bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023‒06‒25
35 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation.
  2. Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies.
  3. Histone demethylase KDM5D upregulation drives sex differences in colon cancer.
  4. Weaving the nest: extracellular matrix roles in pre-metastatic niche formation.
  5. Micro-engineering and nano-engineering approaches to investigate tumour ecosystems.
  6. An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets.
  7. Unique amphipathic α helix drives membrane insertion and enzymatic activity of ATG3.
  8. Trapping all ERBB ligands decreases pancreatic lesions in a murine model of pancreatic ductal adenocarcinoma.
  9. Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation.
  10. A multimodal atlas of tumour metabolism reveals the architecture of gene-metabolite covariation.
  11. Genetic susceptibility to nonalcoholic fatty liver disease and risk for pancreatic cancer: Mendelian randomization.
  12. Variable body and tissue weight reporting in preclinical cachexia literature may alter study outcomes and interpretation.
  13. Mechanisms of action of NME metastasis suppressors - a family affair.
  14. Normal saline remodels the omentum and stimulates its receptivity for transcoelomic metastasis.
  15. Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.
  16. Injury prevents Ras mutant cell expansion in mosaic skin.
  17. Cellular barcoding: From developmental tracing to anti-tumor drug discovery.
  18. Physiology and diseases of tissue-resident macrophages.
  19. Relationship between ABO blood group alleles and pancreatic cancer is modulated by secretor (FUT2) genotype, but not Lewis antigen (FUT3) genotype.
  20. Sequential apoptotic and multiplexed proteomic evaluation of single cancer cells.
  21. The emerging potential role of p62 in cancer treatment by regulating metabolism.
  22. Onco-condensates: formation, multi-component organization, and biological functions.
  23. Measurement of SQSTM1 by flow cytometry.
  24. Somatic loss of ATM is a late event in pancreatic tumorigenesis.
  25. The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation?
  26. High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers.
  27. Structural basis of mitochondrial protein import by the TIM23 complex.
  28. A non-conserved histidine residue on KRAS drives paralog selectivity of the KRASG12D inhibitor MRTX1133.
  29. "Diet for the prevention and management of sarcopenia".
  30. SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.
  31. Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes.
  32. Two-Step Tag-Free Isolation of Mitochondria for Improved Protein Discovery and Quantification.
  33. Q-VAT: Quantitative Vascular Analysis Tool.
  34. Pancreatic regional blood flow links the endocrine and exocrine diseases.
  35. tidytof: a user-friendly framework for scalable and reproducible high-dimensional cytometry data analysis.
  1. Nat Commun. 2023 Jun 23. 14(1): 3761
    NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation.
    Isidoro Cobo, Sumit Paliwal, Cristina Bodas, Irene Felipe, Júlia Melià-Alomà, Ariadna Torres, Jaime Martínez-Villarreal, Marina Malumbres, Fernando García, Irene Millán, Natalia Del Pozo, Joo-Cheol Park, Ray J MacDonald, Javier Muñoz, Raúl Méndez, Francisco X Real.
      Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.
    DOI:  https://doi.org/10.1038/s41467-023-39291-x
  2. Dev Cell. 2023 06 19. pii: S1534-5807(23)00243-5. [Epub ahead of print]58(12): 1007-1021
    Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies.
    Mariantonietta D'Ambrosio, Jesús Gil.
      Cellular senescence is a stress response associated with aging and disease, including cancer. Senescent cells undergo a stable cell cycle arrest, undergo a change in morphology and metabolic reprogramming, and produce a bioactive secretome termed the senescence-associated secretory phenotype (SASP). In cancer, senescence is an important barrier to tumor progression. Induction of senescence in preneoplastic cells limits cancer initiation, and many cancer therapies act in part by inducing senescence in cancer cells. Paradoxically, senescent cells lingering in the tumor microenvironment (TME) can contribute to tumor progression, metastasis, and therapy resistance. In this review, we discuss the different types of senescent cells present in the TME and how these senescent cells and their SASP reshape the TME, affect immune responses, and influence cancer progression. Furthermore, we will highlight the importance of senotherapies, including senolytic drugs that eliminate senescent cells and impede tumor progression and metastasis by restoring anti-tumor immune responses and influencing the TME.
    Keywords:  SASP; TME; cancer; senescence; senescence-associated secretory phenotype; senolytics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.devcel.2023.05.010
  3. Nature. 2023 Jun 21.
    Histone demethylase KDM5D upregulation drives sex differences in colon cancer.
    Jiexi Li, Zhengdao Lan, Wenting Liao, James W Horner, Xueping Xu, Jielin Liu, Yohei Yoshihama, Shan Jiang, Hong Seok Shim, Max Slotnik, Kyle A LaBella, Chang-Jiun Wu, Kenneth Dunner, Wen-Hao Hsu, Rumi Lee, Isha Khanduri, Christopher Terranova, Kadir Akdemir, Deepavali Chakravarti, Xiaoying Shang, Denise J Spring, Y Alan Wang, Ronald A DePinho.
      Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.
    DOI:  https://doi.org/10.1038/s41586-023-06254-7
  4. Front Oncol. 2023 ;13 1163786
    Weaving the nest: extracellular matrix roles in pre-metastatic niche formation.
    Laura Patras, Doru Paul, Irina R Matei.
      The discovery that primary tumors condition distant organ sites of future metastasis for seeding by disseminating tumor cells through a process described as the pre-metastatic niche (PMN) formation revolutionized our understanding of cancer progression and opened new avenues for therapeutic interventions. Given the inherent inefficiency of metastasis, PMN generation is crucial to ensure the survival of rare tumor cells in the otherwise hostile environments of metastatic organs. Early on, it was recognized that preparing the "soil" of the distal organ to support the outgrowth of metastatic cells is the initiating event in PMN development, achieved through the remodeling of the organ's extracellular matrix (ECM). Remote restructuring of ECM at future sites of metastasis under the influence of primary tumor-secreted factors is an iterative process orchestrated through the crosstalk between resident stromal cells, such as fibroblasts, epithelial and endothelial cells, and recruited innate immune cells. In this review, we will explore the ECM changes, cellular effectors, and the mechanisms of ECM remodeling throughout PMN progression, as well as its impact on shaping the PMN and ultimately promoting metastasis. Moreover, we highlight the clinical and translational implications of PMN ECM changes and opportunities for therapeutically targeting the ECM to hinder PMN formation.
