinar cells. These organelles develop in acinar cells exposed to several inducers of acute pancreatitis (including taurolithocholic acid and high concentrations of secretagogues cholecystokinin and acetylcholine). Notably, early trypsinogen activation occurs in the endocytic vacuoles. These trypsinogen-activating organelles undergo activation, long-distance trafficking, and non-canonical autophagy. In this review, we will discuss the role of autophagy in acute pancreatitis and particularly focus on the recently discovered LAP-like non-canonical autophagy (LNCA) of endocytic vacuoles.
    Keywords:  ATG8; CASM; LAP; LAP-like non-canonical autophagy; LC3; LC3-associated phagocytosis; LNCA; acute pancreatitis; autophagy; cholecystokinin; endocytic vacuole; non-canonical autophagy; pancreatic acinar cell; trypsin; trypsinogen; zymogen granule
    DOI:  https://doi.org/10.3390/cells11162514
  3. Nat Rev Cancer. 2022 Aug 23.
    Oncofetal reprogramming in tumour development and progression.
    Ankur Sharma, Camille Blériot, Jennifer Currenti, Florent Ginhoux.
      Embryonic development is characterized by rapidly dividing cells, cellular plasticity and a highly vascular microenvironment. These features are similar to those of tumour tissue, in that malignant cells are characterized by their ability to proliferate and exhibit cellular plasticity. The tumour microenvironment also often includes immunosuppressive features. Reciprocal communication between various cellular subpopulations enables fetal and tumour tissues to proliferate, migrate and escape immune responses. Fetal-like reprogramming has been demonstrated in the tumour microenvironment, indicating extraordinary cellular plasticity and bringing an additional layer of cellular heterogeneity. More importantly, some of these features are also present during inflammation. This Perspective discusses the similarity between embryogenesis, inflammation and tumorigenesis, and describes the mechanisms of oncofetal reprogramming that enable tumour cells to escape from immune responses, promoting tumour growth and metastasis.
    DOI:  https://doi.org/10.1038/s41568-022-00497-8
  4. Autophagy. 2022 Aug 21. 1-9
    BECN1F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner.
    Salwa Sebti, Zhongju Zou, Michael U Shiloh.
      Macroautophagy/autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer lived Becn1F121A mutant mice. However, both autophagic and lysosomal activities decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here, we demonstrate that old wild-type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.
    Keywords:  Aging; BECN1; autophagic flux; liver; mouse; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2022.2111852
  5. Autophagy. 2022 Aug 26.
    LEAP: a novel LC3C-dependent pathway connects autophagy, endocytic trafficking and signaling.
    Paula P Coelho, Morag Park.
      Macroautophagy/autophagy acts to promote homeostasis and is increasingly understood to selectively target cargo for degradation. The LC3-family of proteins mediate diverse yet distinct cargo recruitment to phagophores. However, what underlies specificity for cargo engagement among LC3 proteins is poorly understood. Using an unbiased protein interaction screen of LC3B and LC3C we uncover a novel LC3C-endocytic-associated-pathway (LEAP) that recruits selective plasma membrane (PM) cargo to phagophores. We show LC3C but not LC3B localizes to peripheral endosomes and engages proteins that traffic between the PM, endosomes and autophagosomes. We establish that endocytic LC3C binds cargo internalized from the PM, including MET receptor tyrosine kinase and TFRC (transferrin receptor), and targets them towards autophagic degradation. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signaling and autophagic degradation with important implications in cancer and other disease states.
    Keywords:  Atg8-orthologs; LC3C; MET-RTK; autophagy; endocytic trafficking; selective cargo recruitment; signalophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2117973
  6. Science. 2022 Aug 25. eabg6621
    Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.
    Hijai R Shin, Y Rose Citron, Lei Wang, Laura Tribouillard, Claire S Goul, Robin Stipp, Yusuke Sugasawa, Aakriti Jain, Nolwenn Samson, Chun-Yan Lim, Oliver B Davis, David Castaneda-Carpio, Mingxing Qian, Daniel K Nomura, Rushika M Perera, Eunyong Park, Douglas F Covey, Mathieu Laplante, Alex S Evers, Roberto Zoncu.
      Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified LYsosomal CHOlesterol Signaling (LYCHOS, previously annotated as G-protein coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1). Cholesterol bound to the N-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a GTPase-activating protein for the Rag guanosine triphosphatases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing, and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
    DOI:  https://doi.org/10.1126/science.abg6621
  7. Signal Transduct Target Ther. 2022 Aug 23. 7(1): 296
    Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis.
    Goodwin G Jinesh, Andrew S Brohl.
