bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–12–25
fifty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer.
  2. Collagen VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche.
  3. Orchestration of selective autophagy by cargo receptors.
  4. mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.
  5. Cancer Cachexia and Dysregulated Phosphate Metabolism: Insights from Mutant p53 and Mutant Klotho Mouse Models.
  6. Epigenetic clocks, aging, and cancer.
  7. ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.
  8. Metabolic switch in cancer - Survival of the fittest.
  9. The Sag-Shoc2 axis regulates conversion of mPanINs to cystic lesions in Kras pancreatic tumor model.
  10. Spatial proteomics in three-dimensional intact specimens.
  11. The importance of being generous.
  12. Role of autophagy in aging: The good, the bad, and the ugly.
  13. Mechanisms of RNA and Protein Quality Control and Their Roles in Cellular Senescence and Age-Related Diseases.
  14. Autophagic degradation of membrane-bound organelles in plants.
  15. Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.
  16. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.
  17. A small Rho GTPase RAB25 with a potential role in chemotherapy resistance in pancreatic cancer.
  18. Development and validation of an online dynamic nomogram system for predicting cancer cachexia among inpatients: a real-world cohort study in China.
  19. Dietary stress remodels the genetic architecture of lifespan variation in outbred Drosophila.
  20. CyTOF protocol for immune monitoring of solid tumors from mouse models.
  21. The crucial role of elasticity in regulating liquid-liquid phase separation in cells.
  22. Dissecting the recruitment and self-organization of αSMA-positive fibroblasts in the foreign body response.
  23. Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis.
  24. Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.
  25. Kinase regulation by liquid-liquid phase separation.
  26. The 2022 George E Palade Medal Lecture: Toxic Ca2+ signals in acinar, stellate and endogenous immune cells are important drivers of acute pancreatitis.
  27. Caveolin-1 dolines form a distinct and rapid caveolae-independent mechanoadaptation system.
  28. Transcriptomic pan-cancer analysis using rank-based Bayesian inference.
  29. Systematic interrogation of tumor cell resistance to CAR T cell therapy in pancreatic cancer.
  30. Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.
  31. Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis.
  32. USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity.
  33. Targeting KRASG12C in colorectal cancer: the beginning of a new era.
  34. Association between type 2 diabetes and 5-year overall survival in early-stage pancreatic cancer: a retrospective cohort study.
  35. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.
  36. Smoking Cessation after Cancer Diagnosis and Enhanced Therapy Response: Mechanisms and Significance.
  37. Ubiquitin modulates 26S proteasome conformational dynamics and promotes substrate degradation.
  38. KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?
  39. Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis.
  40. Exercise and mitochondrial mechanisms in patients with sarcopenia.
  41. Association between diabetes and cancer. Current mechanistic insights into the association and future challenges.
  42. Current treatment landscape of pancreatic cancer patients in a network of office-based oncologists in Germany.
  43. Modeling membrane reshaping driven by dynamic protein assemblies.
  44. Technologies for Viable Circulating Tumor Cell Isolation.
  45. The Multidisciplinary Cancer Conference.
  46. Guiding the choice of informatics software and tools for lipidomics research applications.
  47. dSCOPE: a software to detect sequences critical for liquid-liquid phase separation.
  48. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.
  49. Understanding the Link between Sugar and Cancer: An Examination of the Preclinical and Clinical Evidence.
  50. Nanobody-tethered transposition enables multifactorial chromatin profiling at single-cell resolution.
  1. Cell Mol Life Sci. 2022 Dec 19. 80(1): 12
    AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer.
    Christian Schneeweis, Sandra Diersch, Zonera Hassan, Lukas Krauß, Carolin Schneider, Daniele Lucarelli, Chiara Falcomatà, Katja Steiger, Rupert Öllinger, Oliver H Krämer, Alexander Arlt, Marian Grade, Marc Schmidt-Supprian, Elisabeth Hessmann, Matthias Wirth, Roland Rad, Maximilian Reichert, Dieter Saur, Günter Schneider.
      Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF-MEK-ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.
    Keywords:  AP1; ERK; FRA1; KRAS; MEK; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s00018-022-04638-y
  2. J Cell Sci. 2022 Dec 15. pii: jcs259978. [Epub ahead of print]135(24):
    Collagen VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche.
    Vasileios Papalazarou, James Drew, Amelie Juin, Heather J Spence, Jamie Whitelaw, Colin Nixon, Manuel Salmeron-Sanchez, Laura M Machesky.
      Pancreatic cancer is a deadly and highly metastatic disease, although how metastatic lesions establish is not fully understood. A key feature of pancreatic tumours is extensive fibrosis and deposition of extracellular matrix (ECM). While pancreatic cancer cells are programmed by stimuli derived from a stiff ECM, metastasis requires loss of attachment and adaptation to a softer microenvironment at distant sites. Growing evidence suggests that stiff ECM influences pancreatic cancer cell behaviour. Here, we argue that this influence is reversible and that pancreatic cancer cells can be reprogrammed upon sensing soft substrates. Using engineered polyacrylamide hydrogels with tuneable mechanical properties, we show that collagen VI is specifically upregulated in pancreatic cancer cells on soft substrates, due to a lack of integrin engagement. Furthermore, the expression of collagen VI is inversely correlated with mechanosensing and activity of YAP (also known as YAP1), which might be due to a direct or indirect effect on transcription of genes encoding collagen VI. Collagen VI supports migration in vitro and metastasis formation in vivo. Metastatic nodules formed by pancreatic cancer cells lacking Col6a1 display stromal cell-derived collagen VI deposition, suggesting that collagen VI derived from either cancer cells or the stroma is an essential component of the metastatic niche. This article has an associated First Person interview with Vasileios Papalazarou, joint first author of the paper.
    Keywords:  Cancer metastasis; Collagen VI; Extracellular matrix; Integrin adhesion; Mechanosensing; Pancreatic cancer
    DOI:  https://doi.org/10.1242/jcs.259978
  3. Curr Biol. 2022 Dec 19. pii: S0960-9822(22)01758-4. [Epub ahead of print]32(24): R1357-R1371
    Orchestration of selective autophagy by cargo receptors.
    Elias Adriaenssens, Luca Ferrari, Sascha Martens.
      Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo material. This is achieved by the sequestration of the cargo within double-membrane vesicles termed autophagosomes, which form de novo around the cargo and subsequently deliver their content to lysosomes for degradation. The importance of selective autophagy is exemplified by the various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. It has become evident that cargo receptors are acting as Swiss army knives in selective autophagy by recognizing the cargo, orchestrating the recruitment of the machinery for autophagosome biogenesis, and closely aligning the membrane with the cargo. Furthermore, cargo receptors sequester ubiquitinated proteins into larger condensates upstream of autophagy induction. Here, we review recent insights into the mechanisms of action of cargo receptors in selective autophagy by focusing on the roles of sequestosome-like cargo receptors in the degradation of misfolded, ubiquitinated proteins and damaged mitochondria. We also highlight at which steps defects in their function result in the accumulation of harmful material and how this knowledge may guide the design of future therapies.
    DOI:  https://doi.org/10.1016/j.cub.2022.11.002
  4. Nat Metab. 2022 Dec;4(12): 1792-1811
    mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species.
    Aaron M Hosios, Meghan E Wilkinson, Molly C McNamara, Krystle C Kalafut, Margaret E Torrence, John M Asara, Brendan D Manning.
      The mechanistic target of rapamycin complex 1 (mTORC1) senses and relays environmental signals from growth factors and nutrients to metabolic networks and adaptive cellular systems to control the synthesis and breakdown of macromolecules; however, beyond inducing de novo lipid synthesis, the role of mTORC1 in controlling cellular lipid content remains poorly understood. Here we show that inhibition of mTORC1 via small molecule inhibitors or nutrient deprivation leads to the accumulation of intracellular triglycerides in both cultured cells and a mouse tumor model. The elevated triglyceride pool following mTORC1 inhibition stems from the lysosome-dependent, but autophagy-independent, hydrolysis of phospholipid fatty acids. The liberated fatty acids are available for either triglyceride synthesis or β-oxidation. Distinct from the established role of mTORC1 activation in promoting de novo lipid synthesis, our data indicate that mTORC1 inhibition triggers membrane phospholipid trafficking to the lysosome for catabolism and an adaptive shift in the use of constituent fatty acids for storage or energy production.