    Keywords:  cancer metastasis; extracellular matrix; extracellular vesicles; pre-metastatic niche; systemic disease
    DOI:  https://doi.org/10.3389/fonc.2023.1163786
  5. Nat Rev Cancer. 2023 Jun 23.
    Micro-engineering and nano-engineering approaches to investigate tumour ecosystems.
    Mijin Kim, Magdalini Panagiotakopoulou, Chen Chen, Stephen B Ruiz, Karuna Ganesh, Tuomas Tammela, Daniel A Heller.
      The interactions among tumour cells, the tumour microenvironment (TME) and non-tumour tissues are of interest to many cancer researchers. Micro-engineering approaches and nanotechnologies are under extensive exploration for modelling these interactions and measuring them in situ and in vivo to investigate therapeutic vulnerabilities in cancer and extend a systemic view of tumour ecosystems. Here we highlight the greatest opportunities for improving the understanding of tumour ecosystems using microfluidic devices, bioprinting or organ-on-a-chip approaches. We also discuss the potential of nanosensors that can transmit information from within the TME or elsewhere in the body to address scientific and clinical questions about changes in chemical gradients, enzymatic activities, metabolic and immune profiles of the TME and circulating analytes. This Review aims to connect the cancer biology and engineering communities, presenting biomedical technologies that may expand the methodologies of the former, while inspiring the latter to develop approaches for interrogating cancer ecosystems.
    DOI:  https://doi.org/10.1038/s41568-023-00593-3
  6. Cancer Cell. 2023 Jun 19. pii: S1535-6108(23)00208-8. [Epub ahead of print]
    An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets.
    Joscha Griger, Sebastian A Widholz, Moritz Jesinghaus, Niklas de Andrade Krätzig, Sebastian Lange, Thomas Engleitner, Juan José Montero, Ekaterina Zhigalova, Rupert Öllinger, Veveeyan Suresh, Wiebke Winkler, Svenja Lier, Olga Baranov, Riccardo Trozzo, Najib Ben Khaled, Shounak Chakraborty, Jiakun Yu, Björn Konukiewitz, Katja Steiger, Nicole Pfarr, Ashish Rajput, David Sailer, Gisela Keller, Peter Schirmacher, Christoph Röcken, Klaus W Fagerstedt, Julia Mayerle, Marc Schmidt-Supprian, Günter Schneider, Wilko Weichert, Dinis P Calado, Thomas Sommermann, Günter Klöppel, Klaus Rajewsky, Dieter Saur, Roland Rad.
      Gastric neuroendocrine carcinomas (G-NEC) are aggressive malignancies with poorly understood biology and a lack of disease models. Here, we use genome sequencing to characterize the genomic landscapes of human G-NEC and its histologic variants. We identify global and subtype-specific alterations and expose hitherto unappreciated gains of MYC family members in a large part of cases. Genetic engineering and lineage tracing in mice delineate a model of G-NEC evolution, which defines MYC as a critical driver and positions the cancer cell of origin to the neuroendocrine compartment. MYC-driven tumors have pronounced metastatic competence and display defined signaling addictions, as revealed by large-scale genetic and pharmacologic screening of cell lines and organoid resources. We create global maps of G-NEC dependencies, highlight critical vulnerabilities, and validate therapeutic targets, including candidates for clinical drug repurposing. Our study gives comprehensive insights into G-NEC biology.
    Keywords:  CRISPR screen; MANEC; NEC; WGS; gastric cancer; genetic screening; mouse model; neuroendocrine cancer; pharmacologic screening; stomach
    DOI:  https://doi.org/10.1016/j.ccell.2023.06.001
  7. Sci Adv. 2023 Jun 23. 9(25): eadh1281
    Unique amphipathic α helix drives membrane insertion and enzymatic activity of ATG3.
    Taki Nishimura, Gianmarco Lazzeri, Noboru Mizushima, Roberto Covino, Sharon A Tooze.
      Autophagosome biogenesis requires a localized perturbation of lipid membrane dynamics and a unique protein-lipid conjugate. Autophagy-related (ATG) proteins catalyze this biogenesis on cellular membranes, but the underlying molecular mechanism remains unclear. Focusing on the final step of the protein-lipid conjugation reaction, the ATG8/LC3 lipidation, we show how the membrane association of the conjugation machinery is organized and fine-tuned at the atomistic level. Amphipathic α helices in ATG3 proteins (AHATG3) have low hydrophobicity and contain less bulky residues. Molecular dynamics simulations reveal that AHATG3 regulates the dynamics and accessibility of the thioester bond of the ATG3~LC3 conjugate to lipids, enabling the covalent lipidation of LC3. Live-cell imaging shows that the transient membrane association of ATG3 with autophagic membranes is governed by the less bulky-hydrophobic feature of AHATG3. The unique properties of AHATG3 facilitate protein-lipid bilayer association, leading to the remodeling of the lipid bilayer required for the formation of autophagosomes.
    DOI:  https://doi.org/10.1126/sciadv.adh1281
  8. Mol Oncol. 2023 Jun 21.
    Trapping all ERBB ligands decreases pancreatic lesions in a murine model of pancreatic ductal adenocarcinoma.
    Kathrin Hedegger, Andreas Blutke, Theresa Hommel, Kerstin E Auer, Nishanth B Nataraj, Moshit Lindzen, Yosef Yarden, Maik Dahlhoff.
      Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of cancers. Attempts to develop targeted therapies still need to be established. Some oncogenic mechanisms in PDAC carcinogenesis harness the EGFR/ERBB receptor family. To explore the effects on pancreatic lesions, we attempted simultaneous blockade of all ERBB ligands in a PDAC mouse model. To this end, we engineered a molecular decoy, TRAP-FC , comprising the ligand-binding domains of both EGFR and ERBB4 and able to trap all ERBB ligands. Next, we generated a transgenic mouse model (CBATRAP/0 ) expressing TRAP-FC ubiquitously under the control of the chicken beta-actin promoter and crossed these mice with KRASG12D/+ mice (Kras) to generate Trap/Kras mice. The resulting mice displayed decreased emergence of spontaneous pancreatic lesion areas and exhibited reduced RAS activity and decreased activities of ERBBs, with the exception of ERBB4, which showed increased activity. To identify the involved receptor(s), we employed CRISPR/Cas9 DNA editing to singly delete each ERBB receptor in the human pancreatic carcinoma cell line Panc1. Ablation of each ERBB family member, especially loss of EGFR or ERBB2/HER2, altered signaling downstream of the other three ERBB receptors and decreased cell proliferation, migration and tumor growth. We conclude that simultaneously blocking the entire ERBB receptor family is therapeutically more effective than individually inhibiting only one receptor or ligand in terms of reducing pancreatic tumor burden. In summary, trapping all ERBB ligands can reduce pancreatic lesion area and RAS activity in a murine model of pancreatic adenocarcinoma; hence, it might represent a promising approach to treat PDAC in patients.
    Keywords:  EGF-family ligands; ERBB receptors; Kras; PDAC; Panc-1; decoy molecule; mouse model
    DOI:  https://doi.org/10.1002/1878-0261.13473
  9. Curr Biol. 2023 Jun 13. pii: S0960-9822(23)00723-6. [Epub ahead of print]
    Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation.
    Sushila Ganguli, Tom Wyatt, Agata Nyga, Rachel H Lawson, Tim Meyer, Buzz Baum, Helen K Matthews.
      Oncogenic Ras has been shown to change the way cancer cells divide by increasing the forces generated during mitotic rounding. In this way, RasV12 enables cancer cells to divide across a wider range of mechanical environments than normal cells. Here, we identify a further role for oncogenic Ras-ERK signaling in division by showing that RasV12 expression alters the shape, division orientation, and respreading dynamics of cells as they exit mitosis. Many of these effects appear to result from the impact of RasV12 signaling on actomyosin contractility, because RasV12 induces the severing of retraction fibers that normally guide spindle positioning and provide a memory of the interphase cell shape. In support of this idea, the RasV12 phenotype is reversed by inhibition of actomyosin contractility and can be mimicked by the loss of cell-substrate adhesion during mitosis. Finally, we show that RasV12 activation also perturbs division orientation in cells cultured in 2D epithelial monolayers and 3D spheroids. Thus, the induction of oncogenic Ras-ERK signaling leads to rapid changes in division orientation that, along with the effects of RasV12 on cell growth and cell-cycle progression, are likely to disrupt epithelial tissue organization and contribute to cancer dissemination.
    Keywords:  MAPK signaling; actin cytoskeleton; cell division; division orientation; focal adhesions; mitosis; mitotic rounding; mitotic spindle
    DOI:  https://doi.org/10.1016/j.cub.2023.05.061
  10. Nat Metab. 2023 Jun 19.
    A multimodal atlas of tumour metabolism reveals the architecture of gene-metabolite covariation.
    Elisa Benedetti, Eric Minwei Liu, Cerise Tang, Fengshen Kuo, Mustafa Buyukozkan, Tricia Park, Jinsung Park, Fabian Correa, A Ari Hakimi, Andrew M Intlekofer, Jan Krumsiek, Ed Reznik.
      Tumour metabolism is controlled by coordinated changes in metabolite abundance and gene expression, but simultaneous quantification of metabolites and transcripts in primary tissue is rare. To overcome this limitation and to study gene-metabolite covariation in cancer, we assemble the Cancer Atlas of Metabolic Profiles of metabolomic and transcriptomic data from 988 tumour and control specimens spanning 11 cancer types in published and newly generated datasets. Meta-analysis of the Cancer Atlas of Metabolic Profiles reveals two classes of gene-metabolite covariation that transcend cancer types. The first corresponds to gene-metabolite pairs engaged in direct enzyme-substrate interactions, identifying putative genes controlling metabolite pool sizes. A second class of gene-metabolite covariation represents a small number of hub metabolites, including quinolinate and nicotinamide adenine dinucleotide, which correlate to many genes specifically expressed in immune cell populations. These results provide evidence that gene-metabolite covariation in cellularly heterogeneous tissue arises, in part, from both mechanistic interactions between genes and metabolites, and from remodelling of the bulk metabolome in specific immune microenvironments.
    DOI:  https://doi.org/10.1038/s42255-023-00817-8
  11. Cancer Epidemiol Biomarkers Prev. 2023 Jun 23. pii: EPI-23-0453. [Epub ahead of print]
    Genetic susceptibility to nonalcoholic fatty liver disease and risk for pancreatic cancer: Mendelian randomization.
    Sontoria D King, Swathi Veliginti, Martijn C G J Brouwers, Zhewen Ren, Wei Zheng, Veronica Wendy Setiawan, Lynne R Wilkens, Xiao-Ou Shu, Alan A Arslan, Laura E Beane Freeman, Paige M Bracci, Federico Canzian, Mengmeng Du, Steven J Gallinger, Graham G Giles, Phyllis J Goodman, Christopher A Haiman, Manolis Kogevinas, Charles Kooperberg, Loic Le Marchand, Rachel E Neale, Kala Visvanathan, Emily White, Demetrius Albanes, Gabriella Andreotti, Ana Babic, Sonja I Berndt, Lauren K Brais, Paul Brennan, Julie E Buring, Kari G Rabe, William R Bamlet, Stephen J Chanock, Charles S Fuchs, J Michael Gaziano, Edward L Giovannucci, Thilo Hackert, Manal M Hassan, Verena Katzke, Robert C Kurtz, I-Min Lee, Nuria Malats, Neil Murphy, Ann L Oberg, Irene Orlow, Miquel Porta, Francisco X Real, Nathaniel Rothman, Howard D Sesso, Debra T Silverman, Ian M Thompson, Jean Wactawski-Wende, Xiaoliang Wang, Nicolas Wentzensen, Herbert Yu, Anne Zeleniuch-Jacquotte, Kai Yu, Brian M Wolpin, Eric J Duell, Donghui Li, Rayjean J Hung, Sandra Perdomo, Marjorie L McCullough, Neal D Freedman, Alpa V Patel, Ulrike Peters, Elio Riboli, Malin Sund, Anne Tjønneland, Jun Zhong, Stephen K Van Den Eeden, Peter Kraft, Harvey A Risch, Laufey T Amundadottir, Alison P Klein, Rachael Z Stolzenberg-Solomon, Samuel O Antwi.
      BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer (PC). Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for PC.METHODS: Data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium (PanScan; cases n=5090, controls n=8733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n=4,163, controls n=3,792) were analyzed. We used data on 68 genetic variants with four different MR methods (inverse variance weighting [IVW], MR-Egger, simple median, and penalized weighted median) separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and PC risk, using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for PC risk factors, including obesity and diabetes.
    RESULTS: No association was found between genetically predicted NAFLD and PC risk in the PanScan or PanC4 samples (e.g., PanScan, IVW OR=1.04, 95% CI: 0.88-1.22, MR-Egger OR=0.89, 95% CI: 0.65-1.21; PanC4, IVW OR=1.07, 95% CI: 0.90-1.27, MR-Egger OR=0.93, 95% CI: 0.67-1.28). None of the four MR methods indicated an association between genetically predicted NAFLD and PC risk in either sample.
    CONCLUSIONS: Genetic predisposition to NAFLD is not associated with PC risk.
    IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and PC might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and PC.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-23-0453
  12. Dis Model Mech. 2023 Jun 23. pii: dmm.050148. [Epub ahead of print]
    Variable body and tissue weight reporting in preclinical cachexia literature may alter study outcomes and interpretation.
    Anna G Beaudry, Michelle L Law.
      Cancer cachexia is a multifactorial syndrome of body weight loss, muscle wasting, and progressive functional decline affecting many advanced cancer patients and leading to worsened clinical outcomes. Despite inherent limitations of many preclinical cachexia models, including large tumor burden, rapid tumor growth, and young age of animals, these animal models are widely used and imperative for the study of cachexia mechanisms and experimental therapeutics. However, there are currently no guidelines for reporting and representation of data in preclinical cachexia literature. We examined the current state of data reporting in publications using the colon-26 adenocarcinoma (C26) model of cachexia and compared statistical differences in reporting mechanisms using animals from our laboratory. We show that data reporting and representation in C26 preclinical cachexia literature is diverse, making comparison of study outcomes difficult. Further, different expression of body and tissue weights in our animals led to differential statistical significance, which could significantly alter data interpretation. This study highlights a need for consistent data reporting in preclinical cancer cachexia literature to effectively compare outcomes between studies and increase translatability to the human condition.
    Keywords:  Cancer cachexia; Colon-26 adenocarcinoma; Data representation; Mouse model; Preclinical
    DOI:  https://doi.org/10.1242/dmm.050148
  13. Cancer Metastasis Rev. 2023 Jun 24.
    Mechanisms of action of NME metastasis suppressors - a family affair.
    Céline Prunier, Philippe Chavrier, Mathieu Boissan.
      Metastatic progression is regulated by metastasis promoter and suppressor genes. NME1, the prototypic and first described metastasis suppressor gene, encodes a nucleoside diphosphate kinase (NDPK) involved in nucleotide metabolism; two related family members, NME2 and NME4, are also reported as metastasis suppressors. These proteins physically interact with members of the GTPase dynamin family, which have key functions in membrane fission and fusion reactions necessary for endocytosis and mitochondrial dynamics. Evidence supports a model in which NDPKs provide GTP to dynamins to maintain a high local GTP concentration for optimal dynamin function. NME1 and NME2 are cytosolic enzymes that provide GTP to dynamins at the plasma membrane, which drive endocytosis, suggesting that these NMEs are necessary to attenuate signaling by receptors on the cell surface. Disruption of NDPK activity in NME-deficient tumors may thus drive metastasis by prolonging signaling. NME4 is a mitochondrial enzyme that interacts with the dynamin OPA1 at the mitochondria inner membrane to drive inner membrane fusion and maintain a fused mitochondrial network. This function is consistent with the current view that mitochondrial fusion inhibits the metastatic potential of tumor cells whereas mitochondrial fission promotes metastasis progression. The roles of NME family members in dynamin-mediated endocytosis and mitochondrial dynamics and the intimate link between these processes and metastasis provide a new framework to understand the metastasis suppressor functions of NME proteins.
    Keywords:  Channeling; Dynamin; GTP; Metastasis; Nucleoside diphosphate kinase
    DOI:  https://doi.org/10.1007/s10555-023-10118-x
  14. JCI Insight. 2023 06 22. pii: e167336. [Epub ahead of print]8(12):
    Normal saline remodels the omentum and stimulates its receptivity for transcoelomic metastasis.
    Hironari Akasaka, WonJae Lee, Song Yi Ko, Ernst Lengyel, Honami Naora.
      The omentum contains immune cell structures called milky spots that are niches for transcoelomic metastasis. It is difficult to remove the omentum completely, and there are no effective strategies to minimize the risk of colonization of preserved omental tissues by cancer cells that circulate in the peritoneal fluid. Normal saline is commonly administered into the peritoneal cavity for diagnostic and intraoperative lavage. Here we show that normal saline, when administered into the peritoneal cavity of mice, is prominently absorbed by the omentum, exfoliates its mesothelium, and induces expression of CX3CL1, the ligand for CX3CR1, within and surrounding the omental vasculature. Studies using CX3CR1-competent and CX3CR1-deficient mice showed that the predominant response in the omentum following saline administration is an accumulation of CX3CR1+ monocytes/macrophages that expand milky spots and promote neoangiogenesis within these niches. Moreover, saline administration promoted the implantation of cancer cells of ovarian and colorectal origin onto the omentum. By contrast, these deleterious effects were not observed following i.p. administration of lactated Ringer's solution. Our findings suggest that normal saline stimulates the receptivity of the omentum for cancer cells and that the risk of colonization can be minimized by using a biocompatible crystalloid for lavage procedures.
    Keywords:  Adipose tissue; Cancer; Macrophages; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.167336
  15. Dev Cell. 2023 Jun 14. pii: S1534-5807(23)00266-6. [Epub ahead of print]
    Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.
    John Devany, Martin J Falk, Liam J Holt, Arvind Murugan, Margaret L Gardel.