      Metastasis is a pivotal event that accelerates the prognosis of cancer patients towards mortality. Therapies that aim to induce cell death in metastatic cells require a more detailed understanding of the metastasis for better mitigation. Towards this goal, we discuss the details of two distinct but overlapping pathways of metastasis: a classical reversible epithelial-to-mesenchymal transition (hybrid-EMT)-driven transport pathway and an alternative cell death process-driven blebbishield metastatic-witch (BMW) transport pathway involving reversible cell death process. The knowledge about the EMT and BMW pathways is important for the therapy of metastatic cancers as these pathways confer drug resistance coupled to immune evasion/suppression. We initially discuss the EMT pathway and compare it with the BMW pathway in the contexts of coordinated oncogenic, metabolic, immunologic, and cell biological events that drive metastasis. In particular, we discuss how the cell death environment involving apoptosis, ferroptosis, necroptosis, and NETosis in BMW or EMT pathways recruits immune cells, fuses with it, migrates, permeabilizes vasculature, and settles at distant sites to establish metastasis. Finally, we discuss the therapeutic targets that are common to both EMT and BMW pathways.
    DOI:  https://doi.org/10.1038/s41392-022-01132-6
  8. NPJ Precis Oncol. 2022 Aug 20. 6(1): 59
    Reclassifying tumour cell cycle activity in terms of its tissue of origin.
    Arian Lundberg, Joan Jong Jing Yi, Linda S Lindström, Nicholas P Tobin.
      Genomic alterations resulting in loss of control over the cell cycle is a fundamental hallmark of human malignancies. Whilst pan-cancer studies have broadly assessed tumour genomics and their impact on oncogenic pathways, analyses taking the baseline signalling levels in normal tissue into account are lacking. To this end, we aimed to reclassify the cell cycle activity of tumours in terms of their tissue of origin and determine if any common DNA mutations, chromosome arm-level changes or signalling pathways contribute to an increase in baseline corrected cell cycle activity. Combining normal tissue and pan-cancer data from over 13,000 samples we demonstrate that tumours of gynaecological origin show the highest levels of corrected cell cycle activity, partially owing to hormonal signalling and gene expression changes. We also show that normal and tumour tissues can be separated into groups (quadrants) of low/high cell cycle activity and propose the hypothesis of an upper limit on these activity levels in tumours.
    DOI:  https://doi.org/10.1038/s41698-022-00302-7
  9. Autophagy. 2022 Aug 26.
    EATING YOUR OWN FAT TO STAY FIT: LIPOPHAGY SUSTAINS LYMPHANGIOGENESIS.
    Odeta Mece, Diede Houbaert, Patrizia Agostinis.
      Lymphatic endothelial cells (LECs) exploit fatty acid oxidation (FAO) to grow and to maintain lymphatic vessel identity through the epigenetic regulation of the essential transcription factor PROX1. In our recent study, we found that LEC-specific loss of ATG5 prevents injury-induced lymphangiogenesis in vivo. Inadequate degradation of lipid droplets (LDs) caused by genetic ablation of ATG5 in LECs disturbs mitochondrial fitness, and reduces mitochondrial FAO and acetyl-CoA levels, ultimately affecting PROX1-mediated epigenetic regulation of CPT1A and key lymphatic markers, most importantly FLT4/VEGFR3. Supplementing the fatty acid precursor acetate rescues defective inflammation-driven lymphangiogenesis in LEC-specific atg5 knockout mice. Thus, efficient macroautophagy/autophagy-mediated LD breakdown is critical to maintain mitochondrial metabolism and acetyl-CoA levels, which sustain a PROX1-mediated lymphatic gene program required for LEC identity and inflammation-driven lymphangiogenesis.
    Keywords:  autophagy; lipid metabolism; lipophagy; lymphangiogenesis; lymphatic endothelial cells; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2022.2117513
  10. Mol Cell. 2022 Aug 15. pii: S1097-2765(22)00713-4. [Epub ahead of print]
    Increasing cell size remodels the proteome and promotes senescence.
    Michael C Lanz, Evgeny Zatulovskiy, Matthew P Swaffer, Lichao Zhang, Ilayda Ilerten, Shuyuan Zhang, Dong Shin You, Georgi Marinov, Patrick McAlpine, Joshua E Elias, Jan M Skotheim.
      Cell size is tightly controlled in healthy tissues, but it is unclear how deviations in cell size affect cell physiology. To address this, we measured how the cell's proteome changes with increasing cell size. Size-dependent protein concentration changes are widespread and predicted by subcellular localization, size-dependent mRNA concentrations, and protein turnover. As proliferating cells grow larger, concentration changes typically associated with cellular senescence are increasingly pronounced, suggesting that large size may be a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative, DNA-damage-induced, and CDK4/6i-induced senescence. Size-dependent changes to the proteome, including those associated with senescence, are not observed when an increase in cell size is accompanied by an increase in ploidy. Together, our findings show how cell size could impact many aspects of cell physiology by remodeling the proteome and provide a rationale for cell size control and polyploidization.
    Keywords:  DNA damage; SA-beta-Gal; cell cycle; cell size; p16(INK4); palbociclib; polyploidy; proteomics; senescence; size-scaling
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.017
  11. Cells. 2022 Aug 19. pii: 2583. [Epub ahead of print]11(16):
    Single Cell Analysis of Cultivated Fibroblasts from Chronic Pancreatitis and Pancreatic Cancer Patients.