    DOI:  https://doi.org/10.1038/s42255-022-00706-6
  5. Metabolites. 2022 Dec 17. pii: 1284. [Epub ahead of print]12(12):
    Cancer Cachexia and Dysregulated Phosphate Metabolism: Insights from Mutant p53 and Mutant Klotho Mouse Models.
    Ronald B Brown.
      The present perspective article proposes that cachexia, muscle wasting in cancer, is mediated by dysregulated phosphate metabolism and phosphate toxicity that can damage tissues in most major organ systems. A diet high in phosphorus fed to mice deficient in klotho, a cofactor that regulates phosphate metabolism, accelerates aging, sarcopenia, general organ atrophy, kyphosis, and osteoporosis. Similar effects are seen in phenotypes of mutant p53 mice that overexpress the p53 tumor suppressor gene. Although mutant p53 mice do not develop tumors compared to wild-type mice, mutant p53 mice have shorter mean lifespans. Furthermore, tumorigenesis is associated with the sequestration of excessive inorganic phosphate, and dangerous levels of phosphate are released into circulation during tumor lysis syndrome. In total, this evidence implies that tumorigenesis may be a compensatory mechanism that provides protective effects against systemic exposure to dysregulated phosphate metabolism and phosphate toxicity related to cachexia in cancer. Moreover, the hypothetical protection against phosphate toxicity afforded by tumorigenesis also provides an alternate explanation for putative tumor evasion of the immune system. Insights proposed in this perspective paper provide new directions for further research, with potential to develop novel interventions and clinical applications that modify dietary phosphate intake to reduce cachexia in cancer patients.
    Keywords:  aging; bone disorders; cancer cachexia; dysregulated phosphate metabolism; klotho; muscle wasting; mutant klotho mice; mutant p53 mice; phosphate toxicity
    DOI:  https://doi.org/10.3390/metabo12121284
  6. Science. 2022 Dec 23. 378(6626): 1276-1277
    Epigenetic clocks, aging, and cancer.
    Sarah E Johnstone, Vadim N Gladyshev, Martin J Aryee, Bradley E Bernstein.
      Global methylation changes in aging cells affect cancer risk and tissue homeostasis.
    DOI:  https://doi.org/10.1126/science.abn4009
  7. Dev Cell. 2022 Dec 19. pii: S1534-5807(22)00815-2. [Epub ahead of print]57(24): 2714-2730.e8
    ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.
    Arthur W Lambert, Christopher Fiore, Yogesh Chutake, Elisha R Verhaar, Patrick C Strasser, Mei Wei Chen, Daneyal Farouq, Sunny Das, Xin Li, Elinor Ng Eaton, Yun Zhang, Joana Liu Donaher, Ian Engstrom, Ferenc Reinhardt, Bingbing Yuan, Sumeet Gupta, Bruce Wollison, Matthew Eaton, Brian Bierie, John Carulli, Eric R Olson, Matthew G Guenther, Robert A Weinberg.
      Cancer stem cells (CSCs) may serve as the cellular seeds of tumor recurrence and metastasis, and they can be generated via epithelial-mesenchymal transitions (EMTs). Isolating pure populations of CSCs is difficult because EMT programs generate multiple alternative cell states, and phenotypic plasticity permits frequent interconversions between these states. Here, we used cell-surface expression of integrin β4 (ITGB4) to isolate highly enriched populations of human breast CSCs, and we identified the gene regulatory network operating in ITGB4+ CSCs. Specifically, we identified ΔNp63 and p73, the latter of which transactivates ΔNp63, as centrally important transcriptional regulators of quasi-mesenchymal CSCs that reside in an intermediate EMT state. We found that the transcriptional program controlled by ΔNp63 in CSCs is largely distinct from the one that it orchestrates in normal basal mammary stem cells and, instead, it more closely resembles a regenerative epithelial stem cell response to wounding. Moreover, quasi-mesenchymal CSCs repurpose this program to drive metastatic colonization via autocrine EGFR signaling.
    Keywords:  EMT; breast cancer; cancer stem cells; epigenetics; metastasis
    DOI:  https://doi.org/10.1016/j.devcel.2022.11.015
  8. Eur J Cancer. 2022 Nov 26. pii: S0959-8049(22)01770-1. [Epub ahead of print]180 30-51
    Metabolic switch in cancer - Survival of the fittest.
    Hans Raskov, Shruti Gaggar, Asma Tajik, Adile Orhan, Ismail Gögenur.
      Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring of cancer cell metabolism. Driver gene mutations direct malignant cells away from oxidation to maximise energy production and biosynthesis while tumour-secreted factors degrade peripheral tissues to fuel disease progression and initiate metastasis. As it is vital to understand cancer cell metabolism and survival mechanisms, this review discusses the metabolic switch and current drug targets and clinical trials. In the future, metabolic markers may be included when phenotyping individual tumours to improve the therapeutic opportunities for personalised therapy.
    Keywords:  Biosynthesis; Energy production; Hypoxia; Metabolic reprogramming; Nutrient exploitation; Wasting syndrome
    DOI:  https://doi.org/10.1016/j.ejca.2022.11.025
  9. Cell Rep. 2022 Dec 20. pii: S2211-1247(22)01729-6. [Epub ahead of print]41(12): 111837
    The Sag-Shoc2 axis regulates conversion of mPanINs to cystic lesions in Kras pancreatic tumor model.
    Mingjia Tan, Yu Chang, Xiaoqiang Liu, Hua Li, Zaiming Tang, Mukesh K Nyati, Yi Sun.
      SAG/RBX2 is an E3 ligase, whereas SHOC2 is a RAS-RAF positive regulator. In this study, we address how Sag-Shoc2 crosstalk regulates pancreatic tumorigenesis induced by KrasG12D. Sag deletion increases the size of pancreas and causes the conversion of murine pancreatic intraepithelial neoplasms (mPanINs) to neoplastic cystic lesions with a mechanism involving Shoc2 accumulation, suggesting that Sag determines the pathological process via targeting Shoc2. Shoc2 deletion significantly inhibits pancreas growth, mPanIN formation, and acinar cell transdifferentiation, indicating that Shoc2 is essential for KrasG12D-induced pancreatic tumorigenesis. Likewise, in a primary acinar 3D culture, Sag deletion inhibits acinar-to-ductal transdifferentiation, while Shoc2 deletion significantly reduces the duct-like structures. Mechanistically, SAG is an E3 ligase that targets SHOC2 for degradation to affect both Mapk and mTorc1 pathways. Shoc2 deletion completely rescues the phenotype of neoplastic cystic lesions induced by Sag deletion, indicating physiological relevance of the Sag-Shoc2 crosstalk. Thus, the Sag-Shoc2 axis specifies the pancreatic tumor types induced by KrasG12D.
    Keywords:  CP: Cancer; Deptor; KRAS; MAPK and mTORC1 signals; Sag/Rbx2 E3 ligase; Shoc2; cystic lesions; cystogenesis; pancreatic tumorigenesis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111837
  10. Cell. 2022 Dec 22. pii: S0092-8674(22)01465-9. [Epub ahead of print]185(26): 5040-5058.e19
    Spatial proteomics in three-dimensional intact specimens.
    Harsharan Singh Bhatia, Andreas-David Brunner, Furkan Öztürk, Saketh Kapoor, Zhouyi Rong, Hongcheng Mai, Marvin Thielert, Mayar Ali, Rami Al-Maskari, Johannes Christian Paetzold, Florian Kofler, Mihail Ivilinov Todorov, Muge Molbay, Zeynep Ilgin Kolabas, Moritz Negwer, Luciano Hoeher, Hanno Steinke, Alina Dima, Basavdatta Gupta, Doris Kaltenecker, Özüm Sehnaz Caliskan, Daniel Brandt, Natalie Krahmer, Stephan Müller, Stefan Frieder Lichtenthaler, Farida Hellal, Ingo Bechmann, Bjoern Menze, Fabian Theis, Matthias Mann, Ali Ertürk.
      Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer's disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. VIDEO ABSTRACT.
    Keywords:  AI; Alzheimer’s; TBI; deep learning; human heart; mass spectrometry; proteomics; robotics; spatial-omics; tissue clearing
    DOI:  https://doi.org/10.1016/j.cell.2022.11.021
  11. Nat Cancer. 2022 Dec;3(12): 1423-1425
    The importance of being generous.
    Alexia-Ileana Zaromytidou.
