bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–08–07
thirty-two papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy.
  2. Regulation of mitochondrial proteostasis by the proton gradient.
  3. Tieing together loose ends: telomere instability in cancer and aging.
  4. Nucleotide imbalance decouples cell growth from cell proliferation.
  5. Cellular senescence: a key therapeutic target in aging and diseases.
  6. Emerging metabolomic tools to study cancer metastasis.
  7. CD9 mediates the uptake of extracellular vesicles from cancer-associated fibroblasts that promote pancreatic cancer cell aggressiveness.
  8. The urgent need to improve childhood cancer cachexia.
  9. Roles of mitochondrial genetics in cancer metastasis.
  10. The role of cellular quiescence in cancer - beyond a quiet passenger.
  11. Nutrient scavenging from muscle cells: A survival strategy of pancreatic cancer cells ends in cachexia.
  12. Cellular senescence: the good, the bad and the unknown.
  13. A new fluorescent sensor mitoferrofluor indicates the presence of chelatable iron in polarized and depolarized mitochondria.
  14. A Phase I Study of Gemcitabine/Nab-Paclitaxel/S-1 Chemotherapy in Patients With Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma.
  15. The molecular landscape of pancreatic ductal adenocarcinoma.
  16. An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinations.
  17. Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment.
  18. Neoadjuvant Therapy Versus Upfront Resection for Nonpancreatic Periampullary Adenocarcinoma.
  19. Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes.
  20. The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis.
  21. Triple-negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin.
  22. Transformed cells after senescence give rise to more severe tumor phenotypes than transformed non-senescent cells.
  23. Generation of nanoscopic membrane curvature for membrane trafficking.
  24. Discovery of non-autonomous modulators of activated Ras.
  25. Glioblastoma hijacks neuronal mechanisms for brain invasion.
  26. Wound healing, fibroblast heterogeneity, and fibrosis.
  27. Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress.
  28. Targeting KRAS mutant cancers: from druggable therapy to drug resistance.
  29. Deacetylation of ATG4B promotes autophagy initiation under starvation.
  30. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.
  31. Live-Cell RNA Imaging with Metabolically Incorporated Fluorescent Nucleosides.
  32. Does acute pancreatitis herald pancreatic ductal adenocarcinoma? A multicenter electronic health research network study.
  1. Biochem Soc Trans. 2022 Aug 05. pii: BST20220162. [Epub ahead of print]
    Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy.
    Kendelle J Murphy, Jessie Zhu, Michael Trpceski, Brooke A Pereira, Paul Timpson, David Herrmann.
      The dense desmoplastic and fibrotic stroma is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC), regulating disease progression, metastasis and response to treatment. Reciprocal interactions between the tumour and stroma are mediated by bidirectional integrin-mediated signalling, in particular by Focal Adhesion Kinase (FAK). FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. Therapeutic targeting of the PDAC stroma is an evolving area of interest for pre-clinical and clinical research, where a subtle reshaping of the stromal architecture prior to chemotherapy may prove promising in the clinical management of disease and overall patient survival. Here, we describe how transient stromal manipulation (or 'priming') via short-term FAK inhibition, rather than chronic treatment, can render PDAC cells exquisitely vulnerable to subsequent standard-of-care chemotherapy. We assess how our priming publication fits with the recent literature and describe in this perspective how this could impact future cancer treatment. This highlights the significance of treatment timing and warrants further consideration of anti-fibrotic therapies in the clinical management of PDAC and other fibrotic diseases.
    Keywords:  FAK; biomechanics; fibrosis; pancreatic cancer; priming
    DOI:  https://doi.org/10.1042/BST20220162
  2. EMBO J. 2022 Aug 01. e110476
    Regulation of mitochondrial proteostasis by the proton gradient.
    Maria Patron, Daryna Tarasenko, Hendrik Nolte, Lara Kroczek, Mausumi Ghosh, Yohsuke Ohba, Yvonne Lasarzewski, Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Akinori Eyiama, Tim Kellermann, Elena I Rugarli, Ulrich Brandt, Michael Meinecke, Thomas Langer.
      Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca2+ /H+ exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca2+ efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca2+ signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.
    Keywords:  AFG3L2; TMBIM5; mitochondrial calcium; proton gradient; respiratory chain
    DOI:  https://doi.org/10.15252/embj.2021110476
  3. Mol Oncol. 2022 Aug 03.
    Tieing together loose ends: telomere instability in cancer and aging.
    Gustavo Borges, Mélanie Criqui, Lea Harrington.
      Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure, and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.
    Keywords:  Telomeres; aging; cancer; genome instability; senescence; telomerase reverse transcriptase
    DOI:  https://doi.org/10.1002/1878-0261.13299
  4. Nat Cell Biol. 2022 Aug 04.
    Nucleotide imbalance decouples cell growth from cell proliferation.
    Frances F Diehl, Teemu P Miettinen, Ryan Elbashir, Christopher S Nabel, Alicia M Darnell, Brian T Do, Scott R Manalis, Caroline A Lewis, Matthew G Vander Heiden.
      Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication and impeding DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways like mTORC1, Akt and AMPK signalling cascades, causing excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signalling to survive during, and recover from, nucleotide imbalance during S phase. We find that ATR-dependent replication stress signalling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signalling to cope with this metabolic problem and disrupting the coordination of cell growth and division.