    Yoshiaki Sunami, Yijun Chen, Bogusz Trojanowicz, Matthias Sommerer, Monika Hämmerle, Roland Eils, Jörg Kleeff.
      Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as chronic pancreatitis named disease-associated fibroblasts (DAFs). However, intra-tumoral heterogeneity of CAFs in pancreatic cancer patients and their pivotal role in cancer-related mechanisms have not been fully elucidated. Further, it has not been elucidated whether CAF subtypes identified in pancreatic cancer also exist in chronic pancreatitis. In this study, we used primary isolated fibroblasts from pancreatic cancer and chronic pancreatitis patients using the outgrowth method. Single-cell RNA sequencing (scRNA-seq) was performed, and bioinformatics analysis identified highly variable genes, including factors associated with overall survival of pancreatic cancer patients. The majority of highly variable genes are involved in the cell cycle. Instead of previously classified myofibroblastic (myCAFs), inflammatory (iCAFs), and antigen-presenting (ap) CAFs, we identified a myCAFs-like subtype in all cases. Most interestingly, after cell cycle regression, we observed 135 highly variable genes commonly identified in chronic pancreatitis and pancreatic cancer patients. This study is the first to conduct scRNAseq and bioinformatics analyses to compare CAFs/DAFs from both chronic pancreatitis and pancreatic cancer patients. Further studies are required to select and identify stromal factors in DAFs from chronic pancreatitis cases, which are commonly expressed also in CAFs potentially contributing to pancreatic cancer development.
    Keywords:  cancer-associated fibroblasts; cellular plasticity; chronic pancreatitis; pancreatic cancer; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/cells11162583
  12. Cancer Gene Ther. 2022 Aug 23.
    Regulation of tumor metabolism by post translational modifications on metabolic enzymes.
    Abhisha Sawant Dessai, Poonam Kalhotra, Aaron T Novickis, Subhamoy Dasgupta.
      Metabolic reprogramming is a hallmark of cancer development, progression, and metastasis. Several metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, lipid metabolism, and glutamine catabolism are frequently altered to support cancer growth. Importantly, the activity of the rate-limiting metabolic enzymes in these pathways are specifically modulated in cancer cells. This is achieved by transcriptional, translational, and post translational regulations that enhance the expression, activity, stability, and substrate sensitivity of the rate-limiting enzymes. These mechanisms allow the enzymes to retain increased activity supporting the metabolic needs of rapidly growing tumors, sustain their survival in the hostile tumor microenvironments and in the metastatic lesions. In this review, we primarily focused on the post translational modifications of the rate-limiting enzymes in the glucose and glutamine metabolism, TCA cycle, and fatty acid metabolism promoting tumor progression and metastasis.
    DOI:  https://doi.org/10.1038/s41417-022-00521-x
  13. JCI Insight. 2022 Aug 23. pii: e155848. [Epub ahead of print]
    FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk.
    Aki T Chaffin, Karlton R Larson, Kuei-Pin Huang, Chih-Ting Wu, Nadejda Godoroja, Yanbin Fang, Devi Jayakrishnan, Karla A Soto Sauza, Landon C Sims, Niloufar Mohajerani, Michael L Goodson, Karen K Ryan.
      The liver regulates energy partitioning and utilization in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor-21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate utilization to reduce hepatic lipid storage. Here we report that FGF21 alters hepatic transcriptional and metabolic responses, and reduces liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor --> cAMP --> EPAC1 signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent, old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex, but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.
    Keywords:  Endocrinology; Growth factors; Hepatology; Obesity; Sex hormones
    DOI:  https://doi.org/10.1172/jci.insight.155848
  14. Cell Rep. 2022 Aug 23. pii: S2211-1247(22)01076-2. [Epub ahead of print]40(8): 111258
    The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.
    Anders B Klein, Trine S Nicolaisen, Kornelia Johann, Andreas M Fritzen, Cecilie V Mathiesen, Cláudia Gil, Nanna S Pilmark, Kristian Karstoft, Martin B Blond, Jonas S Quist, Randy J Seeley, Kristine Færch, Jens Lund, Maximilian Kleinert, Christoffer Clemmensen.
      Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout, and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15, and energy balance.
    Keywords:  CP: Metabolism; GDF15; GFRAL; body weight; diabetes; energy balance; food intake; metformin; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111258
  15. Dig Endosc. 2022 Aug 22.
    Fine-needle biopsies with 19-gauge needle are effective combination modalities of EUS-tissue acquisition for genomic profiling of unresectable pancreatic cancer.