      
    DOI:  https://doi.org/10.1038/s43018-022-00493-9
  12. Aging Cell. 2022 Dec 20. e13753
    Role of autophagy in aging: The good, the bad, and the ugly.
    Siamak Tabibzadeh.
      Autophagy (self-eating) is a conserved catabolic homeostatic process required for cellular metabolic demands by removal of the damaged molecules and organelles and for alleviation of stress initiated by pathology and infection. By such actions, autophagy is essential for the prevention of aging, disease, and cancer. Genetic defects of autophagy genes lead to a host of developmental, metabolic, and pathological aberrations. Similarly, the age-induced decline in autophagy leads to the loss of cellular homeostatic control. Paradoxically, such a valuable mechanism is hijacked by diseases, during tumor progression and by senescence, presumably due to high levels of metabolic demand. Here, we review both the role of autophagy in preventing cellular decline in aging by fulfillment of cellular bioenergetic demands and its contribution to the maintenance of the senescent state and SASP by acting on energy and nutritional sensors and diverse signaling pathways.
    Keywords:  AMPK; SASP; aging; cancer; mTOR; senescence
    DOI:  https://doi.org/10.1111/acel.13753
  13. Cells. 2022 Dec 15. pii: 4062. [Epub ahead of print]11(24):
    Mechanisms of RNA and Protein Quality Control and Their Roles in Cellular Senescence and Age-Related Diseases.
    Donghee Kang, Yurim Baek, Jae-Seon Lee.
      Cellular senescence, a hallmark of aging, is defined as irreversible cell cycle arrest in response to various stimuli. It plays both beneficial and detrimental roles in cellular homeostasis and diseases. Quality control (QC) is important for the proper maintenance of cellular homeostasis. The QC machineries regulate the integrity of RNA and protein by repairing or degrading them, and are dysregulated during cellular senescence. QC dysfunction also contributes to multiple age-related diseases, including cancers and neurodegenerative, muscle, and cardiovascular diseases. In this review, we describe the characters of cellular senescence, discuss the major mechanisms of RNA and protein QC in cellular senescence and aging, and comprehensively describe the involvement of these QC machineries in age-related diseases. There are many open questions regarding RNA and protein QC in cellular senescence and aging. We believe that a better understanding of these topics could propel the development of new strategies for addressing age-related diseases.
    Keywords:  RNA quality control; age-related diseases; cellular senescence; protein quality control
    DOI:  https://doi.org/10.3390/cells11244062
  14. Biosci Rep. 2022 Dec 23. pii: BSR20221204. [Epub ahead of print]
    Autophagic degradation of membrane-bound organelles in plants.
    Jiaojiao Wang, Qian Zhang, Yan Bao, Diane Bassham.
      Eukaryotic cells have evolved membrane-bound organelles, including the endoplasmic reticulum (ER), Golgi, mitochondria, peroxisomes, chloroplasts (in plants and green algae) and lysosomes/vacuoles, for specialized functions. Organelle quality control and their proper interactions are crucial both for normal cell homeostasis and function and for environmental adaption. Dynamic turnover of organelles is tightly controlled, with autophagy playing an essential role. Autophagy is a programmed process for efficient clearing of unwanted or damaged macromolecules or organelles, transporting them to vacuoles for degradation and recycling and thereby enhancing plant environmental plasticity. The specific autophagic engulfment of organelles requires activation of a selective autophagy pathway, recognition of the organelle by a receptor, and selective incorporation of the organelle into autophagosomes. While some of the autophagy machinery and mechanisms for autophagic removal of organelles is conserved across eukaryotes, plants have also developed unique mechanisms and machinery for these pathways. In this review, we discuss recent progress in understanding autophagy regulation in plants, with a focus on autophagic degradation of membrane-bound organelles. We also raise some important outstanding questions to be addressed in the future.
    Keywords:  Autophagosome; degradation; organelle; receptor; selective autophagy; stress
    DOI:  https://doi.org/10.1042/BSR20221204
  15. Nat Commun. 2022 Dec 20. 13(1): 7830
    Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.
    Marco Sciacovelli, Aurelien Dugourd, Lorea Valcarcel Jimenez, Ming Yang, Efterpi Nikitopoulou, Ana S H Costa, Laura Tronci, Veronica Caraffini, Paulo Rodrigues, Christina Schmidt, Dylan Gerard Ryan, Timothy Young, Vincent R Zecchini, Sabrina H Rossi, Charlie Massie, Caroline Lohoff, Maria Masid, Vassily Hatzimanikatis, Christoph Kuppe, Alex Von Kriegsheim, Rafael Kramann, Vincent Gnanapragasam, Anne Y Warren, Grant D Stewart, Ayelet Erez, Sakari Vanharanta, Julio Saez-Rodriguez, Christian Frezza.
      Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.
    DOI:  https://doi.org/10.1038/s41467-022-35036-4
  16. Cell Metab. 2022 Dec 12. pii: S1550-4131(22)00504-6. [Epub ahead of print]
    Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.
    Hannah N Bell, Amanda K Huber, Rashi Singhal, Navyateja Korimerla, Ryan J Rebernick, Roshan Kumar, Marwa O El-Derany, Peter Sajjakulnukit, Nupur K Das, Samuel A Kerk, Sumeet Solanki, Jadyn G James, Donghwan Kim, Li Zhang, Brandon Chen, Rohit Mehra, Timothy L Frankel, Balázs Győrffy, Eric R Fearon, Marina Pasca di Magliano, Frank J Gonzalez, Ruma Banerjee, Daniel R Wahl, Costas A Lyssiotis, Michael Green, Yatrik M Shah.
      Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies.
    Keywords:  ammonia; cancer metabolism; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.013
  17. Cancer Biomark. 2022 Dec 15.
    A small Rho GTPase RAB25 with a potential role in chemotherapy resistance in pancreatic cancer.
    Amira Kohil, Sayeda S Amir, Axel Behrens, Omar M Khan.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is one of the major human health challenges with minimal therapeutic benefits due to its late detection, and de novo - and acquired chemotherapy resistance.
    OBJECTIVE: In this work we unravel the potential pro-survival role of RAB25 in pancreatic cancer chemotherapy resistance and aim to identify if RAB25is a prognostic marker of patients' survival in PDA.
    METHODS: We used RNA sequencing, shRNA mediated gene knockdown, BioGRID open repository of CRISPR screens (ORCS), GEPIA, kmplot.com, and cBioPortal.org databases to identify the role of RAB25 in PDA cell proliferation, chemotherapy response, expression in tumour versus normal tissues, and overall patients' survival.
    RESULTS: RNA sequencing show Rab25 to be one of the top upregulated genes in gemcitabine resistant mouse PDA cells. Knockdown of Rab25 in these cells enhanced gemcitabine toxicity. In addition, re-analysis of previously published CRISPR/Cas9 data confirm RAB25 to be responsible for chemotherapy resistance in KRASG12D mutant human pancreatic cancer cell line. Finally, we used publicly available TCGA datasets and identify the upregulation of RAB25 in tumour tissues compared to the adjacent normal tissue, co-occurrence of KRASG12 mutations with RAB25 amplifications, and poor patients' survival in cohorts with higher mRNA expression of RAB25.
    CONCLUSION: RAB25 expression is a prognostic marker for patient's survival and gemcitabine resistance in PDA.
    Keywords:  KRAS; RAB25; TCGA; chemotherapy resistance; pancreatic cancer
    DOI:  https://doi.org/10.3233/CBM-220214
  18. Support Care Cancer. 2022 Dec 22. 31(1): 72
    Development and validation of an online dynamic nomogram system for predicting cancer cachexia among inpatients: a real-world cohort study in China.
    Zhenyu Huo, Feifei Chong, Liangyu Yin, Na Li, Mengyuan Zhang, Jing Guo, Xin Lin, Yang Fan, Ling Zhang, Hongmei Zhang, Muli Shi, Xiumei He, Zongliang Lu, Jie Liu, Wei Li, Hanping Shi, Hongxia Xu.
       BACKGROUND: Early recognition of cachexia is essential for ensuring the prompt intervention and treatment of cancer patients. However, the diagnosis of cancer cachexia (CC) usually is delayed. This study aimed to establish an accurate and high-efficiency diagnostic system for CC.