      Cell proliferation is a central process in tissue development, homeostasis, and disease, yet how proliferation is regulated in the tissue context remains poorly understood. Here, we introduce a quantitative framework to elucidate how tissue growth dynamics regulate cell proliferation. Using MDCK epithelial monolayers, we show that a limiting rate of tissue expansion creates confinement that suppresses cell growth; however, this confinement does not directly affect the cell cycle. This leads to uncoupling between rates of cell growth and division in epithelia and, thereby, reduces cell volume. Division becomes arrested at a minimal cell volume, which is consistent across diverse epithelia in vivo. Here, the nucleus approaches the minimum volume capable of packaging the genome. Loss of cyclin D1-dependent cell-volume regulation results in an abnormally high nuclear-to-cytoplasmic volume ratio and DNA damage. Overall, we demonstrate how epithelial proliferation is regulated by the interplay between tissue confinement and cell-volume regulation.
    Keywords:  G1 sizer; cell cycle; cell growth; cell proliferation; cell volume; contact inhibition of proliferation; epithelial monolayer; epithelium; tissue confinement; tissue growth
    DOI:  https://doi.org/10.1016/j.devcel.2023.05.018
  16. Nature. 2023 Jun 21.
    Injury prevents Ras mutant cell expansion in mosaic skin.
    Sara Gallini, Karl Annusver, Nur-Taz Rahman, David G Gonzalez, Sangwon Yun, Catherine Matte-Martone, Tianchi Xin, Elizabeth Lathrop, Kathleen C Suozzi, Maria Kasper, Valentina Greco.
      Healthy skin is a mosaic of wild-type and mutant clones1,2. Although injury can cooperate with mutated Ras family proteins to promote tumorigenesis3-12, the consequences in genetically mosaic skin are unknown. Here we show that after injury, wild-type cells suppress aberrant growth induced by oncogenic Ras. HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue but their expansion is prevented after injury owing to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury repair. Inhibition of EGFR signalling via drug or genetic approaches diminishes the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased proliferation of wild-type cells via constitutive loss of the cell cycle inhibitor p21 counteracts the expansion of HrasG12V/+ cells even in the absence of injury. Thus, injury has a role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.
    DOI:  https://doi.org/10.1038/s41586-023-06198-y
  17. Cancer Lett. 2023 Jun 17. pii: S0304-3835(23)00232-X. [Epub ahead of print]567 216281
    Cellular barcoding: From developmental tracing to anti-tumor drug discovery.
    Yuqing Wang, Xi Zhang, Zheng Wang.
      Clonal evolution has gained immense attention in explaining cancer cell status, history, and fate during cancer progression. Current single-cell or spatial transcriptome technologies have broadened our understanding of various mechanisms underlying cancer initiation, relapse, and drug resistance. However, technical challenges still hinder a better understanding of the dynamics of distinctive phenotypic states and abnormal trajectories from normal physiological transition to malignant stages. Cellular barcoding enabled lineage tracing on parallelly massive cells at single-cell resolution through different mechanisms lately, enabling new insights into exploring developmental trajectories, cancer progression, and targeted therapies. This review summarizes the latest noteworthy and robust strategies for different types of cellular barcodes. To introduce the major characteristics, advantages and limitations of these different strategies, this review will further guide in choosing or improving cellular barcoding technologies and their applications in cancer research.
    Keywords:  Barcode technology; Cancer progressive hierarchy; Cellular differential dynamics; High-throughput screening; Single-cell lineage tracing; Therapeutic target discovery
    DOI:  https://doi.org/10.1016/j.canlet.2023.216281
  18. Nature. 2023 Jun;618(7966): 698-707
    Physiology and diseases of tissue-resident macrophages.
    Tomi Lazarov, Sergio Juarez-Carreño, Nehemiah Cox, Frederic Geissmann.
      Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies.
    DOI:  https://doi.org/10.1038/s41586-023-06002-x
  19. Cancer Epidemiol Biomarkers Prev. 2023 Jun 21. pii: EPI-23-0009. [Epub ahead of print]
    Relationship between ABO blood group alleles and pancreatic cancer is modulated by secretor (FUT2) genotype, but not Lewis antigen (FUT3) genotype.
    Jihye Kim, Chen Yuan, Laufey T Amundadottir, Brian M Wolpin, Alison P Klein, Harvey A Risch, Peter Kraft.
      BACKGROUND: In western populations, Pancreatic Ductal Adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC.METHODS: We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by utilizing genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis group by considering each product term between ABO and secretor and between ABO and Lewis group individually.
    RESULTS: We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than non-secretors (ORs 1.28 [95% CI: 1.15-1.42] and 1.17 [95% CI: 1.03-1.32] respectively; interaction p-value = 0.002). We did not find any interactions between ABO and Lewis antigens.
    CONCLUSIONS: Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status.
    IMPACT: Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-23-0009
  20. Sci Adv. 2023 Jun 23. 9(25): eadg4128
    Sequential apoptotic and multiplexed proteomic evaluation of single cancer cells.
    Emmalyn Lecky, Atreyi Mukherji, Rebecca German, Gabriella Antonellis, Jia-Ren Lin, Michael Yorsz, Kelley E McQueeney, Jeremy Ryan, Kimmie Ng, Ewa Sicinska, Peter K Sorger, Anthony Letai, Patrick D Bhola.
      A potential cause of cancer relapse is pretreatment chemoresistant subpopulations. Identifying targetable features of subpopulations that are poorly primed for therapy-induced cell death may improve cancer therapy. Here, we develop and validate real-time BH3 profiling, a live and functional single-cell measurement of pretreatment apoptotic sensitivity that occurs upstream of apoptotic protease activation. On the same single cells, we perform cyclic immunofluorescence, which enables multiplexed immunofluorescence of more than 30 proteins on the same cell. Using cultured cells and rapid ex vivo cultures of colon cancer patient-derived xenograft (PDX) models, we identify Bak as a univariate correlate of apoptotic priming, find that poorly primed subpopulations can correspond to specific stages of the cell cycle, and, in some PDX models, identify increased expression of Bcl-XL, Mcl-1, or Her2 in subpopulations that are poorly primed for apoptosis. Last, we generate and validate mathematical models of single-cell priming that describe how targetable proteins contribute to apoptotic priming.
