bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2024–12–08
23 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer.
  2. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
  3. Cell polarity proteins promote macropinocytosis in response to metabolic stress.
  4. Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.
  5. Human pancreatic cancer single cell atlas reveals association of CXCL10+ fibroblasts and basal subtype tumor cells.
  6. Oncogenic KRAS Promotes Ferroptosis in Pancreatic Cancer through Regulation of the FOSL1-TFRC Axis.
  7. Simultaneous visualization of membrane fluidity and morphology defines adhesion signatures of cancer cells.
  8. Extreme wrinkling of the nuclear lamina is a morphological marker of cancer.
  9. Tumor-intrinsic kinome landscape of pancreatic cancer reveals new therapeutic approaches.
  10. Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues.
  11. Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study.
  12. BioDolphin as a comprehensive database of lipid-protein binding interactions.
  13. The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy.
  14. "Undruggable KRAS": druggable after all.
  15. Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression.
  16. Selective autophagy receptor hinders antitumor immunity.
  17. Image-based force inference by biomechanical simulation.
  18. The Molecular Mechanism of Fluorescence Lifetime of Fluorescent Probes in Cell Membranes.
  19. Triaptosis: an endosome-dependent cell death modality.
  20. Pancreatic Cancer: Current Concepts, Trends, and Future Directions.
  21. Synthetic GPCRs for programmable sensing and control of cell behaviour.
  22. How to ensure only dying cells rupture.
  23. Protocol for identifying key genes using network-based approach as an alternative to differential expression analysis.
  1. Nat Commun. 2024 Dec 03. 15(1): 10534
    Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer.
    Lisa Veghini, Davide Pasini, Rui Fang, Pietro Delfino, Dea Filippini, Christian Neander, Caterina Vicentini, Elena Fiorini, Francesca Lupo, Sabrina L D'Agosto, Carmine Carbone, Antonio Agostini, Geny Piro, Diego Rosa, Michele Bevere, Peter Markus, Diana Behrens, Claudio Luchini, Rita T Lawlor, Aldo Scarpa, Giulia Biffi, Phyllis F Cheung, Jens T Siveke, Vincenzo Corbo.
      Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts' heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-β signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting myofibroblastic CAFs in vivo.
    DOI:  https://doi.org/10.1038/s41467-024-54975-8
  2. Nature. 2024 Dec 04.
    Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
    Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.
      Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.
    DOI:  https://doi.org/10.1038/s41586-024-08285-0
  3. Nat Commun. 2024 Dec 03. 15(1): 10541
    Cell polarity proteins promote macropinocytosis in response to metabolic stress.
    Guillem Lambies, Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska M Galapate, Anagha Deshpande, Aniruddha J Deshpande, David A Scott, David W Dawson, Cosimo Commisso.
      Macropinocytosis has emerged as a scavenging pathway that cancer cells exploit to survive in a nutrient-deprived microenvironment. Tumor cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as regulators of macropinocytosis. In normal epithelial cells, aPKCs associate with the scaffold proteins Par3 and Par6 to regulate cell polarity, affecting several targets, including the Par1 kinases and we find that each of these proteins is required for macropinocytosis. Mechanistically, aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the Par3 relocation to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and aPKCs support PDAC growth in vivo. Our findings enhance our understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.
    DOI:  https://doi.org/10.1038/s41467-024-54788-9
  4. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2416076121
    Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.
    Eric C Cheung, Douglas Strathdee, David Stevenson, Jack Coomes, Karen Blyth, Karen H Vousden.