    DOI:  https://doi.org/10.1038/s41556-022-00965-1
  5. J Clin Invest. 2022 Aug 01. pii: e158450. [Epub ahead of print]132(15):
    Cellular senescence: a key therapeutic target in aging and diseases.
    Lei Zhang, Louise E Pitcher, Matthew J Yousefzadeh, Laura J Niedernhofer, Paul D Robbins, Yi Zhu.
      Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.
    DOI:  https://doi.org/10.1172/JCI158450
  6. Trends Cancer. 2022 Jul 28. pii: S2405-8033(22)00156-X. [Epub ahead of print]
    Emerging metabolomic tools to study cancer metastasis.
    Luiza Martins Nascentes Melo, Nicholas P Lesner, Marie Sabatier, Jessalyn M Ubellacker, Alpaslan Tasdogan.
      Metastasis is responsible for 90% of deaths in patients with cancer. Understanding the role of metabolism during metastasis has been limited by the development of robust and sensitive technologies that capture metabolic processes in metastasizing cancer cells. We discuss the current technologies available to study (i) metabolism in primary and metastatic cancer cells and (ii) metabolic interactions between cancer cells and the tumor microenvironment (TME) at different stages of the metastatic cascade. We identify advantages and disadvantages of each method and discuss how these tools and technologies will further improve our understanding of metastasis. Studies investigating the complex metabolic rewiring of different cells using state-of-the-art metabolomic technologies have the potential to reveal novel biological processes and therapeutic interventions for human cancers.
    Keywords:  analytical techniques; cancer metabolism; cancer metastasis; metabolomics
    DOI:  https://doi.org/10.1016/j.trecan.2022.07.003
  7. Sci Signal. 2022 Aug 02. 15(745): eabg8191
    CD9 mediates the uptake of extracellular vesicles from cancer-associated fibroblasts that promote pancreatic cancer cell aggressiveness.
    Jérémy Nigri, Julie Leca, Sarah-Simha Tubiana, Pascal Finetti, Fabienne Guillaumond, Sébastien Martinez, Sophie Lac, Juan L Iovanna, Stéphane Audebert, Luc Camoin, Sophie Vasseur, François Bertucci, Richard Tomasini.
      In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells is implicated in metastatic progression. Tumor-stroma cross-talk is often mediated through extracellular vesicles (EVs). We previously reported that EVs derived from cancer-associated stromal fibroblasts (CAFs) that are abundant in annexin A6 (ANXA6+ EVs) support tumor cell aggressiveness in PDAC. Here, we found that the cell surface glycoprotein and tetraspanin CD9 is a key component of CAF-derived ANXA6+ EVs for mediating this cross-talk. CD9 was abundant on the surface of ANXA6+ CAFs isolated from patient PDAC samples and from various mouse models of PDAC. CD9 colocalized with CAF markers in the tumor stroma, and CD9 abundance correlated with tumor stage. Blocking CD9 impaired the uptake of ANXA6+ EVs into cultured PDAC cells. Signaling pathway arrays and further analyses revealed that the uptake of CD9+ANXA6+ EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT). Blocking either CD9 or p38 MAPK signaling impaired CD9+ANXA6+ EV-induced cell migration and EMT in PDAC cells. Analysis of bioinformatic datasets indicated that CD9 abundance was an independent marker of poor prognosis in patients with PDAC. Our findings suggest that CD9-mediated stromal cell signaling promotes PDAC progression.
    DOI:  https://doi.org/10.1126/scisignal.abg8191
  8. Trends Cancer. 2022 Aug 03. pii: S2405-8033(22)00158-3. [Epub ahead of print]
    The urgent need to improve childhood cancer cachexia.
    Daniel V Runco, Teresa A Zimmers, Andrea Bonetto.
      Clinical care and research around cancer cachexia in children is lacking. Cachexia increases treatment-related toxicity and long-term morbidity and potentially affects mortality. We highlight the urgent need for specific focus on childhood cancer cachexia and discuss potential solutions to inform cachexia therapeutics for children.
    Keywords:  animal models; cachexia; cancer treatments; inflammation; metabolism; nutrition; pediatric
    DOI:  https://doi.org/10.1016/j.trecan.2022.07.005
  9. Trends Cancer. 2022 Jul 29. pii: S2405-8033(22)00157-1. [Epub ahead of print]
    Roles of mitochondrial genetics in cancer metastasis.
    Danny R Welch, Christian Foster, Isidore Rigoutsos.
      The contributions of mitochondria to cancer have been recognized for decades. However, the focus on the metabolic role of mitochondria and the diminutive size of the mitochondrial genome compared to the nuclear genome have hindered discovery of the roles of mitochondrial genetics in cancer. This review summarizes recent data demonstrating the contributions of mitochondrial DNA (mtDNA) copy-number variants (CNVs), somatic mutations, and germline polymorphisms to cancer initiation, progression, and metastasis. The goal is to summarize accumulating data to establish a framework for exploring the contributions of mtDNA to neoplasia and metastasis.
    Keywords:  metabolism; metastasis; mitochondrial genetics; polymorphism; tumor progression
    DOI:  https://doi.org/10.1016/j.trecan.2022.07.004
  10. J Cell Sci. 2022 Aug 01. pii: jcs259676. [Epub ahead of print]135(15):
    The role of cellular quiescence in cancer - beyond a quiet passenger.
    Rebeka Tomasin, Alexandre Bruni-Cardoso.