    METHODS: A total of 4834 cancer inpatients were enrolled in the INSCOC project from July 2013 to June 2020. All cancer patients in the study were randomly assigned to a development cohort (n=3384, 70%) and a validation cohort (n=1450, 30%). The least absolute shrinkage and selection operator (LASSO) method and multivariable logistic regression were used to identify the independent predictors for developing the dynamic nomogram. Discrimination and calibration were adopted to evaluate the ability of nomogram. A decision curve analysis (DCA) was used to evaluate clinical use.
    RESULTS: We combined 5 independent predictive factors (age, NRS2002, PG-SGA, QOL by the QLQ-C30, and cancer categories) to establish the online dynamic nomogram system. The C-index, sensitivity, and specificity of the nomo-system to predict CC was 0.925 (95%CI, 0.916-0.934, P < 0.001), 0.826, and 0.862 in the development set, while the values were 0.923 (95%CI, 0.909-0.937, P < 0.001), 0.854, and 0.829 in the validation set. In addition, the calibration curves of the diagnostic nomogram also presented good agreement with the actual situation. DCA showed that the model is clinically useful and can increase the clinical benefit in cancer patients.
    CONCLUSIONS: This study developed an online dynamic nomogram system with outstanding accuracy to help clinicians and dieticians estimate the probability of cachexia. This simple-to-use online nomogram can increase the clinical benefit in cancer patients and is expected to be widely adopted.
    Keywords:  Cancer cachexia; Dynamic nomogram; LASSO regression; Prediction; Real-world cohort study
    DOI:  https://doi.org/10.1007/s00520-022-07540-2
  19. Nat Genet. 2022 Dec 22.
    Dietary stress remodels the genetic architecture of lifespan variation in outbred Drosophila.
    Luisa F Pallares, Amanda J Lea, Clair Han, Elena V Filippova, Peter Andolfatto, Julien F Ayroles.
      Evolutionary theory suggests that lifespan-reducing alleles should be purged from the gene pool, and yet decades of genome-wide association and model organism studies have shown that they persist. One potential explanation is that alleles that regulate lifespan do so only in certain environmental contexts. We exposed outbred Drosophila to control and high-sugar diets and genotyped more than 10,000 adult flies to track allele frequency changes over the course of a single adult lifespan. We identified thousands of lifespan-associated alleles associated with early versus late-life trade-offs, late-onset effects and genotype-by-environment interactions. Remarkably, a third of lifespan-associated genetic variation had environmentally dependent effects on lifespan. We find that lifespan-reducing alleles are often recently derived, have stronger effects on a high-sugar diet and show signatures of selection in wild Drosophila populations, consistent with the evolutionary mismatch hypothesis. Our results provide insight into the highly polygenic and context-dependent genetic architecture of lifespan variation and the evolutionary processes that shape this key trait.
    DOI:  https://doi.org/10.1038/s41588-022-01246-1
  20. STAR Protoc. 2022 Dec 19. pii: S2666-1667(22)00829-2. [Epub ahead of print]4(1): 101949
    CyTOF protocol for immune monitoring of solid tumors from mouse models.
    Sarah M Shin, Alexei Hernandez, Erin Coyne, Kabeer Munjal, Nicole E Gross, Soren Charmsaz, Xuan Yuan, Hongqui Yang, Won Jin Ho.
      Techniques for robust immune profiling of mouse tumor and blood are key to understanding immunological responses in mouse models of cancer. Here, we describe mass cytometry (cytometry by time-of-flight) procedures to facilitate high-parameter profiling of low-volume survival blood samples and end-of-study tumor samples. We employ live-cell barcoding systems to mark all cells from each tumor and blood to improve cost-effectiveness and minimize batch effects. For complete details on the use and execution of this protocol, please refer to Charmsaz et al. (2021).1.
    Keywords:  Antibody; Cancer; Flow Cytometry/Mass Cytometry; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2022.101949
  21. Biomech Model Mechanobiol. 2022 Dec 24.
    The crucial role of elasticity in regulating liquid-liquid phase separation in cells.
    Mrityunjay Kothari, Tal Cohen.
      Liquid-liquid phase separation has emerged as a fundamental mechanism underlying intracellular organization, with evidence for it being reported in numerous different systems. However, there is a growing concern regarding the lack of quantitative rigor in the techniques employed to study phase separation, and their ability to account for the complex nature of the cellular milieu, which affects key experimentally observable measures, such as the shape, size and transport dynamics of liquid droplets. Here, we bridge this gap by combining recent experimental data with theoretical predictions that capture the subtleties of nonlinear elasticity and fluid transport. We show that within a biologically accessible range of material parameters, phase separation is highly sensitive to elastic properties and can thus be used as a mechanical switch to rapidly transition between different states in cellular systems. Furthermore, we show that this active mechanically mediated mechanism can drive transport across cells at biologically relevant timescales and could play a crucial role in promoting spatial localization of condensates; whether cells exploit such mechanisms for transport of their constituents remains an open question.
    Keywords:  Elasticity; Front propagation; Liquid–liquid phase separation; Ostwald ripening
    DOI:  https://doi.org/10.1007/s10237-022-01670-6
  22. Sci Adv. 2022 Dec 21. 8(51): eadd0014
    Dissecting the recruitment and self-organization of αSMA-positive fibroblasts in the foreign body response.
    Maria Parlani, Matthew L Bedell, Antonios G Mikos, Peter Friedl, Eleonora Dondossola.
      The foreign body response (FBR) is a clinically relevant issue that can cause malfunction of implanted medical devices by fibrotic encapsulation. Whereas inflammatory aspects of the FBR have been established, underlying fibroblast-dependent mechanisms remain unclear. We here combine multiphoton microscopy with ad hoc reporter mice expressing α-smooth muscle actin (αSMA) protein to determine the locoregional fibroblast dynamics, activation, and fibrotic encapsulation of polymeric materials. Fibroblasts invaded as individual cells and established a multicellular network, which transited to a two-compartment fibrotic response displaying an αSMA cold external capsule and a long-lasting, inner αSMA hot environment. The recruitment of fibroblasts and extent of fibrosis were only incompletely inhibited after depletion of macrophages, implicating coexistence of macrophage-dependent and macrophage-independent mediators. Furthermore, neither altering material type or porosity modulated αSMA+ cell recruitment and distribution. This identifies fibroblast activation and network formation toward a two-compartment FBR as a conserved, self-organizing process partially independent of macrophages.
    DOI:  https://doi.org/10.1126/sciadv.add0014
  23. Mol Cancer. 2022 Dec 22. 21(1): 225
    Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis.
    Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C Are, Surinder K Batra, Moorthy P Ponnusamy.
      Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of cancer cells. The correlation between TME and CSCs remains an enigma in understanding the events of metastasis and therapy resistance in cancer biology. Recent evidence suggests that TME dictates the CSCs maintenance to arbitrate cancer progression and metastasis. The immune, inflammatory, endothelial, adipocyte, and fibroblast cells in the TME release growth factors, cytokines, chemokines, microRNAs, and exosomes that provide cues for the gain and maintenance of CSC features. These intricate cross-talks are fueled to evolve into aggressive, invasive, migratory phenotypes for cancer development. In this review, we have abridged the recent developments in the role of the TME factors in CSC maintenance and how these events influence the transition of tumor progression to further translate into metastasis and therapy resistance in cancer.
    Keywords:  Cancer stem cells; Fibroblasts; Metastatic stem cells; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-022-01682-x
  24. Br J Cancer. 2022 Dec 19.
    Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.
    Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba.
       BACKGROUND: Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT).
    METHODS: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments.
    RESULTS: Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo.
    CONCLUSION: Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.
    DOI:  https://doi.org/10.1038/s41416-022-02106-9
  25. Trends Cell Biol. 2022 Dec 15. pii: S0962-8924(22)00260-4. [Epub ahead of print]
    Kinase regulation by liquid-liquid phase separation.
    Tania P López-Palacios, Joshua L Andersen.
      Liquid-liquid phase separation (LLPS) is emerging as a mechanism of spatiotemporal regulation that could answer long-standing questions about how order is achieved in biochemical signaling. In this review we discuss how LLPS orchestrates kinase signaling, either by creating condensate structures that are sensed by kinases or by direct LLPS of kinases, cofactors, and substrates - thereby acting as a mechanism to compartmentalize kinase-substrate relationships, and in some cases also sequestering the kinase away from inhibitory factors. We also examine the possibility that selective pressure promotes genomic rearrangements that fuse pro-growth kinases to LLPS-prone protein sequences, which in turn drives aberrant kinase activation through LLPS.