      The consequences of reactive oxygen species (ROS) in cancer cells are complex and have been shown to both promote and retard tumorigenesis in different models. In mouse models of pancreatic ductal adenocarcinoma (PDAC), loss of the antioxidant defense gene Tigar results in both a reduction in the development of early pancreatic intraepithelial neoplasia and an increase in invasive and metastatic capacity, accompanied by decreased survival of mice lacking pancreatic TIGAR. We previously demonstrated that increased ROS following loss of TIGAR promotes various cancer cell-intrinsic changes that contribute to metastatic capacity, including epithelial to mesenchymal transition, enhanced migration and invasion, and an increase in ERK signaling. In this study, we show that pancreatic overexpression of TIGAR decreases metastatic capacity and migratory phenotypes in an aggressive model of PDAC, consistent with the concept that dynamic modulation of TIGAR in PDAC contributes to the development and progression of these tumors. Using TIGAR deficient and overexpressing mouse models, we find that the impact of modulation of TIGAR and ROS in PDAC cells also has a profound effect on the normal stromal cells surrounding the tumor. Loss of TIGAR promotes the production of cytokines by cancer cells that induce changes in the surrounding fibroblasts to adopt a tumor-supportive phenotype. Furthermore, these cytokines also attract macrophages that support PDAC dissemination and metastasis. Taken together our work shows that TIGAR-modulated ROS in PDAC can control cell intrinsic and extrinsic changes to impact tumor aggression.
    Keywords:  oxidative stress; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2416076121
  5. Clin Cancer Res. 2024 Dec 05.
    Human pancreatic cancer single cell atlas reveals association of CXCL10+ fibroblasts and basal subtype tumor cells.
    Ian M Loveless, Samantha B Kemp, Kailee M Hartway, Jacob T Mitchell, Yuesong Wu, Samuel D Zwernik, Daniel James Salas-Escabillas, Sydney Brender, Madison George, Yetunde Makinwa, Thais Stockdale, Kendyll Gartrelle, Rohit G Reddy, Daniel W Long, Allison Wombwell, Julie M Clark, Albert M Levin, David Kwon, Ling Huang, Ralph Francescone, Debora B Vendramini-Costa, Ben Stanger, Adam Alessio, Andrew M Waters, Yuehua Cui, Elana J Fertig, Luciane T Kagohara, Brian Theisen, Howard C Crawford, Nina G Steele.
       PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard of care treatments and have significantly worse overall survival (OS) compared to patients with classical subtype enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner.
    EXPERIMENTAL DESIGN: We compiled a single cell RNA sequencing (scRNAseq) atlas of the human pancreas with 229 patient samples, aggregated from publicly available raw data. We mapped cell-type specific scRNAseq gene signatures in bulk RNAseq (n=744) and spatial transcriptomics (ST) (n=22) and performed validation using multiplex immunostaining.
    RESULTS: Analysis of tumor cells from our scRNAseq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse OS in bulk RNAseq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in non-dissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer associated fibroblasts (CAFs) with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in PDAC tumor microenvironment.
    CONCLUSIONS: We show that our scRNAseq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ CAFs and basal tumor cells that could be explored for future targeted therapies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2183
  6. Pancreas. 2024 Nov 29.
    Oncogenic KRAS Promotes Ferroptosis in Pancreatic Cancer through Regulation of the FOSL1-TFRC Axis.
    Huijia Zhao, Qi Huang, Yingao Liu, Wenming Wu.
       ABSTRACT: Mutant KRAS activation occurs in most of pancreatic cancer (PDAC) which induce the sensitivity to ferroptosis of PDAC cells, but the underlying mechanism is still poorly understood. Here, we show how KRAS acts in signaling to activate transcription factor FOSL1, which promotes the expression of the iron uptake receptor TFRC. In PDAC cells, repression of TFRC by KRAS/FOSL1 signaling inhibited intracellular iron levels, thereby restricting the occurrence of ferroptosis. Furthermore, the KRAS/FOSL1/TFRC axis can make the PDAC cells vulnerable to alteration of the iron level in the tumor microenvironment. Our study highlights a pivotal mechanism of PDAC ferroptosis through iron metabolism and supports a new therapeutic strategy for PDAC with superior potential.
    DOI:  https://doi.org/10.1097/MPA.0000000000002426
  7. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2412914121
    Simultaneous visualization of membrane fluidity and morphology defines adhesion signatures of cancer cells.
    Takahisa Matsuzaki, Mai Fujii, Hayata Noro, Shodai Togo, Mami Watanabe, Masami Suganuma, Shivani Sharma, Naritaka Kobayashi, Ryuzo Kawamura, Seiichiro Nakabayashi, Hiroshi Y Yoshikawa.