      Quiescence, the ability to temporarily halt proliferation, is a conserved process that initially allowed survival of unicellular organisms during inhospitable times and later contributed to the rise of multicellular organisms, becoming key for cell differentiation, size control and tissue homeostasis. In this Review, we explore the concept of cancer as a disease that involves abnormal regulation of cellular quiescence at every step, from malignant transformation to metastatic outgrowth. Indeed, disrupted quiescence regulation can be linked to each of the so-called 'hallmarks of cancer'. As we argue here, quiescence induction contributes to immune evasion and resistance against cell death. In contrast, loss of quiescence underlies sustained proliferative signalling, evasion of growth suppressors, pro-tumorigenic inflammation, angiogenesis and genomic instability. Finally, both acquisition and loss of quiescence are involved in replicative immortality, metastasis and deregulated cellular energetics. We believe that a viewpoint that considers quiescence abnormalities that occur during oncogenesis might change the way we ask fundamental questions and the experimental approaches we take, potentially contributing to novel discoveries that might help to alter the course of cancer therapy.
    Keywords:  Cancer progression, Oncogenesis; Cell cycle arrest; Dormancy; Hallmarks of cancer; Tumorigenesis
    DOI:  https://doi.org/10.1242/jcs.259676
  11. Gastroenterology. 2022 Aug 02. pii: S0016-5085(22)00898-8. [Epub ahead of print]
    Nutrient scavenging from muscle cells: A survival strategy of pancreatic cancer cells ends in cachexia.
    Ivonne Regel, Julia Mayerle.
      
    DOI:  https://doi.org/10.1053/j.gastro.2022.07.069
  12. Nat Rev Nephrol. 2022 Aug 03.
    Cellular senescence: the good, the bad and the unknown.
    Weijun Huang, LaTonya J Hickson, Alfonso Eirin, James L Kirkland, Lilach O Lerman.
      Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.
    DOI:  https://doi.org/10.1038/s41581-022-00601-z
  13. J Biol Chem. 2022 Aug 02. pii: S0021-9258(22)00778-5. [Epub ahead of print] 102336
    A new fluorescent sensor mitoferrofluor indicates the presence of chelatable iron in polarized and depolarized mitochondria.
    Andaleb Kholmukhamedov, Li Li, Christopher C Lindsey, Jiangting Hu, Anna-Liisa Nieminen, Kenji Takemoto, Gyda C Beeson, Chad M Beneker, Campbell McInnes, Craig C Beeson, John J Lemasters.
      Mitochondrial chelatable iron contributes to the severity of several injury processes, including ischemia/reperfusion, oxidative stress, and drug toxicity. However, methods to measure this species in living cells are lacking. To measure mitochondrial chelatable iron in living cells, here we synthesized a new fluorescent indicator, mitoferrofluor (MFF). We designed cationic MFF to accumulate electrophoretically in polarized mitochondria, where a reactive group then forms covalent adducts with mitochondrial proteins to retain MFF even after subsequent depolarization. We also show in cell-free medium that Fe2+ (and Cu2+), but not Fe3+, Ca2+, or other biologically relevant divalent cations, strongly quenched MFF fluorescence. Using confocal microscopy, we demonstrate in hepatocytes that red MFF fluorescence co-localized with the green fluorescence of the mitochondrial membrane potential (ΔΨm) indicator, rhodamine 123 (Rh123), indicating selective accumulation into mitochondria. Unlike Rh123, mitochondria retained MFF after ΔΨm collapse. Furthermore, intracellular delivery of iron with membrane-permeant Fe3+/8-hydroxyquinoline (FeHQ) quenched MFF fluorescence by ∼80% in hepatocytes and other cell lines, which was substantially restored by the membrane-permeant transition metal chelator pyridoxal isonicotinoyl hydrazone. We also show FeHQ quenched the fluorescence of cytosolically co-loaded calcein, another Fe2+ indicator, confirming that Fe3+ in FeHQ undergoes intracellular reduction to Fe2+. Finally, MFF fluorescence did not change after addition of the calcium mobilizer thapsigargin, which shows MFF is insensitive to physiologically relevant increases of mitochondrial Ca2+. In conclusion, the new sensor reagent MFF fluorescence is an indicator of mitochondrial chelatable Fe2+ in normal hepatocytes with polarized mitochondria as well as in cells undergoing loss of ΔΨm.
    Keywords:  iron sensor; ischemia/reperfusion; membrane potential; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2022.102336
  14. Oncologist. 2022 Aug 05. pii: oyac146. [Epub ahead of print]
    A Phase I Study of Gemcitabine/Nab-Paclitaxel/S-1 Chemotherapy in Patients With Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma.
    Chen Chang, Xiaofen Li, Ke Cheng, Zhaolun Cai, Junjie Xiong, Wanrui Lv, Ruizhen Li, Pei Zhang, Dan Cao.
       BACKGROUND: Systemic chemotherapy is the primary treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). More effective treatment options are highly awaited. The aim of this study was to evaluate the toxicity and feasibility of gemcitabine/nab-paclitaxel/S-1 (GAS) chemotherapy on a 21-day cycle in patients with locally advanced or metastatic PDAC, determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of S-1 in this regimen, and explore preliminary efficacy.