    Go Ikeda, Susumu Hijioka, Yoshikuni Nagashio, Yuta Maruki, Akihiro Ohba, Yuya Hisada, Motohiro Yoshinari, Shota Harai, Hidetoshi Kitamura, Takehiko Koga, Yumi Murashima, Kosuke Maehara, Mao Okada, Daiki Yamashige, Kohei Okamoto, Hidenobu Hara, Yuya Hagiwara, Daiki Agarie, Tetsuro Takasaki, Kotaro Takeshita, Yuki Kawasaki, Shunsuke Kondo, Chigusa Morizane, Hideki Ueno, Nobuyoshi Hiraoka, Yasushi Yatabe, Yutaka Saito, Katsuhiko Iwakiri, Takuji Okusaka.
      OBJECTIVES: A comprehensive genomic panel (CGP) has been approved in Japan since June 2019, enabling mutation-specific therapy. Although tissue sampling via endoscopic ultrasound-guided tissue acquisition (EUS-TA) is standard in pancreatic cancer, reports on obtaining appropriate samples for CGP, especially for the OncoGuideTM NCC Oncopanel System (NOP) and FoundationOne® CDx (FOne), are lacking. Therefore, we investigated the success rate and factors related to appropriate EUS-TA sampling for CGP analysis suitability in unresectable pancreatic ductal adenocarcinoma (UR-PDAC).METHODS: Participants comprised 150 UR-PDAC patients who underwent EUS-TA and tumor sample evaluation for CGP analysis suitability between June 2019 and December 2021. The proportion of patients meeting the criteria was evaluated considering tumor size, puncture lesion, presence of metastasis, type and size of puncture needle, suction method, number of punctures, and puncture route.
    RESULTS: In total, 39.2% (60/153) of samples met NOP analysis suitability criteria and 0% met FOne analysis suitability criteria. The suitability rate was significantly higher with 19-gauge fine-needle biopsy (FNB) (56.0%; 42/75) than with 22-gauge FNB (32.6%; 14/43) and 22-gauge fine-needle aspiration (11.4%; 4/35). Nineteen-gauge needle (odds ratio [OR]: 2.53; 95% confidence interval [CI]: 1.15-5.57; P=0.021) and FNB (OR: 3.57; 95% CI: 1.05-12.20; P=0.041) were independent factors contributing to NOP analysis suitability. Among 30 patients who underwent actual NOP analysis, the analysis success rate was 100% (30/30).
    CONCLUSIONS: In sample collection via EUS-TA, 19-gauge and FNB needles contribute to NOP analysis suitability.
    Keywords:  Endoscopic ultrasonography; Fine-needle aspiration; Fine-needle biopsy; Genomic profiling; Pancreatic cancer
    DOI:  https://doi.org/10.1111/den.14423
  16. Nature. 2022 Aug 24.
    RASA2 ablation in T cells boosts antigen sensitivity and long-term function.
    Julia Carnevale, Eric Shifrut, Nupura Kale, William A Nyberg, Franziska Blaeschke, Yan Yi Chen, Zhongmei Li, Sagar P Bapat, Morgan E Diolaiti, Patrick O'Leary, Shane Vedova, Julia Belk, Bence Daniel, Theodore L Roth, Stefanie Bachl, Alejandro Allo Anido, Brooke Prinzing, Jorge Ibañez-Vega, Shannon Lange, Dalia Haydar, Marie Luetke-Eversloh, Maelys Born-Bony, Bindu Hegde, Scott Kogan, Tobias Feuchtinger, Hideho Okada, Ansuman T Satpathy, Kevin Shannon, Stephen Gottschalk, Justin Eyquem, Giedre Krenciute, Alan Ashworth, Alexander Marson.
      The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.
    DOI:  https://doi.org/10.1038/s41586-022-05126-w
  17. Cancers (Basel). 2022 Aug 11. pii: 3881. [Epub ahead of print]14(16):
    Myofibroblastic CAF Density, Not Activated Stroma Index, Indicates Prognosis after Neoadjuvant Therapy of Pancreatic Carcinoma.
    Ulrike Heger, Anna Martens, Lisa Schillings, Britta Walter, Domenic Hartmann, Ulf Hinz, Thomas Pausch, Nathalia Giese, Christoph W Michalski, Thilo Hackert.
      Neoadjuvant therapy (NT) for advanced PDAC is an emerging concept, affecting both stroma and tumor. The Activated Stroma Index (ASI; ratio of activated cancer-associated fibroblasts (CAF) to collagen deposition) is a prognostic marker in upfront resected pancreatic adenocarcinoma (PDAC). We assessed ASI and its prognostic relevance after NT. Tissue from resection specimens of n = 48 PDAC patients after neoadjuvant chemotherapy with FOLFIRINOX (FOL; n = 31), gemcitabine + nab-paclitaxel (GEM; 7) or combination treatment (COMB; 10) was compared with upfront resected matched controls (RES; 69). Activated CAFs were assessed by immunohistochemistry for α-SMA, and collagen was stained with aniline blue; the stained area was then determined by computational imaging analysis and ASI was calculated. In GEM, ASI was significantly higher and collagen deposition lower than in controls and FOL. The lowest quartile of ASI values had significantly longer overall survival (OS) in RES, whereas in FOL, the highest quartile had the best prognosis. After NT, OS was significantly improved in the α-SMA-high group; in RES, however, survival was independent of α-SMA. Reversed prognostic association of ASI thus points to the differing significance of stromal composition after FOL, while improved prognosis with high CAF abundance suggests a synergistic effect of myofibroblasts with chemotherapy. These divergences impede usability of ASI after NT.