      We developed an advanced optical microscope for the simultaneous visualization of membrane fluidity and morphology to define cell adhesion signatures. This microscope combines ratiometric spectral imaging of membrane fluidity and interferometric imaging of membrane morphology. As a preliminary demonstration, we simultaneously visualized the interface between a giant unilamellar vesicle (GUV) and a glass substrate at different temperatures. We identified more fluid regions of the membrane and membrane adhesion sites (conversely, low-fluidic, ordered membrane domains correlate with nonadhered regions). This microscopic system was applied to human breast cancer cell lines with different malignancies; then, we identified adhesion signature of cancer cells: 1) low-fluidic, ordered membrane domains at the cell periphery and 2) large fluidic deviation at the nonadhered region. Inhibition of the cholesterol synthesis pathway suppresses the ordered membrane domains at the cancer cell periphery; thus, high level of cholesterol supports the appearance. Furthermore, an inhibitor of the unsaturated lipid synthesis pathway suppressed the large fluidic deviation at the nonadhered region; variation of unsaturated lipids contributes to heterogeneity of the cancer membrane. Therefore, our advanced optical microscopy enables us to couple membrane physical properties with cell adhesion, leading to definition of adhesion signatures of broad cell types, not just for cancer cells, that regulate life phenomena.
    Keywords:  Laurdan; cell adhesion; interference reflection microscopy; membrane physics
    DOI:  https://doi.org/10.1073/pnas.2412914121
  8. NPJ Precis Oncol. 2024 Dec 02. 8(1): 276
    Extreme wrinkling of the nuclear lamina is a morphological marker of cancer.
    Ting-Ching Wang, Christina R Dollahon, Sneha Mishra, Hailee Patel, Samere Abolghasemzade, Ishita Singh, Vilmos Thomazy, Daniel G Rosen, Vlad C Sandulache, Saptarshi Chakraborty, Tanmay P Lele.
      Nuclear atypia is a hallmark of cancer. A recent model posits that excess surface area, visible as folds/wrinkles in the lamina of a rounded nucleus, allows the nucleus to take on diverse shapes with little mechanical resistance. Whether this model is applicable to normal and cancer nuclei in human tissues is unclear. We image nuclear lamins in patient tissues and find: (a) nuclear laminar wrinkles are present in control and cancer tissue but are obscured in hematoxylin and eosin (H&E) images, (b) nuclei rarely have a smooth lamina, and (c) wrinkled nuclei assume diverse shapes. Deep learning reveals the presence of extreme nuclear laminar wrinkling in cancer tissues, which is confirmed by Fourier analysis. These data support a model in which excess surface area in the nuclear lamina enables nuclear shape diversity in vivo. Extreme laminar wrinkling is a marker of cancer, and imaging the lamina may benefit cancer diagnosis.
    DOI:  https://doi.org/10.1038/s41698-024-00775-8
  9. Cancer Discov. 2024 Dec 05.
    Tumor-intrinsic kinome landscape of pancreatic cancer reveals new therapeutic approaches.
    Yi Xu, Xianlu L Peng, Michael P East, Ian C McCabe, Grace C Stroman, Madison R Jenner, Priscilla S Chan, Ashley B Morrison, Emily C Shen, Silvia G Hererra, Chinmaya U Joisa, Naim U Rashid, Alina C Iuga, Shawn M Gomez, Lisa Miller-Phillips, Stefan Boeck, Volker Heinemann, Michael Haas, Steffen Ormanns, Gary L Johnson, Jen Jen Yeh.
      Effective therapies for pancreatic ductal adenocarcinoma (PDAC) have been largely elusive. Here, we perform Multiplexed kinase Inhibitor Bead Mass Spectrometry on 102 patient derived xenografts derived from 14 unique primary PDAC to define the tumor-intrinsic kinome landscape. Our findings uncover three kinome subgroups making up two tumor-intrinsic kinome subtypes that we call kinotypes. The kinotypes show enrichment of different kinase classes and recapitulate previously described molecular subtypes, basal-like and classical. The kinotype characterizing basal-like tumors shows enrichment of receptor tyrosine kinases, whereas the kinotype characterizing classical tumors is enriched in understudied kinases involved in Wnt signaling and immune pathways. We validate our findings in two clinical trials and show that only patients with basal-like tumors derive significant benefit from EGFR inhibitors. Our results provide a comprehensive tumor-intrinsic kinome landscape of PDAC that strongly supports actionable kinotype specific kinase targets and provides a roadmap for kinase inhibitor therapy in PDAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1480
  10. Sci Adv. 2024 Dec 06. 10(49): eadn0220
    Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues.