    METHODS: Eligible patients with locally advanced or metastatic PDAC received GAS chemotherapy on a 21-day cycle. Fixed-dose nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) were given intravenously on days 1 and 8. Different doses of S-1 were given orally twice daily from day 1 to day 14 in a 3+3 dose escalation design. According to patients` body surface area, the dose-escalation design was as follows: patients with a body surface area of 1.25-1.5 m2 received S-1 40 mg/day initially and the dose was increased to 60 mg or 80 mg. Patients with a body surface area of more than 1.5 m2 received S-1 60 mg/day initially and the dose was increased to 80 mg or 100 mg. The primary endpoints were to evaluate the toxicity and determine the DLT and MTD of S-1. The secondary endpoint was to evaluate efficacy, including best objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). adverse events (AEs) were evaluated according to the NCI-CTCAE 5.0. Tumor response was assessed using the RECIST 1.1.
    RESULTS: A total of 21 eligible patients were included. Due to the infrequence of patients with a body surface area of 1.25-1.5 m2, only 2 patients were included in cohort of S-1 40 mg. The dose-escalation for patients in this group failed to be enrolled completely. For patients with a body surface area of more than 1.5 m2, 3 DLTs in 7 patients were detected at cohort of S-1 100 mg (grade 3 thrombocytopenia with hemorrhage, grade 3 rash, and grade 3 mucositis/stomatitis). S-1 80 mg/day (body surface area: >1.5 m2) was considered to be the MTD in GAS chemotherapy on a 21-day cycle. No grade 4 AEs or treatment-related deaths were observed. The most commonly occurring hematologic AE of any grade was anemia (38.1%). The most frequent nonhematologic AEs of any grade were peripheral neuropathy (38.1%), dyspepsia (23.8%), constipation (23.8%), and alopecia (23.8%). Response assessment showed that the best ORR was 36.8% (7 of 19 patients) and the DCR was 94.7% (18 of 19 patients). The median PFS was 5.3 (95% CI, 4.6 to 6.0) months and the median OS was 10.3 (95% CI, 8.1 to 12.5) months.
    CONCLUSION: GAS chemotherapy (21-day cycle) with nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2, and S-1 80 mg/day (body surface area: >1.5 m2) was found to have acceptable toxicity and significant clinical control in patients with locally advanced or metastatic PDAC. We conclude that further trials with this combination are warranted. (Trial Identifier: ChiCTR1900027833 [chictr.org]).
    Keywords:  S-1; gemcitabine; nab-paclitaxel; pancreatic ductal adenocarcinoma; phase I
    DOI:  https://doi.org/10.1093/oncolo/oyac146
  15. Pancreatology. 2022 Jul 21. pii: S1424-3903(22)00465-3. [Epub ahead of print]
    The molecular landscape of pancreatic ductal adenocarcinoma.
    L Sivapalan, H M Kocher, H Ross-Adams, C Chelala.
      Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Surgical resection of early, localised disease provides the only chance for potentially curative treatment; however, most patients with PDAC present with advanced disease and are not suitable for surgery. Genomic analyses of PDAC tumour lesions have identified a small number of recurrent alterations that are detected across most tumours, and beyond that a large number that either occur at a low (<5%) prevalence or are patient-specific in nature. This molecular heterogeneity has presented a significant challenge for the characterisation of tumour subtypes and effective molecular biomarkers, which have not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC. These challenges are compounded by the overall lack of tumour biopsies for sequencing, the invasive nature of tissue sampling and the confounding effects of low tumour cellularity in many PDAC biopsy specimens, which have limited the applications of molecular profiling in unresectable patients and for longitudinal tumour monitoring. Further investigation into alternative sources of tumour analytes that can be sampled using minimally invasive methods and used to complement molecular analyses from tissue sequencing are required.
    Keywords:  Biomarker; Circulating tumour DNA; Molecular subtypes; PDAC; Somatic mutations
    DOI:  https://doi.org/10.1016/j.pan.2022.07.010
  16. Cancer Res. 2022 Aug 05. pii: CAN-22-0325. [Epub ahead of print]
    An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinations.
    Jesse Boumelha, Sophie de Carné Trécesson, Emily K Law, Pablo Romero-Clavijo, Matthew Coelho, Kevin Ng, Edurne Mugarza, Christopher Moore, Sareena Rana, Deborah R Caswell, Miguel Murillo, David C Hancock, Prokopios P Argyris, William L Brown, Cameron Durfee, Lindsay K Larson, Rachel I Vogel, Alejandro Suarez-Bonnet, Simon L Priestnall, Philip East, Sarah J Ross, George Kassiotis, Miriam Molina-Arcas, Charles Swanton, Reuben Harris, Julian Downward.
      Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, anti-tumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0325
  17. Nat Genet. 2022 Aug;54(8): 1192-1201
    Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment.
    Dalia Barkley, Reuben Moncada, Maayan Pour, Deborah A Liberman, Ian Dryg, Gregor Werba, Wei Wang, Maayan Baron, Anjali Rao, Bo Xia, Gustavo S França, Alejandro Weil, Deborah F Delair, Cristina Hajdu, Amanda W Lund, Iman Osman, Itai Yanai.
      Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis.
    DOI:  https://doi.org/10.1038/s41588-022-01141-9
  18. Ann Surg Oncol. 2022 Aug 04.
    Neoadjuvant Therapy Versus Upfront Resection for Nonpancreatic Periampullary Adenocarcinoma.
    Mohamed Abdelgadir Adam, Alexa Glencer, Samer AlMasri, Sharon Winters, Nathan Bahary, Aatur Singhi, Kenneth K Lee, Alessandro Paniccia, Amer H Zureikat.