    Keywords:  CAF; FOLFIRINOX; collagen; neoadjuvant therapy; paclitaxel; pancreatic cancer; tumor stroma
    DOI:  https://doi.org/10.3390/cancers14163881
  18. Pancreatology. 2022 Aug 17. pii: S1424-3903(22)00475-6. [Epub ahead of print]
    Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.
    Makoto Kawamoto, Takeichi Yoshida, Koji Tamura, Mohamad Dbouk, Marcia Irene Canto, Richard Burkhart, Jin He, Nicholas J Roberts, Alison P Klein, Michael Goggins.
      BACKGROUND: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk.METHODS: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress.
    RESULTS: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant.
    CONCLUSION: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer.
    Keywords:  CEL; Endoplasmic reticulum stress; Inherited susceptibility; Pancreatic cancer; Variant
    DOI:  https://doi.org/10.1016/j.pan.2022.08.004
  19. Nat Methods. 2022 Aug 25.
    Advances in measuring cancer cell metabolism with subcellular resolution.
    Victor Ruiz-Rodado, Adrian Lita, Mioara Larion.
      Characterizing metabolism in cancer is crucial for understanding tumor biology and for developing potential therapies. Although most metabolic investigations analyze averaged metabolite levels from all cell compartments, subcellular metabolomics can provide more detailed insight into the biochemical processes associated with the disease. Methodological limitations have historically prevented the wider application of subcellular metabolomics in cancer research. Recently, however, ways to distinguish and identify metabolic pathways within organelles have been developed, including state-of-the-art methods to monitor metabolism in situ (such as mass spectrometry-based imaging, Raman spectroscopy and fluorescence microscopy), to isolate key organelles via new approaches and to use tailored isotope-tracing strategies. Herein, we examine the advantages and limitations of these developments and look to the future of this field of research.
    DOI:  https://doi.org/10.1038/s41592-022-01572-6
  20. JCI Insight. 2022 Aug 22. pii: e153058. [Epub ahead of print]7(16):
    Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis.
    Agata Radwanska, Christopher Travis Cottage, Antonio Piras, Catherine Overed-Sayer, Carina Sihlbom, Ramachandramouli Budida, Catherine Wrench, Jane Connor, Susan Monkley, Petra Hazon, Holger Schluter, Matthew J Thomas, Cory M Hogaboam, Lynne A Murray.
      Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient-derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung-derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type-dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.
    Keywords:  Cell Biology; Cytokines; Extracellular matrix; Fibrosis; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.153058
  21. J Biol Chem. 2022 Aug 18. pii: S0021-9258(22)00837-7. [Epub ahead of print] 102394
    A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes.
    Francis K Fordjour, Chenxu Guo, Yiwei Ai, George G Daaboul, Stephen J Gould.
      Exosomes are small extracellular vesicles (EVs) of ∼30-150 nm that are secreted by all cells, abundant in all biofluids, and play important roles in health and disease. However, details about the mechanism of exosome biogenesis are unclear. Here, we carried out a cargo-based analysis of exosome cargo protein biogenesis in which we identified the most highly enriched exosomal cargo proteins and then followed their biogenesis, trafficking, and exosomal secretion to test different hypotheses for how cells make exosomes. We show that exosome cargo proteins bud from cells (i) in exosome-sized vesicles regardless of whether they are localized to plasma or endosome membranes, (ii) ∼5-fold more efficiently when localized to the plasma membrane, (iii) ∼5-fold less efficiently when targeted to the endosome membrane, (iv) by a stochastic process that leads to ∼100-fold differences in their abundance from one exosome to another, and (v) independently of small GTPase Rab27a, the ESCRT complex-associated protein Alix, or the cargo protein CD63. Taken together, our results demonstrate that cells use a shared, stochastic mechanism to bud exosome cargoes along the spectrum of plasma and endosome membranes, and far more efficiently from the plasma membrane than the endosome. Our observations also indicate that the pronounced variation in content between different exosome-sized vesicles is an inevitable consequence of a stochastic mechanism of small vesicle biogenesis, that the origin membrane of exosome-sized EVs simply cannot be determined, and that most of what we currently know about exosomes has likely come from studies of plasma membrane-derived vesicles.
    Keywords:  CD63; CD81; CD9; Protein budding; Rab27a; SPIR; endosome; extracellular vesicle; interferometric reflectance; interferometry; plasma membrane; tetraspanin
    DOI:  https://doi.org/10.1016/j.jbc.2022.102394
  22. JCO Clin Cancer Inform. 2022 Aug;6 e2200032
    MTPpilot: An Interactive Software for Visualization of Next-Generation Sequencing Results in Molecular Tumor Boards.