    Neel Sanghvi, Camilo Calvo-Alcañiz, Padma S Rajagopal, Stefano Scalera, Valeria Canu, Sanju Sinha, Fiorella Schischlik, Kun Wang, Sanna Madan, Eldad Shulman, Antonios Papanicolau-Sengos, Giovanni Blandino, Eytan Ruppin, Nishanth Ulhas Nair.
      Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to their target tissues remains a fundamental challenge. To address this, we assessed whether primary and metastatic tumors more closely resemble their tissues of origin or target tissues in terms of gene expression. We analyzed expression profiles from multiple cancer types and normal tissues, including single-cell and bulk RNA sequencing data from both paired and unpaired patient cohorts. Primary tumors were overall more transcriptomically similar to their tissues of origin, while metastases shifted toward their target tissues. However, pathway-level analysis highlighted critical metabolic and immune transcriptomic changes toward target tissues during metastasis in both primary and metastatic tumors. In addition, primary tumors exhibited higher activity in cancer hallmarks such as "Activating Invasion and Metastasis" when compared to metastases. This comprehensive analysis provides a transcriptome-wide view of the processes through which cancer tumors adapt to their metastatic environments before and after metastasis.
    DOI:  https://doi.org/10.1126/sciadv.adn0220
  11. Cell Rep Med. 2024 Dec 03. pii: S2666-3791(24)00613-X. [Epub ahead of print] 101842
    Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study.
    Hajime Yamazaki, Samantha A Streicher, Lang Wu, Shunichi Fukuhara, Róbert Wagner, Martin Heni, Steven R Grossman, Heinz-Josef Lenz, Veronica Wendy Setiawan, Loïc Le Marchand, Brian Z Huang.
      
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101842
  12. Commun Chem. 2024 Dec 04. 7(1): 288
    BioDolphin as a comprehensive database of lipid-protein binding interactions.
    Li-Yen Yang, Kaike Ping, Yunan Luo, Andrew C McShan.
      Lipid-protein interactions are crucial for virtually all biological processes in living cells. However, existing structural databases focusing on these interactions are limited to integral membrane proteins. A systematic understanding of diverse lipid-protein interactions also encompassing lipid-anchored, peripheral membrane and soluble lipid binding proteins remains to be elucidated. To address this gap and facilitate the research of universal lipid-protein assemblies, we developed BioDolphin - a curated database with over 127,000 lipid-protein interactions. BioDolphin provides comprehensive annotations, including protein functions, protein families, lipid classifications, lipid-protein binding affinities, membrane association type, and atomic structures. Accessible via a publicly available web server ( www.biodolphin.chemistry.gatech.edu ), users can efficiently search for lipid-protein interactions using a wide range of options and download datasets of interest. Additionally, BioDolphin features interactive 3D visualization of each lipid-protein complex, facilitating the exploration of structure-function relationships. BioDolphin also includes detailed information on atomic-level intermolecular interactions between lipids and proteins that enable large scale analysis of both paired complexes and larger assemblies. As an open-source resource, BioDolphin enables global analysis of lipid-protein interactions and supports data-driven approaches for developing predictive machine learning algorithms for lipid-protein binding affinity and structures.
    DOI:  https://doi.org/10.1038/s42004-024-01384-z
  13. Nature. 2024 Dec 04.
    The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy.
    Laura Bornes, Lennart J van Winden, Veerle C M Geurts, Beaunelle de Bruijn, Leyla Azarang, Mirthe Lanfermeijer, Marika Caruso, Natalie Proost, Manon Boeije, Jeroen O Lohuis, Guillaume Belthier, Eulàlia Noguera Delgado, Nadia de Gruil, Judith R Kroep, Marieke van de Ven, Renee Menezes, Jelle Wesseling, Marleen Kok, Sabine Linn, Annegien Broeks, Huub H van Rossum, Colinda L G J Scheele, Jacco van Rheenen.