       BACKGROUND: In contrast to pancreatic ductal adenocarcinoma (PDAC), neoadjuvant therapy (NAT) for periampullary adenocarcinomas is not well studied, with data limited to single-institution retrospective reviews with small cohorts. We sought to compare outcomes of NAT versus upfront resection (UR) for non-PDAC periampullary adenocarcinomas.
    PATIENTS AND METHODS: Using the National Cancer Database (NCDB), we identified patients who underwent surgery for extrahepatic cholangiocarcinoma, ampullary adenocarcinoma, or duodenal adenocarcinoma from 2006 to 2016. We compared outcomes between NAT versus UR groups for each tumor subtype with 1:3 propensity score matching. Cox regression was used to identify predictors of survival.
    RESULTS: Among 7656 patients who underwent resection for non-PDAC periampullary adenocarcinoma, the proportion of patients who received NAT increased from 6 to 11% for cholangiocarcinoma (p < 0.01), 1 to 4% for ampullary adenocarcinoma (p = 0.01), and 5 to 8% for duodenal adenocarcinoma (p = 0.08). Length of stay, readmission, and 30-day mortality were comparable between NAT and UR. All tumor subtypes were downstaged following NAT (p < 0.01). The R0 resection rate was significantly higher in patients with extrahepatic cholangiocarcinoma who received NAT, and these patients had improved median overall survival (38 vs 26 months, p < 0.001). After adjustment for clinicopathologic factors and adjuvant chemotherapy, use of NAT was associated with improved survival in patients with cholangiocarcinoma [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.54-0.89, p = 0.004] but not duodenal or ampullary adenocarcinoma. The survival advantage for cholangiocarcinoma persisted after propensity matching.
    CONCLUSION: This national cohort analysis suggests, for the first time, that neoadjuvant therapy is associated with improved survival in patients with extrahepatic cholangiocarcinoma.
    DOI:  https://doi.org/10.1245/s10434-022-12257-x
  19. Exp Hematol. 2022 Jul 28. pii: S0301-472X(22)00577-X. [Epub ahead of print]
    Mitochondrial Deep Dive into Hematopoietic Stem Cell Dormancy: Not Much Glycolysis but Plenty of Sluggish Lysosomes.
    Jiajing Qiu, Saghi Ghaffari.
      The discovery of hematopoietic stem cells (HSCs) heterogeneity have had major implications for investigations of hematopoietic stem cell disorders, clonal hematopoiesis and HSC aging. More recent studies of the heterogeneity of HSC organelles have begun to provide additional insights into the HSC behavior with far reaching ramifications for mechanistic understanding of aging of HSCs and stem cell-derived diseases. Mitochondrial heterogeneity has been explored to expose HSC subsets with distinct properties and functions. Here we review some of the recent advances in these lines of studies that challenged the classical view of glycolysis in HSCs and led to the identification of lysosomes as dynamic pivotal switch in controlling HSC quiescence vs. activation beyond their function in autophagy.
    DOI:  https://doi.org/10.1016/j.exphem.2022.07.299
  20. EMBO J. 2022 Aug 01. e111834
    The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis.
    Mindong Ren, Michael Schlame.
      Recent work identifies TMBIM5 as inner mitochondrial membrane Ca2+ /H+ exchanger, linking hyperpolarisation regulation to proteome control and energy metabolism.
    DOI:  https://doi.org/10.15252/embj.2022111834
  21. Sci Transl Med. 2022 Aug 03. 14(656): eabn7571
    Triple-negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin.
    Eloïse M Grasset, Matthew Dunworth, Gaurav Sharma, Melanie Loth, Joseph Tandurella, Ashley Cimino-Mathews, Melissa Gentz, Sydney Bracht, Meagan Haynes, Elana J Fertig, Andrew J Ewald.
      Triple-negative breast cancer (TNBC) is an aggressive subtype associated with early metastatic recurrence and worse patient outcomes. TNBC tumors express molecular markers of the epithelial-mesenchymal transition (EMT), but its requirement during spontaneous TNBC metastasis in vivo remains incompletely understood. We demonstrated that spontaneous TNBC tumors from a genetically engineered mouse model (GEMM), multiple patient-derived xenografts, and archival patient samples exhibited large populations in vivo of hybrid E/M cells that lead invasion ex vivo while expressing both epithelial and mesenchymal characteristics. The mesenchymal marker vimentin promoted invasion and repressed metastatic outgrowth. We next tested the requirement for five EMT transcription factors and observed distinct patterns of utilization during invasion and colony formation. These differences suggested a sequential activation of multiple EMT molecular programs during the metastatic cascade. Consistent with this model, our longitudinal single-cell RNA analysis detected three different EMT-related molecular patterns. We observed cancer cells progressing from epithelial to hybrid E/M and strongly mesenchymal patterns during invasion and from epithelial to a hybrid E/M pattern during colony formation. We next investigated the relative epithelial versus mesenchymal state of cancer cells in both GEMM and patient metastases. In both contexts, we observed heterogeneity between and within metastases in the same individual. We observed a complex spectrum of epithelial, hybrid E/M, and mesenchymal cell states within metastases, suggesting that there are multiple successful molecular strategies for distant organ colonization. Together, our results demonstrate an important and complex role for EMT programs during TNBC metastasis.
    DOI:  https://doi.org/10.1126/scitranslmed.abn7571
  22. Cancer Lett. 2022 Aug 01. pii: S0304-3835(22)00334-2. [Epub ahead of print] 215850
    Transformed cells after senescence give rise to more severe tumor phenotypes than transformed non-senescent cells.