    Keywords:  intrinsically disordered region; kinase; kinase fusion; liquid–liquid phase separation; multivalency; post-translational modification
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.009
  26. Pancreatology. 2022 Dec 15. pii: S1424-3903(22)00832-8. [Epub ahead of print]
    The 2022 George E Palade Medal Lecture: Toxic Ca2+ signals in acinar, stellate and endogenous immune cells are important drivers of acute pancreatitis.
    Ole H Petersen.
      In this account of the 2022 Palade Medal Lecture, an attempt is made to explain, as simply as possible, the most essential features of normal physiological control of pancreatic enzyme secretion, as they have emerged from more than 50 years of experimental work. On that basis, further studies on the mechanism by which acute pancreatitis is initiated are then described. Calcium ion signaling is crucially important for both the normal physiology of secretion control as well as for the development of acute pancreatitis. Although acinar cell processes have, rightly, been central to our understanding of pancreatic physiology and pathophysiology, attention is here drawn to the additional critical influence of calcium signaling events in stellate and immune cells in the acinar environment. These signals contribute significantly to the crucially important inflammatory response in acute pancreatitis.
    Keywords:  Imaging; Macrophages; Necrosis; Stimulus-metabolism coupling; Stimulus-secretion coupling
    DOI:  https://doi.org/10.1016/j.pan.2022.12.010
  27. Nat Cell Biol. 2022 Dec 21.
    Caveolin-1 dolines form a distinct and rapid caveolae-independent mechanoadaptation system.
    Fidel-Nicolás Lolo, Nikhil Walani, Eric Seemann, Dobryna Zalvidea, Dácil María Pavón, Gheorghe Cojoc, Moreno Zamai, Christine Viaris de Lesegno, Fernando Martínez de Benito, Miguel Sánchez-Álvarez, Juan José Uriarte, Asier Echarri, Daniel Jiménez-Carretero, Joan-Carles Escolano, Susana A Sánchez, Valeria R Caiolfa, Daniel Navajas, Xavier Trepat, Jochen Guck, Christophe Lamaze, Pere Roca-Cusachs, Michael M Kessels, Britta Qualmann, Marino Arroyo, Miguel A Del Pozo.
      In response to different types and intensities of mechanical force, cells modulate their physical properties and adapt their plasma membrane (PM). Caveolae are PM nano-invaginations that contribute to mechanoadaptation, buffering tension changes. However, whether core caveolar proteins contribute to PM tension accommodation independently from the caveolar assembly is unknown. Here we provide experimental and computational evidence supporting that caveolin-1 confers deformability and mechanoprotection independently from caveolae, through modulation of PM curvature. Freeze-fracture electron microscopy reveals that caveolin-1 stabilizes non-caveolar invaginations-dolines-capable of responding to low-medium mechanical forces, impacting downstream mechanotransduction and conferring mechanoprotection to cells devoid of caveolae. Upon cavin-1/PTRF binding, doline size is restricted and membrane buffering is limited to relatively high forces, capable of flattening caveolae. Thus, caveolae and dolines constitute two distinct albeit complementary components of a buffering system that allows cells to adapt efficiently to a broad range of mechanical stimuli.
    DOI:  https://doi.org/10.1038/s41556-022-01034-3
  28. Mol Oncol. 2022 Dec 23.
    Transcriptomic pan-cancer analysis using rank-based Bayesian inference.
    Valeria Vitelli, Thomas Fleischer, Jørgen Ankill, Elja Arjas, Arnoldo Frigessi, Vessela N Kristensen, Manuela Zucknick.
      The analysis of whole genomes of pan-cancer data sets provides a challenge for researchers, and we contribute to the literature concerning the identification of robust subgroups with clear biological interpretation. Specifically, we tackle this unsupervised problem via a novel rank-based Bayesian clustering method. The advantages of our method are: the integration and quantification of all uncertainties related to both the input data and the model; the probabilistic interpretation of final results to allow straightforward assessment of the stability of clusters leading to reliable conclusions; and the transparent biological interpretation of the identified clusters, since each cluster is characterized by its top-ranked genomic features. We applied our method to RNA-seq data from cancer samples from 12 tumor types from The Cancer Genome Atlas. We identified a robust clustering that mostly reflects tissue of origin, but also includes pan-cancer clusters. Importantly, we identified three pan-squamous clusters composed of a mix of lung squamous cell carcinoma, head and neck squamous carcinoma and bladder cancer, with different biological functions over-represented in the top genes that characterize the three clusters. We also found two novel subtypes of kidney cancer that show different prognosis, and we reproduced known subtypes of breast cancer. Taken together, our method allows identification of robust and biologically meaningful clusters of pan-cancer samples.
    Keywords:  Bayes Mallows model; cluster analysis; pan-cancer; robust statistics; subgroup analysis; transcriptomics
    DOI:  https://doi.org/10.1002/1878-0261.13354
  29. Cancer Res. 2022 Dec 22. pii: CAN-22-2245. [Epub ahead of print]
    Systematic interrogation of tumor cell resistance to CAR T cell therapy in pancreatic cancer.
    Kimberly R Hagel, Rand Arafeh, Sydney Gang, Taylor E Arnoff, Rebecca C Larson, John G Doench, Nathan D Mathewson, Kai W Wucherpfennig, Marcela V Maus, William C Hahn.
      Chimeric antigen receptor (CAR) T cell therapy can lead to dramatic clinical responses in B cell malignancies. However, early clinical trials with CAR T cell therapy in non-B cell malignancies have been disappointing to date, suggesting that tumor intrinsic features contribute to resistance. To investigate tumor intrinsic modes of resistance, we performed genome scale CRISPR-Cas9 screens in mesothelin (MSLN)-expressing pancreatic cancer cells. Co-culture with MSLN-targeting CAR T cells identified both antigen-dependent and antigen-independent modes of resistance. In particular, loss of the majority of the genes involved in the pathway responsible for GPI-anchor biosynthesis and attachment abrogated the ability of CAR T cells to target pancreatic cancer cells, suggesting that disruption of this pathway may permit MSLN CAR T cell evasion in the clinic. Antigen independent mediators of CAR T cell response included members of the death receptor pathway as well as genes that regulate tumor transcriptional responses, including TFAP4 and INTS12. TFAP4-mediated CAR T resistance depended on the NFκB transcription factor p65, indicating that tumor resistance to CAR T cell therapy likely involves alterations in tumor intrinsic states. Overall, this study uncovers multiple antigen-dependent and -independent mechanisms of CAR T cell evasion by pancreatic cancer, paving the way for overcoming resistance in this disease that is notoriously refractory to immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2245
  30. Ann Surg Oncol. 2022 Dec 20.
    Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study.
    Scientific Committee of the European-African Hepato-Pancreato-Biliary Association
       BACKGROUND: Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.
    METHODS: This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.
    RESULTS: The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.
    CONCLUSIONS: This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.
    DOI:  https://doi.org/10.1245/s10434-022-12387-2
  31. Int J Mol Sci. 2022 Dec 07. pii: 15475. [Epub ahead of print]23(24):
    Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis.
    Dongun Lee, Jeong-Hee Hong.
      PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells.
    Keywords:  PyK2; PyK2-interactive proteins; acidic milieu; metastasis; migration
    DOI:  https://doi.org/10.3390/ijms232415475
  32. Nat Commun. 2022 Dec 17. 13(1): 7799
    USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity.
    Juan Li, Yang Wang, Yue Luo, Yang Liu, Yong Yi, Jinsong Li, Yang Pan, Weiyuxin Li, Wanbang You, Qingyong Hu, Zhiqiang Zhao, Yujun Zhang, Yang Cao, Lingqiang Zhang, Junying Yuan, Zhi-Xiong Jim Xiao.
      Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. KrasG12D mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.
    DOI:  https://doi.org/10.1038/s41467-022-35557-y
  33. ESMO Open. 2022 Dec 20. pii: S2059-7029(22)00379-9. [Epub ahead of print]8(1): 100745
    Targeting KRASG12C in colorectal cancer: the beginning of a new era.
    D Ciardiello, B A Maiorano, E Martinelli.