      The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype1. Here we identify the oestrous cycle as an important contributor to this heterogeneity. In three mouse models of breast cancer, we show reduced responses to NAC when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage. Similar findings were observed in retrospective premenopausal cohorts of human patients. Mechanistically, the dioestrus stage exhibits systemic and localized changes, including (1) an increased number of cells undergoing epithelial-to-mesenchymal transition linked to chemoresistance2-4 and (2) decreased tumour vessel diameter, suggesting potential constraints to drug sensitivity and delivery. In addition, an elevated presence of macrophages, previously associated with chemoresistance induction5, characterizes the dioestrus phase. Whereas NAC disrupts the oestrous cycle, this elevated macrophage prevalence persists and depletion of macrophages mitigates the reduced therapy response observed when initiating treatment during dioestrus. Our data collectively demonstrate the oestrous cycle as a crucial infradian rhythm determining chemosensitivity, warranting future clinical studies to exploit optimal treatment initiation timing for enhanced chemotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-08276-1
  14. Genes Dev. 2024 Dec 05.
    "Undruggable KRAS": druggable after all.
    Adrienne D Cox, Channing J Der.
      The three RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in cancer. KRAS is the predominant isoform mutated in cancer and is most prevalently mutated in major causes of cancer deaths including lung, colorectal, and pancreatic cancers. Despite extensive academic and industry efforts to target KRAS, it would take nearly four decades before approval of the first clinically effective KRAS inhibitors for the treatment of KRAS mutant lung cancer. We revisit past anti-KRAS strategies and painful lessons learned and then focus on the rapidly evolving landscape of direct RAS inhibitors, resistance mechanisms, and potential combination treatments.
    Keywords:  CRC; KRAS; NSCLC; PDAC; colorectal cancer; non-small cell lung cancer; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1101/gad.352081.124
  15. Nat Cancer. 2024 Dec 03.
    Unique structural configuration of EV-DNA primes Kupffer cell-mediated antitumor immunity to prevent metastatic progression.
    Inbal Wortzel, Yura Seo, Ife Akano, Lee Shaashua, Gabriel Cardial Tobias, Jakob Hebert, Kyung-A Kim, DooA Kim, Shani Dror, Yanshen Liu, Griffin Campbell Azrak, Michele Cioffi, Kofi Ennu Johnson, Tammy Hennika, Meshulam Zisha Twerski, Alexis Kushner, Robert Math, Yoon Dae Han, Dai Hoon Han, Minsun Jung, Juyeong Park, Soonmyung Paik, Jeon-Soo Shin, Min Goo Lee, Marco Vincenzo Russo, Daniel Zakheim, Jesse Barnes, Sunjoy Mehta, Katia Manova, Robert E Schwartz, Basant Kumar Thakur, Nancy Boudreau, Irina Matei, Haiying Zhang, Simone Sidoli, Jacqueline Bromberg, Yael David, Han Sang Kim, David Lyden.
      Extracellular vesicles (EVs) transport biomolecules that mediate intercellular communication. We previously showed that EVs contain DNA (EV-DNA) representing the entire genome. However, the mechanism of genomic EV-DNA packaging and its role in cancer remain elusive. We now demonstrate that EV-DNA is predominantly localized on the vesicle surface and associated with uniquely modified and cleaved histones. Moreover, a genome-wide clustered regularly interspaced short palindromic repeats knockout screen revealed that immune developmental pathways and genes, including apoptotic peptidase activating factor 1 (APAF1) and neutrophil cytosolic factor 1 (NCF1), regulate EV-DNA packaging. Furthermore, in colorectal cancer models, uptake of EV-DNA by pre-metastatic liver Kupffer cells (KCs) activated DNA damage responses. This activation rewired KC cytokine production and promoted the formation of tertiary lymphoid structures, thereby suppressing liver metastasis. Conversely, loss of APAF1 decreased EV-DNA packaging and promoted liver metastasis. Importantly, colorectal cancer biopsy EV-DNA secretion could serve as a predictive biomarker for postoperative metastasis. Taken together, our findings indicate that uniquely chromatinized EV-DNA induces antitumor immunity.