    DOI:  https://doi.org/10.1126/sciadv.adg4128
  21. Trends Endocrinol Metab. 2023 Jun 20. pii: S1043-2760(23)00106-6. [Epub ahead of print]
    The emerging potential role of p62 in cancer treatment by regulating metabolism.
    Xiaochuan Zhang, Mengge Dai, Shaotong Li, Meng Li, Bing Cheng, Ting Ma, Zheng Zhou.
      p62 is an important multifunctional adaptor protein participating in autophagy and many other activities. Many studies have revealed that p62 is highly expressed in multiple cancers and decreasing its level can effectively lower the proliferation ability of cancer cells. Moreover, much research has highlighted the significant role of the regulation of cancer cell metabolism in helping to treat tumors. Recent reports demonstrate that p62 could regulate cancer cell metabolism through various mechanisms. However, the relationship between p62 and cancer cell metabolism as well as the related mechanisms has not been fully elucidated. In this review, we describe glucose, glutamine, and fatty acid metabolism in tumor cells and some signaling pathways that can regulate cancer metabolism and are mediated by p62.
    Keywords:  autophagy; cancer cell metabolism; inhibitors; p62
    DOI:  https://doi.org/10.1016/j.tem.2023.05.004
  22. Trends Cancer. 2023 Jun 20. pii: S2405-8033(23)00097-3. [Epub ahead of print]
    Onco-condensates: formation, multi-component organization, and biological functions.
    Chenxi Xu, Arum Kim, Joshua M Corbin, Gang Greg Wang.
      Numerous cellular processes occur in the context of condensates, a type of large, membrane-less biomolecular assembly generated through phase separation. These condensates function as a hub of diversified cellular events by concentrating the required components. Cancer frequently coopts biomolecular condensation mechanisms to promote survival and/or proliferation. Onco-condensates, which refer to those that have causal roles or are critically involved in tumorigenicity, operate to abnormally elevate biological output of a proliferative process, or to suppress a tumor-suppressive pathway, thereby promoting oncogenesis. Here, we summarize advances regarding how multi-component onco-condensates are established and organized to promote oncogenesis, with those related to chromatin and transcription deregulation used as showcases. A better understanding should enable development of new means of targeting onco-condensates as potential therapeutics.
    Keywords:  biomolecular condensation; cancer; disease; intrinsically disordered region (IDR); onco-condensate; phase separation; small molecule; therapeutic
    DOI:  https://doi.org/10.1016/j.trecan.2023.05.006
  23. Autophagy. 2023 Jun 19. 1-11
    Measurement of SQSTM1 by flow cytometry.
    Jessica C Hargarten, Guowu Hu, Waleed Elsegeiny, Peter R Williamson.
      Macroautophagy/autophagy is a regulated cellular degradation process essential as a pro-survival mechanism and integral to the regulation of diverse cellular processes in eukaryotes. During cellular stress and nutrient sensing, SQSTM1/p62 (sequestosome 1) functions as a key receptor for selective autophagy by shuttling ubiquitinated cargoes toward autophagic degradation making it a useful marker for monitoring autophagic flux. We present a straightforward and rapid flow cytometric assay for the quantitative measurement of intracellular SQSTM1 with improved sensitivity to conventional immunoblotting and with the benefit of higher throughput and reduced requirements for starting cellular materials for adequate analysis. We demonstrate that flow cytometry is able to detect similar trends in the measurement of intracellular SQSTM1 levels following serum starvation, genetic manipulations, and bafilomycin A1/chloroquine treatments. The assays utilizes readily available reagents and equipment without the need for transfection and utilizes standard flow cytometry equipment. In the present studies, expression of reporter proteins was applied to a range of SQSTM1 expression levels generated by genetic and chemical manipulation in both mouse as well as human cells. In combination with appropriate controls and attention to cautionary issues, this assay offers the ability to assess an important measure of autophagic capacity and flux.Abbreviations: ATG5: autophagy related 5 ATG7: autophagy related 7 BafA: bafilomycin A1 BMDM: bone marrow-derived macrophages CQ: chloroquine EBV: Epstein-Barr Virus EDTA: ethylenediaminetetraacetic acid FBS: fetal bovine serum gMFI: geometric mean fluorescent intensity HD: healthy donor MAP1LC3/LC3/Atg8: microtubule associated protein 1 light chain 3 MedianFI: median fluorescent intensity NTC: non-target control PBMC: peripheral blood mononuclear cells RPMI: Roswell Park Memorial Institution SQSTM1/p62: sequestosome 1 WT: wild type.
    Keywords:  Autophagy; Bafilomycin A1; Sqstm1/P62; chloroquine; flow cytometry; serum starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2224074
  24. J Pathol. 2023 Jun 22.
    Somatic loss of ATM is a late event in pancreatic tumorigenesis.
    Raymond M Paranal, Zhengdong Jiang, Danielle Hutchings, Valentyna Kryklyva, Christian Gauthier, Kohei Fujikura, Neha Nanda, Bo Huang, Michael Skaro, Christopher L Wolfgang, Jin He, David S Klimstra, Randall E Brand, Aatur D Singhi, Angelo DeMarzo, Lei Zheng, Michael Goggins, Lodewijk Aa Brosens, Ralph H Hruban, Alison P Klein, Tamara Lotan, Laura D Wood, Nicholas J Roberts.
      Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  ATM; DNA; cancer; immunohistochemistry; inherited; pancreatic; pathogenic; sequencing; somatic; variant
    DOI:  https://doi.org/10.1002/path.6136
  25. Am J Physiol Cell Physiol. 2023 Jun 19.
    The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation?
    Cory M Dungan, Jaden M Wells, Kevin A Murach.