      RAS mutation is considered one of the most relevant oncogenic drivers in human cancers. Unfortunately, for more than three decades, RAS has been considered an undruggable target. Recently, the discovery of selective and potent KRASG12C inhibitors represented a light at the end of the tunnel. Indeed, sotorasib and adagrasib proved clinical activity in patients with refractory metastatic colorectal cancer harboring KRASG12C mutation; however, responses are lower than expected, suggesting the presence of intrinsic resistance. Consequently, novel combinatory strategies to disrupt the RAS signaling pathways are under clinical investigation. This review aims to discuss the current knowledge and novel routes of KRASG12C inhibition in metastatic colorectal cancer.
    Keywords:  CRC; KRAS(G12C); precision medicine; target therapies
    DOI:  https://doi.org/10.1016/j.esmoop.2022.100745
  34. PeerJ. 2022 ;10 e14538
    Association between type 2 diabetes and 5-year overall survival in early-stage pancreatic cancer: a retrospective cohort study.
    Zhiyin Tang, Wanfeng Xu, Mingming Zhang.
       Background: This study examined the association between type 2 diabetes mellitus (T2DM) and 5-year overall survival (OS) in patients with pancreatic cancer (PC).
    Methods: This retrospective cohort study included patients diagnosed with stage I/II PC at Shengjing Hospital of China Medical University from January 2012 to December 2017. All patients had pancreatic ductal adenocarcinoma or its subtypes. The outcome was the 5-year OS rate based on data from the patient charts. Data analysis was performed using SPSS 22.0.
    Results: A total of 238 patients were included: 72 with T2DM and 166 without T2DM. There were significant differences in blood glucose levels and OS between the two groups (all P < 0.05). The median OS was 11.4 (95% confidence interval CI [8.49-14.31]) months in the T2DM group and 16.3 (95% CI [12.44-20.16], P = 0.023) months in the non-T2DM group. After adjustment for confounders, T2DM was an independent factor affecting 5-year OS (P = 0.010). Compared with non-T2DM patients, T2DM patients had a higher risk of death (HR = 1.475, 95% CI [1.096-1.985]).
    Conclusions: T2DM is associated with 5-year OS in patients with PC.
    Keywords:  Asian continental ancestry group; Diabetes mellitus; Glycemic control; Pancreatic cancer; Survival analysis
    DOI:  https://doi.org/10.7717/peerj.14538
  35. Cancer Cell. 2022 Dec 17. pii: S1535-6108(22)00588-8. [Epub ahead of print]
    Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.
    Eric Wang, Jose Mario Bello Pineda, Won Jun Kim, Sisi Chen, Jessie Bourcier, Maximilian Stahl, Simon J Hogg, Jan Phillipp Bewersdorf, Cuijuan Han, Michael E Singer, Daniel Cui, Caroline E Erickson, Steven M Tittley, Alexander V Penson, Katherine Knorr, Robert F Stanley, Jahan Rahman, Gnana Krishnamoorthy, James A Fagin, Emily Creger, Elizabeth McMillan, Chi-Ching Mak, Matthew Jarvis, Carine Bossard, Darrin M Beaupre, Robert K Bradley, Omar Abdel-Wahab.
      Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.
    Keywords:  BCL2; CLK; DYRK; RBM10; RNA splicing; XIAP; acute myeloid leukemia; venetoclax
    DOI:  https://doi.org/10.1016/j.ccell.2022.12.002
  36. Curr Oncol. 2022 Dec 17. 29(12): 9956-9969
    Smoking Cessation after Cancer Diagnosis and Enhanced Therapy Response: Mechanisms and Significance.
    Srikumar Chellappan.
      The adverse effects of smoking on human health have been recognized for several decades, especially in the context of cancer. The ability of tobacco smoke components, including tobacco-specific carcinogens and additive compounds such as nicotine, to initiate or promote tumor growth have been described in hundreds of studies. These investigations have revealed the tumor-promoting activities of nicotine and other tobacco smoke components and have also recognized the ability of these agents to suppress the efficacy of cancer therapy; it is now clear that smoking can reduce the efficacy of most of the widely used therapeutic modalities, including immunotherapy, radiation therapy, and chemotherapy. Several studies examined if continued smoking after cancer diagnosis affected therapy response; it was found that while never smokers or non-smokers had the best response to therapy, those who quit smoking at the time of diagnosis had higher overall survival and reduced side-effects than those who continued to smoke. These studies also revealed the multiple mechanisms via which smoking enhances the growth and survival of tumors while suppressing therapy-induced cell death. In conclusion, smoking cessation during the course of cancer therapy markedly increases the chances of survival and the quality of life.
    Keywords:  drug resistance 5; immunotherapy; nicotine; smoking; survival
    DOI:  https://doi.org/10.3390/curroncol29120782
  37. Sci Adv. 2022 Dec 23. 8(51): eadd9520
    Ubiquitin modulates 26S proteasome conformational dynamics and promotes substrate degradation.
    Erik Jonsson, Zaw Min Htet, Jared A M Bard, Ken C Dong, Andreas Martin.
      The 26S proteasome recognizes thousands of appropriate protein substrates in eukaryotic cells through attached ubiquitin chains and uses its adenosine triphosphatase (ATPase) motor for mechanical unfolding and translocation into a proteolytic chamber. Here, we used single-molecule Förster resonance energy transfer measurements to monitor the conformational dynamics of the proteasome, observe individual substrates during their progression toward degradation, and elucidate how these processes are regulated by ubiquitin chains. Rapid transitions between engagement- and processing-competent proteasome conformations control substrate access to the ATPase motor. Ubiquitin chain binding functions as an allosteric regulator to slow these transitions, stabilize the engagement-competent state, and aid substrate capture to accelerate degradation initiation. Upon substrate engagement, the proteasome remains in processing-competent states for translocation and unfolding, except for apparent motor slips when encountering stably folded domains. Our studies revealed how ubiquitin chains allosterically regulate degradation initiation, which ensures substrate selectivity in a crowded cellular environment.
    DOI:  https://doi.org/10.1126/sciadv.add9520
  38. Front Oncol. 2022 ;12 1013902
    KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?
    Sahar F Bannoura, Husain Yar Khan, Asfar S Azmi.
      KRAS mutations are among the most commonly occurring mutations in cancer. After being deemed undruggable for decades, KRAS G12C specific inhibitors showed that small molecule inhibitors can be developed against this notorious target. At the same time, there is still no agent that could target KRAS G12D which is the most common KRAS mutation and is found in the majority of KRAS-mutated pancreatic tumors. Nevertheless, significant progress is now being made in the G12D space with the development of several compounds that can bind to and inhibit KRAS G12D, most notably MRTX1133. Exciting advances in this field also include an immunotherapeutic approach that uses adoptive T-cell transfer to specifically target G12D in pancreatic cancer. In this mini-review, we discuss recent advances in KRAS G12D targeting and the potential for further clinical development of the various approaches.
    Keywords:  KRAS; KRAS G12C; KRAS G12D; MRTX1133; adagrasib; adoptive cell therapy; immunotherapy; sotorasib
    DOI:  https://doi.org/10.3389/fonc.2022.1013902
  39. J Physiol. 2022 Dec 19.
    Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis.
    Amy H Attaway, Annette Bellar, Saurabh Mishra, Manikandan Karthikeyan, Jinendiran Sekar, Nicole Welch, Ryan Musich, Shashi Shekhar Singh, Avinash Kumar, Aishwarya Menon, Jasmine King, Ramon Langen, Justine Webster, Rachel Scheraga, Kristy Rochon, Jason Mears, Sathyamangla V Naga Prasad, Maria Hatzoglou, Abhishek A Chakraborty, Srinivasan Dasarathy.
       KEY POINTS: Sarcopenia or skeletal muscle loss is one of the most frequent complications that contributes to mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). Unlike chronic hypoxia, prolonged intermittent hypoxia is a frequent, underappreciated and clinically relevant model of hypoxia in patients with COPD. We developed a novel, in vitro myotube model of prolonged intermittent hypoxia with molecular and metabolic perturbations, mitochondrial oxidative dysfunction and consequent sarcopenic phenotype. In vivo studies in skeletal muscle from a mouse model of COPD shared responses with our myotube model establishing pathophysiological relevance of our studies. These data lay the foundation for translational studies in human COPD to target prolonged, nocturnal hypoxemia to prevent sarcopenia in these patients.