    Abdullah Kahraman, Fabian M Arnold, Jacob Hanimann, Marta Nowak, Chantal Pauli, Christian Britschgi, Holger Moch, Martin Zoche.
      PURPOSE: Comprehensive targeted next-generation sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards, the detected genomic alterations are often discussed to decide the next treatment options for patients with cancer. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology.METHODS: We have developed the Molecular Tumor Profiling pilot (MTPpilot) webservice using HTML, PHP, JavaScript, and MySQL to support the clinical discussion of NGS results at molecular tumor boards.
    RESULTS: MTPpilot integrates various public genome, network, and cancer mutation databases with interactive visualization tools to assess the functional impact of mutations and support clinical decision making at tumor boards.
    CONCLUSION: MTPpilot is tailored for discussion of NGS gene panel results at molecular tumor boards. It is freely available as a webservice at MTPpilot.
    DOI:  https://doi.org/10.1200/CCI.22.00032
  23. Geroscience. 2022 Aug 24.
    Old plasma dilution reduces human biological age: a clinical study.
    Daehwan Kim, Dobri D Kiprov, Connor Luellen, Michael Lieb, Chao Liu, Etsuko Watanabe, Xiaoyue Mei, Kaitlin Cassaleto, Joel Kramer, Michael J Conboy, Irina M Conboy.
      This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.
    Keywords:  Aging; Biological noise; Lymphoid/myeloid markers; Plasmapheresis; Proteomics; Rejuvenation
    DOI:  https://doi.org/10.1007/s11357-022-00645-w
  24. EMBO J. 2022 Aug 23. e111528
    SPICE-Met: profiling and imaging energy metabolism at the single-cell level using a fluorescent reporter mouse.
    Erica Russo, Fabrice Lemaître, Béatrice Corre, Aleksandra S Chikina, Francina Langa-Vives, Philippe Bousso.
      The regulation of cellular energy metabolism is central to most physiological and pathophysiological processes. However, most current methods have limited ability to functionally probe metabolic pathways in individual cells. Here, we describe SPICE-Met (Single-cell Profiling and Imaging of Cell Energy Metabolism), a method for profiling energy metabolism in single cells using flow cytometry or imaging. We generated a transgenic mouse expressing PercevalHR, a fluorescent reporter for cellular ATP:ADP ratio. Modulation of PercevalHR fluorescence with metabolic inhibitors was used to infer the dependence of energy metabolism on oxidative phosphorylation and glycolysis in defined cell populations identified by flow cytometry. We applied SPICE-Met to analyze T-cell memory development during vaccination. Finally, we used SPICE-Met in combination with real-time imaging to dissect the heterogeneity and plasticity of energy metabolism in single macrophages ex vivo and identify three distinct metabolic patterns. Functional probing of energy metabolism with single-cell resolution should greatly facilitate the study of immunometabolism at a steady state, during disease pathogenesis or in response to therapy.
    Keywords:  OXPHOS; energy; glycolysis; imaging; immunometabolism
    DOI:  https://doi.org/10.15252/embj.2022111528
  25. ESMO Open. 2022 Aug 19. pii: S2059-7029(22)00178-8. [Epub ahead of print]7(5): 100550
    EPIC: an evaluation of the psychological impact of early-phase clinical trials in cancer patients.
    P Jittla, D M Graham, C Zhou, J Halliwell, S O'Reilly, S Aruketty, A Azizi, T Germetaki, J Lowe, M Little, G Punnett, P McMahon, L Benson, L Carter, M G Krebs, F C Thistlethwaite, E Darlington, J Yorke, N Cook.
      BACKGROUND: Anxiety and depression in patients with cancer is associated with decreased quality of life and increased morbidity and mortality. However, these are often overlooked and untreated. Early-phase clinical trials (EPCTs) recruit patients with advanced cancers who frequently lack future treatment options, which may lead to increased anxiety and depression. Despite this, EPCTs do not routinely consider psychological screening for patients.PATIENTS AND METHODS: This prospective observational study explored levels of anxiety and depression alongside impact of trial participation in the context of EPCTs. The Hospital Anxiety and Depression Scale and the Brief Illness Perceptions Questionnaire were completed at the point of EPCT consent, the end of screening and at pre-specified time points thereafter.
    RESULTS: Sixty-four patients (median age 56 years; median Eastern Cooperative Oncology Group performance status 1) were recruited. At consent, 57 patients returned questionnaires; 39% reported clinically relevant levels of anxiety whilst 18% reported clinically relevant levels of depression. Sixty-three percent of patients experiencing psychological distress had never previously reported this. Males were more likely to be depressed (P = 0.037) and females were more likely to be anxious (P = 0.011). Changes in anxiety or depression were observed after trial enrolment on an individual level, but not significant on a population level.