      A gradual decline in skeletal muscle mass and function is closely tied to increased mortality and disease risk during organismal aging. Exercise training is the most effective way to enhance muscle health, but the adaptive response to exercise as well as muscle repair potential is blunted in older individuals. Numerous mechanisms contribute to the loss of muscle mass and plasticity as aging progresses. An emerging body of recent evidence implicates an accumulation of senescent ("zombie") cells in muscle as a contributing factor to the aging phenotype. Senescent cells cannot divide but can release inflammatory factors and create an unfavorable environment for homeostasis and adaptation. On balance, some evidence suggests that cells with senescent characteristics can be beneficial for the muscle adaptive process, specifically at younger ages. Emerging evidence also suggests multinuclear post-mitotic muscle fibers could become senescent. In this review, we summarize current literature on the prevalence of senescent cells in skeletal muscle and highlight the consequences of senescent cell removal on muscle mass, function, and adaptability. We examine key limitations in the field of senescence specifically in skeletal muscle and identify areas of research that require future investigation.
    Keywords:  Exercise; Myonuclei; SA Beta Gal; p16; p21
    DOI:  https://doi.org/10.1152/ajpcell.00553.2022
  26. Nat Cancer. 2023 Jun 22.
    High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers.
    Jia-Ren Lin, Yu-An Chen, Daniel Campton, Jeremy Cooper, Shannon Coy, Clarence Yapp, Juliann B Tefft, Erin McCarty, Keith L Ligon, Scott J Rodig, Steven Reese, Tad George, Sandro Santagata, Peter K Sorger.
      Precision medicine is critically dependent on better methods for diagnosing and staging disease and predicting drug response. Histopathology using hematoxylin and eosin (H&E)-stained tissue (not genomics) remains the primary diagnostic method in cancer. Recently developed highly multiplexed tissue imaging methods promise to enhance research studies and clinical practice with precise, spatially resolved single-cell data. Here, we describe the 'Orion' platform for collecting H&E and high-plex immunofluorescence images from the same cells in a whole-slide format suitable for diagnosis. Using a retrospective cohort of 74 colorectal cancer resections, we show that immunofluorescence and H&E images provide human experts and machine learning algorithms with complementary information that can be used to generate interpretable, multiplexed image-based models predictive of progression-free survival. Combining models of immune infiltration and tumor-intrinsic features achieves a 10- to 20-fold discrimination between rapid and slow (or no) progression, demonstrating the ability of multimodal tissue imaging to generate high-performance biomarkers.
    DOI:  https://doi.org/10.1038/s43018-023-00576-1
  27. Nature. 2023 Jun 21.
    Structural basis of mitochondrial protein import by the TIM23 complex.
    Sue Im Sim, Yuanyuan Chen, Diane L Lynch, James C Gumbart, Eunyong Park.
      Mitochondria import nearly all of their approximately 1,000-2,000 constituent proteins from the cytosol across their double-membrane envelope1-5. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM23 complex, mediates import of presequence-containing proteins (preproteins) into the mitochondrial matrix and inner membrane. Among about ten different subunits of the TIM23 complex, the essential multipass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel6-11. However, the mechanism by which these subunits form a translocation path in the membrane and enable the import process remains unclear due to a lack of structural information. Here we determined the cryo-electron microscopy structure of the core TIM23 complex (heterotrimeric Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. Contrary to the prevailing model, Tim23 and Tim17 themselves do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Our structural and biochemical analyses show that the cavity of Tim17, but not Tim23, forms the protein translocation path, whereas Tim23 probably has a structural role. The results further suggest that, during translocation of substrate polypeptides, the nonessential subunit Mgr2 seals the lateral opening of the Tim17 cavity to facilitate the translocation process. We propose a new model for the TIM23-mediated protein import and sorting mechanism, a central pathway in mitochondrial biogenesis.
    DOI:  https://doi.org/10.1038/s41586-023-06239-6
  28. Cancer Res. 2023 Jun 20. pii: CAN-23-0592. [Epub ahead of print]
    A non-conserved histidine residue on KRAS drives paralog selectivity of the KRASG12D inhibitor MRTX1133.
    Miles Keats, John J W Han, Yeon-Hwa Lee, Chih-Shia Lee, Ji Luo.
      MRTX1133 is the first non-covalent inhibitor against the KRASG12D mutant that demonstrated specificity and potency in pre-clinical tumor models. Here, we used isogenic cell lines expressing a single Ras allele to evaluate the selectivity of this compound. In addition to KRASG12D, MRTX1133 showed significant activity against several other KRAS mutants as well as wildtype KRAS protein. In contrast, MRTX1133 exhibited no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards KRAS is associated with its binding to H95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three Ras paralogs resulted in reciprocal change in their sensitivity towards MRTX1133. Thus, H95 is an essential selectivity handle for MRTX1133 towards KRAS. Amino acid diversity at residue 95 could facilitate the discovery of pan-KRAS inhibitors as well as HRAS and NRAS paralog-selective inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0592
  29. Metabolism. 2023 Jun 21. pii: S0026-0495(23)00241-X. [Epub ahead of print] 155637
    "Diet for the prevention and management of sarcopenia".
    Riccardo Calvani, Anna Picca, Hélio José Coelho-Júnior, Matteo Tosato, Emanuele Marzetti, Francesco Landi.
      Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced quality of life, mortality). Pharmacological remedies are currently unavailable for preventing the development of sarcopenia, halting its progression, or impeding its negative health outcomes. The most effective strategies to contrast sarcopenia rely on the adoption of healthier lifestyle behaviors, including adherence to high-quality diets and regular physical activity. In this review, the role of nutrition in the prevention and management of sarcopenia is summarized. Special attention is given to current "blockbuster" dietary regimes and agents used to counteract age-related muscle wasting, together with their putative mechanisms of action. Issues related to the design and implementation of effective nutritional strategies are discussed, with a focus on unanswered questions on the most appropriate timing of nutritional interventions to preserve muscle health and function into old age. A brief description is also provided on new technologies that can facilitate the development and implementation of personalized nutrition plans to contrast sarcopenia.
    Keywords:  Handgrip strength; Mediterranean diet; Muscle mass; Nutrition; Physical function; Protein
    DOI:  https://doi.org/10.1016/j.metabol.2023.155637
  30. Nat Commun. 2023 Jun 21. 14(1): 3673
    SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.
    Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan.
      The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.
    DOI:  https://doi.org/10.1038/s41467-023-39401-9
  31. J Exp Med. 2023 Sep 04. pii: e20221847. [Epub ahead of print]220(9):
    Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes.