    DOI:  https://doi.org/10.1038/s43018-024-00862-6
  16. Trends Cancer. 2024 Dec 02. pii: S2405-8033(24)00259-0. [Epub ahead of print]
    Selective autophagy receptor hinders antitumor immunity.
    Jiao Liu, Rui Kang, Daolin Tang.
      Autophagy has a dual role in tumor progression and therapy, influenced by specific receptors and cargo selection. Recent research published in Cell by Herhaus et al. identifies immunity-related GTPase Q (IRGQ) as a novel autophagy receptor that facilitates immune evasion in hepatocellular carcinoma (HCC) by degrading histocompatibility complex class I (MHC-I) molecules, highlighting a potential target to enhance immunotherapy.
    Keywords:  antigen presentation; autophagy receptor; hepatocellular carcinoma; peptide degradation; tumor immune evasion
    DOI:  https://doi.org/10.1016/j.trecan.2024.11.004
  17. PLoS Comput Biol. 2024 Dec 02. 20(12): e1012629
    Image-based force inference by biomechanical simulation.
    Michiel Vanslambrouck, Wim Thiels, Jef Vangheel, Casper van Bavel, Bart Smeets, Rob Jelier.
      During morphogenesis, cells precisely generate forces that drive cell shape changes and cellular motion. These forces predominantly arise from contractility of the actomyosin cortex, allowing for cortical tension, protrusion formation, and cell division. Image-based force inference can derive such forces from microscopy images, without complicated and time-consuming experimental set-ups. However, current methods do not account for common effects, such as physical confinement and local force generation. Here we propose a force-inference method based on a biophysical model of cell shape, and assess relative cellular surface tension, adhesive tension between cells, as well as cytokinesis and protrusion formation. We applied our method on fluorescent microscopy images of the early C. elegans embryo. Predictions for cell surface tension at the 7-cell stage were validated by measurements using cortical laser ablation. Our non-invasive method facilitates the accurate tracking of force generation, and offers many new perspectives for studying morphogenesis.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012629
  18. J Phys Chem Lett. 2024 Dec 05. 12293-12300
    The Molecular Mechanism of Fluorescence Lifetime of Fluorescent Probes in Cell Membranes.
    Yanqi Liu, Lydia Mathew, Chaofan Yu, Liang Fu, Zhengyu Shu, Shobhna Kapoor, Mojie Duan.
      Fluorescence probes play crucial roles in unraveling the structure and dynamics of cell membranes including membrane fluidity, polarity, and lipid molecule ordering. The fluorescence lifetime of probes describes the average duration of time that a fluorescent molecule remains in an excited state before returning to the ground state, which is sensitive to environmental changes. However, the molecular mechanism and inherent properties to determine the fluorescence lifetimes remain unexplored and inadequately studied. Furthermore, the effects of the probe on the membrane are also unclear. In this study, we investigated the interactions between probes and lipids, as well as the structural properties of probes within the outer and inner membrane of Mycobacterium smegmatis (Msm) by combining molecular dynamics (MD) simulations, enhanced sampling methods, fluorescence lifetime imaging microscopy (FLIM), and time-correlated single photon counting (TCSPC). The results show that even though the probes have very little effect on the membrane lipids, different membrane environments significantly affect the fluorescence lifetime of the probes. The analysis based on the all-atom simulations shows a strong correlation between the probe's immersion depth within the membrane and its fluorescence lifetime. Specifically, probes buried in the membrane environment shielded from rapid water molecule collisions exhibit longer fluorescence lifetimes. The molecular basis of the fluorescence lifetime of probes in cell membranes revealed in this work would enhance the comprehension of fluorescence probes and facilitate the rational design of novel efficient probes.
    DOI:  https://doi.org/10.1021/acs.jpclett.4c02731
  19. Cell Res. 2024 Dec 06.
    Triaptosis: an endosome-dependent cell death modality.
    Daolin Tang, Rui Kang, Guido Kroemer.
      
    DOI:  https://doi.org/10.1038/s41422-024-01053-9
  20. Turk J Gastroenterol. 2024 Nov 18.
    Pancreatic Cancer: Current Concepts, Trends, and Future Directions.