    CONCLUSIONS: Patients on EPCTs are at an increased risk of anxiety and depression but may not seek relevant support. Sites offering EPCTs should consider including psychological screening to encourage a more holistic approach to cancer care and consider the sex of individuals when tailoring psychological support to meet specific needs.
    Keywords:  anxiety; cancer; clinical trials; depression; early phase; phase I
    DOI:  https://doi.org/10.1016/j.esmoop.2022.100550
  26. JCI Insight. 2022 Aug 23. pii: e155296. [Epub ahead of print]
    ADAM17-mediated EGFR ligand shedding directs macrophage promoted cancer cell invasion.
    Sebastian Gnosa, Laia Puig-Blasco, Krzysztof B Piotrowski, Marie L Freiberg, Simonas Savickas, Daniel H Madsen, Ulrich Auf dem Keller, Pauliina Kronqvist, Marie Kveiborg.
      Macrophages in the tumor microenvironment have a significant impact on tumor progression. Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor progression. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of ADAM proteases, which are key mediators of cell-cell signaling, to the expression of pro-tumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several pro-tumorigenic markers in neighboring macrophages in vitro as well as in mouse models. Moreover, ADAM17-/- educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using mass spectrometry-based proteomics and ELISA, we identified HB-EGF and AREG, shed by ADAM17 in the cancer cells, as the implicated molecular mediators of macrophage education. Additionally, RNA-seq and ELISA experiments revealed that ADAM17-dependent HB-EGF-ligand release induces the expression and secretion of CXCL chemokines in macrophages, which in turn stimulates cancer cell invasion.In conclusion, we provide evidence that ADAM17 mediates a paracrine EGFR-ligand-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.
    Keywords:  Cancer; Macrophages; Oncology; Proteases
    DOI:  https://doi.org/10.1172/jci.insight.155296
  27. Lab Chip. 2022 Aug 23.
    Automated biophysical classification of apoptotic pancreatic cancer cell subpopulations by using machine learning approaches with impedance cytometry.
    Carlos Honrado, Armita Salahi, Sara J Adair, John H Moore, Todd W Bauer, Nathan S Swami.
      Unrestricted cell death can lead to an immunosuppressive tumor microenvironment, with dysregulated apoptotic signaling that causes resistance of pancreatic cancer cells to cytotoxic therapies. Hence, modulating cell death by distinguishing the progression of subpopulations under drug treatment from viable towards early apoptotic, late apoptotic, and necrotic states is of interest. While flow cytometry after fluorescent staining can monitor apoptosis with single-cell sensitivity, the background of non-viable cells within non-immortalized pancreatic tumors from xenografts can confound distinction of the intensity of each apoptotic state. Based on single-cell impedance cytometry of drug-treated pancreatic cancer cells that are obtained from tumor xenografts with differing levels of gemcitabine sensitivity, we identify the biophysical metrics that can distinguish and quantify cellular subpopulations at the early apoptotic versus late apoptotic and necrotic states, by using machine learning methods to train for the recognition of each phenotype. While supervised learning has previously been used for classification of datasets with known classes, our advancement is the utilization of optimal positive controls for each class, so that clustering by unsupervised learning and classification by supervised learning can occur on unknown datasets, without human interference or manual gating. In this manner, automated biophysical classification can be used to follow the progression of apoptotic states in each heterogeneous drug-treated sample, for developing drug treatments to modulate cancer cell death and advance longitudinal analysis to discern the emergence of drug resistant phenotypes.
    DOI:  https://doi.org/10.1039/d2lc00304j
  28. Pancreatology. 2022 Aug 12. pii: S1424-3903(22)00477-X. [Epub ahead of print]
    Intraductal pressure in experimental models of acute and chronic pancreatitis in mice.
    Mengya Niu, Xiuli Zhang, Pengli Song, Liang Li, Li Wen.
      BACKGROUND/OBJECTIVES: Pancreatic intraductal pressure is related to the development of pancreatitis, including post-ERCP (endoscopic retrograde cholangiopancreatography) pancreatitis. In this study, we investigate pancreatic intraductal pressure in various mouse models of acute and chronic pancreatitis.METHODS: Post-ERCP pancreatitis was induced by retrograde infusion of normal saline or radiocontrast at the constant rate of 10 or 20 μL/min. Obstructive pancreatitis was induced by ligation of the pancreatic duct followed by a single injection of caerulein and the changes of intraductal pressure were recorded in day 3 for obstructive acute pancreatitis and day 14 for obstructive chronic pancreatitis. Non-obstructive pancreatitis was induced by repetitive intraperitoneal injections of caerulein. The changes of intraductal pressure were recorded right after the last caerulein injection for non-obstructive acute pancreatitis and after the completion of 4-week caerulein injections for non-obstructive chronic pancreatitis.