    Alberta Palazzo, Hector Hernandez-Vargas, Delphine Goehrig, Jean-Jacques Médard, David Vindrieux, Jean-Michel Flaman, David Bernard.
      Oncogenic stress-induced senescence initially inhibits tumor initiation by blocking proliferation and by attracting immune cells to clear potentially harmful cells. If these cells are not eliminated they may resume proliferation upon loss-of-tumor suppressors, and be at risk of transformation. During tumor formation, depending on the sequence of events of gain-of-oncogenes and/or loss-of-tumor suppressors, cancer cells may emerge from senescent cells. Here, we show that these transformed cells after senescence (TS) display more aggressive tumorigenic features, with a greater capacity to migrate and a higher resistance to anti-tumoral drugs than cells having undergone transformation without senescence. Bulk transcriptomic analysis and single cell RNA sequencing revealed a signature unique to TS cells. A score of this signature was then generated and a high score was correlated with decreased survival of patients with lung adenocarcinoma, head-neck squamous cell carcinoma, adrenocortical carcinoma, liver hepatocellular carcinoma, skin cutaneous melanoma and low-grade glioma. Together, these findings strongly support that cancer cells arising from senescent cells are more dangerous, and that a molecular signature of these cells may be of prognostic value for some human cancers. It also raises questions about modeling human tumors, using cells or mice, without regards to the sequence of events leading to transformation.
    Keywords:  Cellular senescence; RAS oncogene; Tumor aggressiveness; p53 tumor suppressor
    DOI:  https://doi.org/10.1016/j.canlet.2022.215850
  23. Nat Rev Mol Cell Biol. 2022 Aug 02.
    Generation of nanoscopic membrane curvature for membrane trafficking.
    Michael M Kozlov, Justin W Taraska.
      Curved membranes are key features of intracellular organelles, and their generation involves dynamic protein complexes. Here we describe the fundamental mechanisms such as the hydrophobic insertion, scaffolding and crowding mechanisms these proteins use to produce membrane curvatures and complex shapes required to form intracellular organelles and vesicular structures involved in endocytosis and secretion. For each mechanism, we discuss its cellular functions as well as the underlying physical principles and the specific membrane properties required for the mechanism to be feasible. We propose that the integration of individual mechanisms into a highly controlled, robust process of curvature generation often relies on the assembly of proteins into coats. How cells unify and organize the curvature-generating factors at the nanoscale is presented for three ubiquitous coats central for membrane trafficking in eukaryotes: clathrin-coated pits, caveolae, and COPI and COPII coats. The emerging theme is that these coats arrange and coordinate curvature-generating factors in time and space to dynamically shape membranes to accomplish membrane trafficking within cells.
    DOI:  https://doi.org/10.1038/s41580-022-00511-9
  24. G3 (Bethesda). 2022 Aug 05. pii: jkac200. [Epub ahead of print]
    Discovery of non-autonomous modulators of activated Ras.
    Marcos Corchado-Sonera, Komal Rambani, Kristen Navarro, Raleigh Kladney, James Dowdle, Gustavo Leone, Helen M Chamberlin.
      Communication between mesodermal cells and epithelial cells is fundamental to normal animal development and is frequently disrupted in cancer. However, the genes and processes that mediate this communication are incompletely understood. To identify genes that mediate this communication and alter the proliferation of cells with an oncogenic Ras genotype, we carried out a tissue-specific genome-wide RNAi screen in C. elegans animals bearing a let-60(n1046gf) (RasG13E) allele. The screen identifies 24 genes that, when knocked down in adjacent mesodermal tissue, suppress the increased vulval epithelial cell proliferation defect associated with let-60(n1046gf). Importantly, gene knockdown reverts the mutant animals to a wild-type phenotype. Using chimeric animals, we genetically confirm that two of the genes function non-autonomously to revert the let-60(n1046gf) phenotype. The effect is genotype-restricted, as knockdown does not alter development in a wild type (let-60(+)) or activated EGF receptor (let-23(sa62gf)) background. Although many of the genes identified encode proteins involved in essential cellular processes including chromatin formation, ribosome function and mitochondrial ATP metabolism, knockdown does not alter the normal development or function of targeted mesodermal tissues, indicating that the phenotype derives from specific functions performed by these cells. We show that the genes act in a manner distinct from two signal ligand classes (EGF and Wnt) known to influence the development of vulval epithelial cells. Altogether, the results identify genes with a novel function in mesodermal cells required for communicating with and promoting the proliferation of adjacent epithelial cells with an activated Ras genotype.
    Keywords:   C. elegans ; ATP synthase; Cell communication; Ras; vulval development
    DOI:  https://doi.org/10.1093/g3journal/jkac200
  25. Cell. 2022 Aug 04. pii: S0092-8674(22)00847-9. [Epub ahead of print]185(16): 2899-2917.e31
    Glioblastoma hijacks neuronal mechanisms for brain invasion.