    ABSTRACT: Nocturnal hypoxemia that is common in chronic obstructive pulmonary disease (COPD) patients is associated with skeletal muscle loss or sarcopenia, which contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of hypoxia in skeletal muscle occurs through the duration of sleep followed by normoxia during the day in contrast to recurrent brief hypoxic episodes during obstructive sleep apnea (OSA). Adaptive cellular responses to PIH are not known. Responses to PIH induced by 3-cycles of 8h hypoxia followed by 16h normoxia were compared to those during chronic hypoxia (CH) or normoxia for 72h in murine C2C12 and human inducible pluripotent stem cell-derived differentiated myotubes. RNA sequencing followed by downstream analyses were complemented by experimental validation of responses that included both unique and shared perturbations in ribosomal and mitochondrial function during PIH and CH. A sarcopenic phenotype characterized by decreased myotube diameter and protein synthesis, and increased phosphorylation of eIF2α (Ser51) by eIF2α kinase, GCN-2 (general controlled non-derepressed-2), occurred during both PIH and CH. Mitochondrial oxidative dysfunction, disrupted supercomplex assembly, lower activity of Complexes I, III, IV and V, and reduced intermediary metabolite concentrations occurred during PIH and CH. Decreased mitochondrial fission occurred during CH. Physiological relevance was established in skeletal muscle of mice with COPD that had increased phosphorylation of eIF2α, lower protein synthesis, and mitochondrial oxidative dysfunction. Molecular and metabolic responses with PIH suggests an adaptive exhaustion with failure to restore homeostasis during normoxia. Abstract figure legend Prolonged intermittent hypoxia (PIH) is commonly demonstrated in patients with COPD (chronic obstructive pulmonary disease); however, the effects of PIH on skeletal muscle are unclear. We tested the hypothesis that PIH causes skeletal muscle loss or sarcopenia in vitro by down-regulating protein synthesis and causing mitochondrial oxidative dysfunction associated with dysregulation of hypoxia inducible factors (HIF1α and HIF2α). α-ketoglutarate (αKG), a critical TCA cycle intermediate and co-factor for the degradation of HIF1α, was reduced due to PIH. Physiological relevance was established in skeletal muscle of mice with COPD. Our findings suggest that PIH causes sarcopenia through adaptive exhaustion and failure to restore homeostasis during normoxia. This article is protected by copyright. All rights reserved.
    Keywords:  Prolonged intermittent hypoxia; RNA sequencing; intermediary metabolites; mitochondrial oxidation; unbiased data
    DOI:  https://doi.org/10.1113/JP283700
  40. Front Physiol. 2022 ;13 1040381
    Exercise and mitochondrial mechanisms in patients with sarcopenia.
    Hamed Alizadeh Pahlavani, Ismail Laher, Beat Knechtle, Hassane Zouhal.
      Sarcopenia is a severe loss of muscle mass and functional decline during aging that can lead to reduced quality of life, limited patient independence, and increased risk of falls. The causes of sarcopenia include inactivity, oxidant production, reduction of antioxidant defense, disruption of mitochondrial activity, disruption of mitophagy, and change in mitochondrial biogenesis. There is evidence that mitochondrial dysfunction is an important cause of sarcopenia. Oxidative stress and reduction of antioxidant defenses in mitochondria form a vicious cycle that leads to the intensification of mitochondrial separation, suppression of mitochondrial fusion/fission, inhibition of electron transport chain, reduction of ATP production, an increase of mitochondrial DNA damage, and mitochondrial biogenesis disorder. On the other hand, exercise adds to the healthy mitochondrial network by increasing markers of mitochondrial fusion and fission, and transforms defective mitochondria into efficient mitochondria. Sarcopenia also leads to a decrease in mitochondrial dynamics, mitophagy markers, and mitochondrial network efficiency by increasing the level of ROS and apoptosis. In contrast, exercise increases mitochondrial biogenesis by activating genes affected by PGC1-ɑ (such as CaMK, AMPK, MAPKs) and altering cellular calcium, ATP-AMP ratio, and cellular stress. Activation of PGC1-ɑ also regulates transcription factors (such as TFAM, MEFs, and NRFs) and leads to the formation of new mitochondrial networks. Hence, moderate-intensity exercise can be used as a non-invasive treatment for sarcopenia by activating pathways that regulate the mitochondrial network in skeletal muscle.
    Keywords:  aging; exercise; mechanism; mitochondria; sarcopenia
    DOI:  https://doi.org/10.3389/fphys.2022.1040381
  41. Mol Cell Biochem. 2022 Dec 24.
    Association between diabetes and cancer. Current mechanistic insights into the association and future challenges.
    Armando Rojas, Ivan Schneider, Cristian Lindner, Ileana Gonzalez, Miguel A Morales.
      Compelling pieces of epidemiological, clinical, and experimental research have demonstrated that Diabetes mellitus (DM) is a major risk factor associated with increased cancer incidence and mortality in many human neoplasms. In the pathophysiology context of DM, many of the main classical actors are relevant elements that can fuel the different steps of the carcinogenesis process. Hyperglycemia, hyperinsulinemia, metabolic inflammation, and dyslipidemia are among the classic contributors to this association. Furthermore, new emerging actors have received particular attention in the last few years, and compelling data support that the microbiome, the epigenetic changes, the reticulum endoplasmic stress, and the increased glycolytic influx also play important roles in promoting the development of many cancer types. The arsenal of glucose-lowering therapeutic agents used for treating diabetes is wide and diverse, and a growing body of data raised during the last two decades has tried to clarify the contribution of therapeutic agents to this association. However, this research area remains controversial, because some anti-diabetic drugs are now considered as either promotors or protecting elements. In the present review, we intend to highlight the compelling epidemiological shreds of evidence that support this association, as well as the mechanistic contributions of many of these potential pathological mechanisms, some controversial points as well as future challenges.
    Keywords:  Cancer; Chronic inflammation; Diabetes mellitus; Hyperglycemia; Hyperinsulinemia; Obesity
    DOI:  https://doi.org/10.1007/s11010-022-04630-x
  42. Future Oncol. 2022 Dec 19.
    Current treatment landscape of pancreatic cancer patients in a network of office-based oncologists in Germany.
    Susanna Hegewisch-Becker, Karsten Kratz-Albers, Jan Wierecky, Steffen Gerhardt, Daniel Reschke, Jens Borchardt, Ralf Reichelt, Felix Walter Friedrich.
      Background: Pancreatic cancer is one of the most aggressive cancers, with comparatively poor outcomes despite the use of multiagent conventional chemotherapy regimens. Real-world data from clinical practice are still rare but are the basis for understanding and improving the current standard of care. Materials & methods: In this multi-institutional retrospective analysis of 24 office-based oncology practices in Germany, the authors documented 1786 pancreatic cancer patients who received systemic treatment between April 2017 and June 2021. Results: The authors' analysis showed that results from recent clinical studies are promptly incorporated into practice. Conclusion: It was striking that, during the analyzed period, the use of platinum-based therapy regimens in adjuvant and palliative first-line therapy increased predominantly in younger patients (<70 years).
    Keywords:  adjuvant therapy; chemotherapy; clinical practice; palliative care; palliative first-line therapy; pancreatic cancer; platinum-based therapy; real-world data; systemic treatments
    DOI:  https://doi.org/10.2217/fon-2022-0141
  43. Curr Opin Struct Biol. 2022 Dec 16. pii: S0959-440X(22)00184-1. [Epub ahead of print]78 102505
    Modeling membrane reshaping driven by dynamic protein assemblies.
    Yiben Fu, Margaret E Johnson.
      Remodeling of membranes in living systems is almost universally coupled to self-assembly of soluble proteins. Proteins assemble into semi-rigid shells that reshape attached membranes, and into filaments that protrude membranes. These assemblies are temporary, building from reversible protein and membrane interactions that must nucleate in the proper location. The interactions are strongly influenced by the nonequilibrium environment of the cell, such as gradients of components or active modifications by kinases. From a modeling perspective, understanding mechanisms and control thus requires 1. time-dependent approaches that ideally incorporate 2. macromolecular structure, 3. out-of-equilibrium processes, and 4. deformable membranes over microns and seconds. Realistically, tradeoffs must be made with these last three features. However, we see recent developments from the highly coarsened molecule-based scale, the continuum reaction-diffusion scale, and hybrid approaches as stimulating efforts in diverse applications. We discuss here methodological advances and progress towards simulating these processes as they occur physiologically.
    DOI:  https://doi.org/10.1016/j.sbi.2022.102505
  44. Int J Mol Sci. 2022 Dec 15. pii: 15979. [Epub ahead of print]23(24):
    Technologies for Viable Circulating Tumor Cell Isolation.