    Patrick Wenzel, Carolin Mogler, Kıvanç Görgülü, Hana Algül.
      Pancreatic ductal adenocarcinoma (PC) ranks among the deadliest cancers, with a less than 15% 5-year survival rate. Epidemiological studies project that it will become the second leading cause of cancer-associated mortalities in the following decades. The hallmarks of pancreatic cancer lead to tumor aggressiveness and therapeutic resistance. For this reason, the field has been focusing on multiple dimensions to generate better therapeutic approaches, including new adjuvant, neoadjuvant, and palliative concepts to extend the survival of PC patients. Over the last 2 decades, clinical trials have significantly improved disease prognosis and patient survival. To achieve better outcomes and to deeply understand the therapeutic approaches, molecular tumor boards have become crucial for deeper exploitation of tumor genetics and tumor biology, providing better stratification markers for therapeutic regimens. Using recently developed targeted therapies, such as KRAS inhibitors, the field has gathered momentum and been tooled up with the help of new sequencing technologies. Therefore, researchers and clinicians have geared up for the battle against PC. This review will systematically discuss recent developments in adjuvant, neoadjuvant, and palliative treatment modalities. Moreover, the paradigm-shifting importance of genetic profiling on pancreatic cancer. will be explained through a showcase to frame future directions.
    Keywords:  Pancreatic cancer; adjuvant therapy; genetic profiling; neoadjuvant therapy; palliative therapy; targeted therapy
    DOI:  https://doi.org/10.5152/tjg.2024.24544
  21. Nature. 2024 Dec 04.
    Synthetic GPCRs for programmable sensing and control of cell behaviour.
    Nicholas A Kalogriopoulos, Reika Tei, Yuqi Yan, Peter M Klein, Matthew Ravalin, Bo Cai, Ivan Soltesz, Yulong Li, Alice Ting.
      Synthetic receptors that mediate antigen-dependent cell responses are transforming therapeutics, drug discovery and basic research1,2. However, established technologies such as chimeric antigen receptors3 can only detect immobilized antigens, have limited output scope and lack built-in drug control3-7. Here we engineer synthetic G-protein-coupled receptors (GPCRs) that are capable of driving a wide range of native or non-native cellular processes in response to a user-defined antigen. We achieve modular antigen gating by engineering and fusing a conditional auto-inhibitory domain onto GPCR scaffolds. Antigen binding to a fused nanobody relieves auto-inhibition and enables receptor activation by drug, thus generating programmable antigen-gated G-protein-coupled engineered receptors (PAGERs). We create PAGERs that are responsive to more than a dozen biologically and therapeutically important soluble and cell-surface antigens in a single step from corresponding nanobody binders. Different PAGER scaffolds allow antigen binding to drive transgene expression, real-time fluorescence or endogenous G-protein activation, enabling control of diverse cellular functions. We demonstrate multiple applications of PAGER, including induction of T cell migration along a soluble antigen gradient, control of macrophage differentiation, secretion of therapeutic antibodies and inhibition of neuronal activity in mouse brain slices. Owing to its modular design and generalizability, we expect PAGERs to have broad utility in discovery and translational science.
    DOI:  https://doi.org/10.1038/s41586-024-08282-3
  22. Nature. 2024 Dec 04.
    How to ensure only dying cells rupture.
    Elliott M Bernard, Petr Broz.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-024-03851-y
  23. STAR Protoc. 2024 Dec 04. pii: S2666-1667(24)00637-3. [Epub ahead of print]5(4): 103472
    Protocol for identifying key genes using network-based approach as an alternative to differential expression analysis.
    Piyush Agrawal, Sridhar Hannenhalli.
      In a variety of biological contexts, characterizing genes associated with disease etiology and mediating global transcriptomic change is a key initial step. Here, we present a protocol to identify such key genes using our tool "PathExt," a tool that implements a network-based approach. We describe steps for installing libraries, preparing input data and detailed procedures for running PathExt, and characterizing differential pathways and key genes based on ripple centrality scores. For complete details on the use and execution of this protocol, please refer to Agrawal et al.1,2.
    Keywords:  Bioinformatics; Cancer; Computer sciences; Genomics; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2024.103472
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