    Varun Venkataramani, Yvonne Yang, Marc Cicero Schubert, Ekin Reyhan, Svenja Kristin Tetzlaff, Niklas Wißmann, Michael Botz, Stella Judith Soyka, Carlo Antonio Beretta, Rangel Lyubomirov Pramatarov, Laura Fankhauser, Luciano Garofano, Alexander Freudenberg, Julia Wagner, Dimitar Ivanov Tanev, Miriam Ratliff, Ruifan Xie, Tobias Kessler, Dirk C Hoffmann, Ling Hai, Yvette Dörflinger, Simone Hoppe, Yahaya A Yabo, Anna Golebiewska, Simone P Niclou, Felix Sahm, Anna Lasorella, Martin Slowik, Leif Döring, Antonio Iavarone, Wolfgang Wick, Thomas Kuner, Frank Winkler.
      Glioblastomas are incurable tumors infiltrating the brain. A subpopulation of glioblastoma cells forms a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs). Other subpopulations appear unconnected, and their biological role remains unclear. Here, we demonstrate that whole-brain colonization is fueled by glioblastoma cells that lack connections with other tumor cells and astrocytes yet receive synaptic input from neurons. This subpopulation corresponds to neuronal and neural-progenitor-like tumor cell states, as defined by single-cell transcriptomics, both in mouse models and in the human disease. Tumor cell invasion resembled neuronal migration mechanisms and adopted a Lévy-like movement pattern of probing the environment. Neuronal activity induced complex calcium signals in glioblastoma cells followed by the de novo formation of TMs and increased invasion speed. Collectively, superimposing molecular and functional single-cell data revealed that neuronal mechanisms govern glioblastoma cell invasion on multiple levels. This explains how glioblastoma's dissemination and cellular heterogeneity are closely interlinked.
    Keywords:  cancer neuroscience; cell heterogeneity; glioblastoma; glutamatergic synapse; neurogliomal synapses; neuron-tumor interaction; tumor cell networks; tumor microtubes
    DOI:  https://doi.org/10.1016/j.cell.2022.06.054
  26. Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00301-0. [Epub ahead of print]29(8): 1161-1180
    Wound healing, fibroblast heterogeneity, and fibrosis.
    Heather E Talbott, Shamik Mascharak, Michelle Griffin, Derrick C Wan, Michael T Longaker.
      Fibroblasts are highly dynamic cells that play a central role in tissue repair and fibrosis. However, the mechanisms by which they contribute to both physiologic and pathologic states of extracellular matrix deposition and remodeling are just starting to be understood. In this review article, we discuss the current state of knowledge in fibroblast biology and heterogeneity, with a primary focus on the role of fibroblasts in skin wound repair. We also consider emerging techniques in the field, which enable an increasingly nuanced and contextualized understanding of these complex systems, and evaluate limitations of existing methodologies and knowledge. Collectively, this review spotlights a diverse body of research examining an often-overlooked cell type-the fibroblast-and its critical functions in wound repair and beyond.
    Keywords:  fibroblast heterogeneity; fibroblasts; fibrosis; regeneration; wound healing
    DOI:  https://doi.org/10.1016/j.stem.2022.07.006
  27. Am J Physiol Heart Circ Physiol. 2022 Aug 05.
    Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress.
    Jean C Bikomeye, Janée M Terwoord, Janine H Santos, Andreas M Beyer.
      Many anti-cancer therapies (CTx) have cardiotoxic side effects that limit their therapeutic potential and cause long-term cardiovascular complications in cancer survivors. This has given rise to the field of cardio-oncology, which recognizes the need for basic, translational, and clinical research focused on understanding the complex signaling events that drive CTx-induced cardiovascular toxicity. Several CTx agents cause mitochondrial damage in the form of mitochondrial DNA deletions, mutations, and suppression of respiratory function and ATP production. In this review, we provide a brief overview of the cardiovascular complications of clinically used CTx agents and discuss current knowledge of local and systemic secondary signaling events that arise in response to mitochondrial stress/damage. Mitochondrial oxidative stress has long been recognized as a contributor to CTx-induced cardiotoxicity; thus, we focus on emerging roles for mitochondria in epigenetic regulation, innate immunity, and signaling via non-coding RNAs and mitochondrial hormones. Because data exploring mitochondrial secondary signaling in the context of cardio-oncology are limited, we also draw upon clinical and pre-clinical studies which have examined these pathways in other relevant pathologies.
    Keywords:  Cardio-Oncology; DAMPs; cardiotoxisity; chemotherpay; mitochondria
    DOI:  https://doi.org/10.1152/ajpheart.00231.2022
  28. Mol Cancer. 2022 Aug 04. 21(1): 159
    Targeting KRAS mutant cancers: from druggable therapy to drug resistance.
    Chunxiao Zhu, Xiaoqing Guan, Xinuo Zhang, Xin Luan, Zhengbo Song, Xiangdong Cheng, Weidong Zhang, Jiang-Jiang Qin.
      Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.
    Keywords:  Combination therapy; Druggable; KRAS mutations; Resistance
    DOI:  https://doi.org/10.1186/s12943-022-01629-2
  29. Sci Adv. 2022 Aug 05. 8(31): eabo0412
    Deacetylation of ATG4B promotes autophagy initiation under starvation.
    Liangbo Sun, Haojun Xiong, Lingxi Chen, Xufang Dai, Xiaojing Yan, Yaran Wu, Mingzhen Yang, Meihua Shan, Tao Li, Jie Yao, Wenbin Jiang, Haiyan He, Fengtian He, Jiqin Lian.