    Pin-Ji Lei, Ethel R Pereira, Patrik Andersson, Zohreh Amoozgar, Jan Willem Van Wijnbergen, Meghan J O'Melia, Hengbo Zhou, Sampurna Chatterjee, William W Ho, Jessica M Posada, Ashwin S Kumar, Satoru Morita, Lutz Menzel, Charlie Chung, Ilgin Ergin, Dennis Jones, Peigen Huang, Semir Beyaz, Timothy P Padera.
      Tumor-draining lymph nodes (TDLNs) are important for tumor antigen-specific T cell generation and effective anticancer immune responses. However, TDLNs are often the primary site of metastasis, causing immune suppression and worse outcomes. Through cross-species single-cell RNA-Seq analysis, we identified features defining cancer cell heterogeneity, plasticity, and immune evasion during breast cancer progression and lymph node metastasis (LNM). A subset of cancer cells in the lymph nodes exhibited elevated MHC class II (MHC-II) gene expression in both mice and humans. MHC-II+ cancer cells lacked costimulatory molecule expression, leading to regulatory T cell (Treg) expansion and fewer CD4+ effector T cells in TDLNs. Genetic knockout of MHC-II reduced LNM and Treg expansion, while overexpression of the MHC-II transactivator, Ciita, worsened LNM and caused excessive Treg expansion. These findings demonstrate that cancer cell MHC-II expression promotes metastasis and immune evasion in TDLNs.
    DOI:  https://doi.org/10.1084/jem.20221847
  32. J Vis Exp. 2023 Jun 02.
    Two-Step Tag-Free Isolation of Mitochondria for Improved Protein Discovery and Quantification.
    Joan Blanco-Fernandez, Alexis A Jourdain.
      Most physiological and disease processes, from central metabolism to immune response to neurodegeneration, involve mitochondria. The mitochondrial proteome is composed of more than 1,000 proteins, and the abundance of each can vary dynamically in response to external stimuli or during disease progression. Here, we describe a protocol for isolating high-quality mitochondria from primary cells and tissues. The two-step procedure comprises (1) mechanical homogenization and differential centrifugation to isolate crude mitochondria, and (2) tag-free immune capture of mitochondria to isolate pure organelles and eliminate contaminants. Mitochondrial proteins from each purification stage are analyzed by quantitative mass spectrometry, and enrichment yields are calculated, allowing the discovery of novel mitochondrial proteins by subtractive proteomics. Our protocol provides a sensitive and comprehensive approach to studying mitochondrial content in cell lines, primary cells, and tissues.
    DOI:  https://doi.org/10.3791/65252
  33. Front Cardiovasc Med. 2023 ;10 1147462
    Q-VAT: Quantitative Vascular Analysis Tool.
    Bram Callewaert, Willy Gsell, Uwe Himmelreich, Elizabeth A V Jones.
      As our imaging capability increase, so does our need for appropriate image quantification tools. Quantitative Vascular Analysis Tool (Q-VAT) is an open-source software, written for Fiji (ImageJ), that perform automated analysis and quantification on large two-dimensional images of whole tissue sections. Importantly, it allows separation of the vessel measurement based on diameter, allowing the macro- and microvasculature to be quantified separately. To enable analysis of entire tissue sections on regular laboratory computers, the vascular network of large samples is analyzed in a tile-wise manner, significantly reducing labor and bypassing several limitations related to manual quantification. Double or triple-stained slides can be analyzed, with a quantification of the percentage of vessels where the staining's overlap. To demonstrate the versatility, we applied Q-VAT to obtain morphological read-outs of the vasculature network in microscopy images of whole-mount immuno-stained sections of various mouse tissues.
    Keywords:  density; immunohisthochemistry; morphometric analysis; quantification; vasculature
    DOI:  https://doi.org/10.3389/fcvm.2023.1147462
  34. J Clin Invest. 2023 Jun 20. pii: e166185. [Epub ahead of print]
    Pancreatic regional blood flow links the endocrine and exocrine diseases.
    Adam A Rizk, Michael P Dybala, Khalil C Rodriguez, Marjan Slak Rupnik, Manami Hara.
      Increasing studies have demonstrated that disease states of the endocrine or exocrine pancreas aggravate one another, which implies bi-directional blood flow between islets and exocrine cells. However, this is inconsistent with the current model of uni-directional blood flow, which is strictly from islets to exocrine tissues. This conventional model was first proposed in 1932 and it has never been revisited to date. Here, large-scale image capture was used to examine the spatial relationship between islets and blood vessels in the following species; human, monkey, pig, rabbit, ferret, and mouse. While some arterioles passed by or traveled through islets, the majority of islets had no association with them. Islets with direct contact with the arteriole were significantly larger in size and less in number than those without contact. Unique to the pancreas, capillaries directly branched out from the arterioles, and have been labeled as "small arterioles" in the past studies. Overall, the arterioles emerged to feed the pancreas regionally, not specifically targeting individual islets. Vascularizing the pancreas in this way may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to changes in the blood levels of glucose, hormones and other circulating factors.
    Keywords:  Endocrinology; Islet cells
    DOI:  https://doi.org/10.1172/JCI166185
  35. Bioinform Adv. 2023 ;3(1): vbad071
    tidytof: a user-friendly framework for scalable and reproducible high-dimensional cytometry data analysis.
    Timothy J Keyes, Abhishek Koladiya, Yu-Chen Lo, Garry P Nolan, Kara L Davis.
      Summary: While many algorithms for analyzing high-dimensional cytometry data have now been developed, the software implementations of these algorithms remain highly customized-this means that exploring a dataset requires users to learn unique, often poorly interoperable package syntaxes for each step of data processing. To solve this problem, we developed {tidytof}, an open-source R package for analyzing high-dimensional cytometry data using the increasingly popular 'tidy data' interface.Availability and implementation: {tidytof} is available at https://github.com/keyes-timothy/tidytof and is released under the MIT license. It is supported on Linux, MS Windows and MacOS. Additional documentation is available at the package website (https://keyes-timothy.github.io/tidytof/).
    Supplementary information: Supplementary data are available at Bioinformatics Advances online.
    DOI:  https://doi.org/10.1093/bioadv/vbad071
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