    RESULTS: Elevated pancreatic intraductal pressure was observed in both normal saline and radiocontrast infusion groups and was furtherly indicated that was positively correlated with the viscosity of solution but not genders. In the models of obstructive pancreatitis, a rise in intraductal pressure was observed in both acute and chronic pancreatitis; whereas in the models of non-obstructive pancreatitis, a rise in intraductal pressure was only observed in chronic, but not acute pancreatitis.
    CONCLUSIONS: During ERCP, the elevations in pancreatic intraductal pressure are induced by increasing rate or viscous solution of infusion. During different forms of experimental acute and chronic pancreatitis, obstructive or non-obstructive etiologies of pancreatitis also induces the elevations in pancreatic intraductal pressure.
    Keywords:  Infusion rate; Obstructive etiologies; Pancreatic intraductal pressure; Pancreatitis; Solution viscosity
    DOI:  https://doi.org/10.1016/j.pan.2022.08.006
  29. Cancer Discov. 2022 Aug 23. OF1-OF22
    Science-Driven Nutritional Interventions for the Prevention and Treatment of Cancer.
    Léa Montégut, Rafael de Cabo, Laurence Zitvogel, Guido Kroemer.
      In population studies, dietary patterns clearly influence the development, progression, and therapeutic response of cancers. Nonetheless, interventional dietary trials have had relatively little impact on the prevention and treatment of malignant disease. Standardization of nutritional interventions combined with high-level mode-of-action studies holds the promise of identifying specific entities and pathways endowed with antineoplastic properties. Here, we critically review the effects of caloric restriction and more specific interventions on macro- and micronutrients in preclinical models as well as in clinical studies. We place special emphasis on the prospect of using defined nutrition-relevant molecules to enhance the efficacy of established anticancer treatments.SIGNIFICANCE: The avoidance of intrinsically hypercaloric and toxic diets contributes to the prevention and cure of cancer. In addition, specific diet-induced molecules such as ketone bodies and micronutrients, including specific vitamins, have drug-like effects that are clearly demonstrable in preclinical models, mostly in the context of immunotherapies. Multiple trials are underway to determine the clinical utility of such molecules.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0504
  30. Eur Radiol. 2022 Aug 25.
    Correlation of transcriptional subtypes with a validated CT radiomics score in resectable pancreatic ductal adenocarcinoma.
    Emmanuel Salinas-Miranda, Gerard M Healy, Barbara Grünwald, Rahi Jain, Dominik Deniffel, Grainne M O'Kane, Robert Grant, Julie Wilson, Jennifer Knox, Steven Gallinger, Sandra Fischer, Rama Khokha, Masoom A Haider.
      OBJECTIVES: Transcriptional classifiers (Bailey, Moffitt and Collison) are key prognostic factors of pancreatic ductal adenocarcinoma (PDAC). Among these classifiers, the squamous, basal-like, and quasimesenchymal subtypes overlap and have inferior survival. Currently, only an invasive biopsy can determine these subtypes, possibly resulting in treatment delay. This study aimed to investigate the association between transcriptional subtypes and an externally validated preoperative CT-based radiomic prognostic score (Rad-score).METHODS: We retrospectively evaluated 122 patients who underwent resection for PDAC. All treatment decisions were determined at multidisciplinary tumor boards. Tumor Rad-score values from preoperative CT were dichotomized into high or llow categories. The primary endpoint was the correlation between the transcriptional subtypes and the Rad-score using multivariable linear regression, adjusting for clinical and histopathological variables (i.e., tumor size). Prediction of overall survival (OS) was secondary endpoint.
    RESULTS: The Bailey transcriptional classifier significantly associated with the Rad-score (coefficient = 0.31, 95% confidence interval [CI]: 0.13-0.44, p = 0.001). Squamous subtype was associated with high Rad-scores while non-squamous subtype was associated with low Rad-scores (adjusted p = 0.03). Squamous subtype and high Rad-score were both prognostic for OS at multivariable analysis with hazard ratios (HR) of 2.79 (95% CI: 1.12-6.92, p = 0.03) and 4.03 (95% CI: 1.42-11.39, p = 0.01), respectively.
    CONCLUSIONS: In patients with resectable PDAC, an externally validated prognostic radiomic model derived from preoperative CT is associated with the Bailey transcriptional classifier. Higher Rad-scores were correlated with the squamous subtype, while lower Rad-scores were associated with the less lethal subtypes (immunogenic, ADEX, pancreatic progenitor).
    KEY POINTS: • The transcriptional subtypes of PDAC have been shown to have prognostic importance but they require invasive biopsy to be assessed. • The Rad-score radiomic biomarker, which is obtained non-invasively from preoperative CT, correlates with the Bailey squamous transcriptional subtype and both are negative prognostic biomarkers. • The Rad-score is a promising non-invasive imaging biomarker for personalizing neoadjuvant approaches in patients undergoing resection for PDAC, although additional validation studies are required.
    Keywords:  Biomarkers; Carcinoma, Pancreatic ductal; Microarray analysis; Prognosis; Tomography, X-ray computed
    DOI:  https://doi.org/10.1007/s00330-022-09057-y
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