      Eukaryotes initiate autophagy when facing environmental changes such as a lack of external nutrients. However, the mechanisms of autophagy initiation are still not fully elucidated. Here, we showed that deacetylation of ATG4B plays a key role in starvation-induced autophagy initiation. Specifically, we demonstrated that ATG4B is activated during starvation through deacetylation at K39 by the deacetylase SIRT2. Moreover, starvation triggers SIRT2 dephosphorylation and activation in a cyclin E/CDK2 suppression-dependent manner. Meanwhile, starvation down-regulates p300, leading to a decrease in ATG4B acetylation at K39. K39 deacetylation also enhances the interaction of ATG4B with pro-LC3, which promotes LC3-II formation. Furthermore, an in vivo experiment using Sirt2 knockout mice also confirmed that SIRT2-mediated ATG4B deacetylation at K39 promotes starvation-induced autophagy initiation. In summary, this study reveals an acetylation-dependent regulatory mechanism that controls the role of ATG4B in autophagy initiation in response to nutritional deficiency.
    DOI:  https://doi.org/10.1126/sciadv.abo0412
  30. Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00303-4. [Epub ahead of print]29(8): 1213-1228.e8
    Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.
    Ester Gil Vasquez, Nadia Nasreddin, Gabriel N Valbuena, Eoghan J Mulholland, Hayley L Belnoue-Davis, Holly R Eggington, Ryan O Schenck, Valérie M Wouters, Pratyaksha Wirapati, Kathryn Gilroy, Tamsin R M Lannagan, Dustin J Flanagan, Arafath K Najumudeen, Sulochana Omwenga, Amy M B McCorry, Alistair Easton, Viktor H Koelzer, James E East, Dion Morton, Livio Trusolino, Timothy Maughan, Andrew D Campbell, Maurice B Loughrey, Philip D Dunne, Petros Tsantoulis, David J Huels, Sabine Tejpar, Owen J Sansom, Simon J Leedham.
      Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.
    Keywords:  cell plasticity; colorectal cancer; colorectal neoplasia; intestinal polyps; intestinal stem cells; molecular phenotyping; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2022.07.008
  31. J Am Chem Soc. 2022 Aug 05.
    Live-Cell RNA Imaging with Metabolically Incorporated Fluorescent Nucleosides.
    Danyang Wang, Ana Shalamberidze, A Emilia Arguello, Byron W Purse, Ralph E Kleiner.
      Fluorescence imaging is a powerful method for probing macromolecular dynamics in biological systems; however, approaches for cellular RNA imaging are limited to the investigation of individual RNA constructs or bulk RNA labeling methods compatible primarily with fixed samples. Here, we develop a platform for fluorescence imaging of bulk RNA dynamics in living cells. We show that fluorescent bicyclic and tricyclic cytidine analogues can be metabolically incorporated into cellular RNA by overexpression of uridine-cytidine kinase 2. In particular, metabolic feeding with the tricyclic cytidine-derived nucleoside tC combined with confocal imaging enables the investigation of RNA synthesis, degradation, and trafficking at single-cell resolution. We apply our imaging modality to study RNA metabolism and localization during the oxidative stress response and find that bulk RNA turnover is greatly accelerated upon NaAsO2 treatment. Furthermore, we identify cytoplasmic RNA granules containing RNA transcripts generated during oxidative stress that are distinct from canonical stress granules and P-bodies and co-localize with the RNA helicase DDX6. Taken together, our work provides a powerful approach for live-cell RNA imaging and reveals how cells reshape RNA transcriptome dynamics in response to oxidative stress.
    DOI:  https://doi.org/10.1021/jacs.2c04142
  32. Cancer Med. 2022 Jul 31.
    Does acute pancreatitis herald pancreatic ductal adenocarcinoma? A multicenter electronic health research network study.
    Ritu R Singh, Alison P Klein, Neil R Sharma, Eileen M O'Reilly.
       BACKGROUND AND OBJECTIVES: High mortality in pancreas ductal adenocarcinoma (PDAC) is related to delayed diagnosis and lack of cost-effective early detection strategies. Retrospective studies have demonstrated an association between PDAC and acute pancreatitis (AP). Herein, we explore the incidence of PDAC in patients with non-biliary and non-alcoholic AP.
    METHODS: A population-based, retrospective cohort study was conducted utilizing TriNetX (Cambridge, MA). Patients ≥40 years with AP (ICD-10-CM code: K85) and without biliary AP (K85.1), alcohol-induced AP (K85.2) or chronic pancreatitis (K86.0, K86.1), were identified. The primary outcome was incidence of PDAC (C25) in patients at defined intervals following AP. We compared the rate of early-stage diagnosis (stage 1-2) and surgical resection among patients with and without preceding AP.
    RESULTS: The incidence of PDAC ranged from 2.16% (1 year) to 3.43% (5 years). Patients with PDAC and AP in preceding year were more likely to undergo surgical resection relative to those without AP (10.1% vs. 6.3%, risk ratio 1.62: 95% confidence interval, CI 1.47-1.79). Early-stage diagnosis of PDAC was more frequent in patients with preceding AP; however, difference was insignificant (p = 0.48; 95% CI 0.64-2.58).
    CONCLUSION: AP is infrequently associated with PDAC and can precede a diagnosis of PDAC in a minority of patients without another known etiology of pancreatitis. Patients with a recent AP are more likely to undergo surgical resection of PDAC and a trend toward diagnosis at an earlier stage compared to patients with PDAC and without AP. The impact of AP-related PDAC on survival is unknown.
    Keywords:  acute pancreatitis; database; pancreas ductal adenocarcinoma; pancreatic neoplasm
    DOI:  https://doi.org/10.1002/cam4.5094
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