    Maria S Tretyakova, Maxim E Menyailo, Anastasia A Schegoleva, Ustinia A Bokova, Irina V Larionova, Evgeny V Denisov.
      The spread of tumor cells throughout the body by traveling through the bloodstream is a critical step in metastasis, which continues to be the main cause of cancer-related death. The detection and analysis of circulating tumor cells (CTCs) is important for understanding the biology of metastasis and the development of antimetastatic therapy. However, the isolation of CTCs is challenging due to their high heterogeneity and low representation in the bloodstream. Different isolation methods have been suggested, but most of them lead to CTC damage. However, viable CTCs are an effective source for developing preclinical models to perform drug screening and model the metastatic cascade. In this review, we summarize the available literature on methods for isolating viable CTCs based on different properties of cells. Particular attention is paid to the importance of in vitro and in vivo models obtained from CTCs. Finally, we emphasize the current limitations in CTC isolation and suggest potential solutions to overcome them.
    Keywords:  CTC; cancer; in vitro; in vivo; isolation; metastasis
    DOI:  https://doi.org/10.3390/ijms232415979
  45. JAMA Oncol. 2022 Dec 22.
    The Multidisciplinary Cancer Conference.
    Eric K Singhi, Jill Feldman, Howard Jack West.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2022.4924
  46. Nat Methods. 2022 Dec 21.
    Guiding the choice of informatics software and tools for lipidomics research applications.
    Zhixu Ni, Michele Wölk, Geoff Jukes, Karla Mendivelso Espinosa, Robert Ahrends, Lucila Aimo, Jorge Alvarez-Jarreta, Simon Andrews, Robert Andrews, Alan Bridge, Geremy C Clair, Matthew J Conroy, Eoin Fahy, Caroline Gaud, Laura Goracci, Jürgen Hartler, Nils Hoffmann, Dominik Kopczyinki, Ansgar Korf, Andrea F Lopez-Clavijo, Adnan Malik, Jacobo Miranda Ackerman, Martijn R Molenaar, Claire O'Donovan, Tomáš Pluskal, Andrej Shevchenko, Denise Slenter, Gary Siuzdak, Martina Kutmon, Hiroshi Tsugawa, Egon L Willighagen, Jianguo Xia, Valerie B O'Donnell, Maria Fedorova.
      Progress in mass spectrometry lipidomics has led to a rapid proliferation of studies across biology and biomedicine. These generate extremely large raw datasets requiring sophisticated solutions to support automated data processing. To address this, numerous software tools have been developed and tailored for specific tasks. However, for researchers, deciding which approach best suits their application relies on ad hoc testing, which is inefficient and time consuming. Here we first review the data processing pipeline, summarizing the scope of available tools. Next, to support researchers, LIPID MAPS provides an interactive online portal listing open-access tools with a graphical user interface. This guides users towards appropriate solutions within major areas in data processing, including (1) lipid-oriented databases, (2) mass spectrometry data repositories, (3) analysis of targeted lipidomics datasets, (4) lipid identification and (5) quantification from untargeted lipidomics datasets, (6) statistical analysis and visualization, and (7) data integration solutions. Detailed descriptions of functions and requirements are provided to guide customized data analysis workflows.
    DOI:  https://doi.org/10.1038/s41592-022-01710-0
  47. Brief Bioinform. 2022 Dec 17. pii: bbac550. [Epub ahead of print]
    dSCOPE: a software to detect sequences critical for liquid-liquid phase separation.
    Kai Yu, Zekun Liu, Haoyang Cheng, Shihua Li, Qingfeng Zhang, Jia Liu, Huai-Qiang Ju, Zhixiang Zuo, Qi Zhao, Shiyang Kang, Ze-Xian Liu.
      Membrane-based cells are the fundamental structural and functional units of organisms, while evidences demonstrate that liquid-liquid phase separation (LLPS) is associated with the formation of membraneless organelles, such as P-bodies, nucleoli and stress granules. Many studies have been undertaken to explore the functions of protein phase separation (PS), but these studies lacked an effective tool to identify the sequence segments that critical for LLPS. In this study, we presented a novel software called dSCOPE (http://dscope.omicsbio.info) to predict the PS-driving regions. To develop the predictor, we curated experimentally identified sequence segments that can drive LLPS from published literature. Then sliding sequence window based physiological, biochemical, structural and coding features were integrated by random forest algorithm to perform prediction. Through rigorous evaluation, dSCOPE was demonstrated to achieve satisfactory performance. Furthermore, large-scale analysis of human proteome based on dSCOPE showed that the predicted PS-driving regions enriched various protein post-translational modifications and cancer mutations, and the proteins which contain predicted PS-driving regions enriched critical cellular signaling pathways. Taken together, dSCOPE precisely predicted the protein sequence segments critical for LLPS, with various helpful information visualized in the webserver to facilitate LLPS-related research.
    Keywords:  deep learning; phase separation; prediction; random forest; sequence segments
    DOI:  https://doi.org/10.1093/bib/bbac550
  48. N Engl J Med. 2022 Dec 21.
    Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.
    Rona Yaeger, Jared Weiss, Meredith S Pelster, Alexander I Spira, Minal Barve, Sai-Hong I Ou, Ticiana A Leal, Tanios S Bekaii-Saab, Cloud P Paweletz, Grace A Heavey, James G Christensen, Karen Velastegui, Thian Kheoh, Hirak Der-Torossian, Samuel J Klempner.
       BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy.
    METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety.
    RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed.
    CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).
    DOI:  https://doi.org/10.1056/NEJMoa2212419
  49. Cancers (Basel). 2022 Dec 08. pii: 6042. [Epub ahead of print]14(24):
    Understanding the Link between Sugar and Cancer: An Examination of the Preclinical and Clinical Evidence.
    Margeaux Epner, Peiying Yang, Richard W Wagner, Lorenzo Cohen.
      Per capita sugar consumption has increased in the United States to over 45 kg per year. The average person in the US currently consumes significantly more added sugar in their diet than the World Health Organization's, the American Cancer Society's, and the American Heart Association's recommendations for daily sugar consumption. Evidence from epidemiologic and preclinical studies demonstrates that excess sugar consumption can lead to development of cancer and progression of disease for those with cancer independent of the association between sugar and obesity. Human epidemiologic studies and mechanistic preclinical studies in multiple cancers support a causal link between excess sugar and cancer. Preclinical studies show that high-sucrose or high-fructose diets activate several mechanistic pathways, including inflammation, glucose, and lipid metabolic pathways. Although human studies are limited, compelling human and primate studies have explored the link between added sugar and metabolic syndrome (MetS), a risk factor for cancer. Substantial evidence suggests a causal link between MetS and added sugar, indicating important implications in the association between excess sugar consumption and cancer. Human clinical trials are needed to determine whether sugar increases cancer development and progression independently of its established role in causing obesity as well as for further exploration of the mechanisms involved.
    Keywords:  cancer; cancer metabolism; fructose; inflammation; sucrose; sugar
    DOI:  https://doi.org/10.3390/cancers14246042
  50. Nat Biotechnol. 2022 Dec 19.
    Nanobody-tethered transposition enables multifactorial chromatin profiling at single-cell resolution.
    Tim Stuart, Stephanie Hao, Bingjie Zhang, Levan Mekerishvili, Dan A Landau, Silas Maniatis, Rahul Satija, Ivan Raimondi.
      Chromatin states are functionally defined by a complex combination of histone modifications, transcription factor binding, DNA accessibility and other factors. Current methods for defining chromatin states cannot measure more than one aspect in a single experiment at single-cell resolution. Here we introduce nanobody-tethered transposition followed by sequencing (NTT-seq), an assay capable of measuring the genome-wide presence of up to three histone modifications and protein-DNA binding sites at single-cell resolution. NTT-seq uses recombinant Tn5 transposase fused to a set of secondary nanobodies (nb). Each nb-Tn5 fusion protein specifically binds to different immunoglobulin-G antibodies, enabling a mixture of primary antibodies binding different epitopes to be used in a single experiment. We apply bulk-cell and single-cell NTT-seq to generate high-resolution multimodal maps of chromatin states in cell culture and in human immune cells. We also extend NTT-seq to enable simultaneous profiling of cell surface protein expression and multimodal chromatin states to study cells of the immune system.
    DOI:  https://doi.org/10.1038/s41587-022-01588-5
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