المؤلفون: Biermann, Jana, Melms, Johannes C, Amin, Amit Dipak, Wang, Yiping, Caprio, Lindsay A, Karz, Alcida, Tagore, Somnath, Barrera, Irving, Ibarra-Arellano, Miguel A, Andreatta, Massimo, Fullerton, Benjamin T, Gretarsson, Kristjan H, Sahu, Varun, Mangipudy, Vaibhav S, Nguyen, Trang TT, Nair, Ajay, Rogava, Meri, Ho, Patricia, Koch, Peter D, Banu, Matei, Humala, Nelson, Mahajan, Aayushi, Walsh, Zachary H, Shah, Shivem B, Vaccaro, Daniel H, Caldwell, Blake, Mu, Michael, Wünnemann, Florian, Chazotte, Margot, Berhe, Simon, Luoma, Adrienne M, Driver, Joseph, Ingham, Matthew, Khan, Shaheer A, Rapisuwon, Suthee, Slingluff, Craig L, Eigentler, Thomas, Röcken, Martin, Carvajal, Richard, Atkins, Michael B, Davies, Michael A, Agustinus, Albert, Bakhoum, Samuel F, Azizi, Elham, Siegelin, Markus, Lu, Chao, Carmona, Santiago J, Hibshoosh, Hanina, Ribas, Antoni, Canoll, Peter, Bruce, Jeffrey N, Bi, Wenya Linda, Agrawal, Praveen, Schapiro, Denis, Hernando, Eva, Macosko, Evan Z, Chen, Fei, Schwartz, Gary K, Izar, Benjamin

المصدر: Cell. 185(14)

مصطلحات موضوعية: Cancer, Biotechnology, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Brain Neoplasms, CD8-Positive T-Lymphocytes, Ecosystem, Humans, Melanoma, RNA-Seq, brain metastasis, chromosomal instability, melanoma, neuronal-like cell state, single-cell genomics, spatial transcriptomics, tumor-microenvironment, Biological Sciences, Medical and Health Sciences, Developmental Biology

الوصف: Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3087t3dxTest

المؤلفون: Affo, Silvia, Nair, Ajay, Brundu, Francesco, Ravichandra, Aashreya, Bhattacharjee, Sonakshi, Matsuda, Michitaka, Chin, LiKang, Filliol, Aveline, Wen, Wen, Song, Xinhua, Decker, Aubrianna, Worley, Jeremy, Caviglia, Jorge Matias, Yu, Lexing, Yin, Deqi, Saito, Yoshinobu, Savage, Thomas, Wells, Rebecca G, Mack, Matthias, Zender, Lars, Arpaia, Nicholas, Remotti, Helen E, Rabadan, Raul, Sims, Peter, Leblond, Anne-Laure, Weber, Achim, Riener, Marc-Oliver, Stockwell, Brent R, Gaublomme, Jellert, Llovet, Josep M, Kalluri, Raghu, Michalopoulos, George K, Seki, Ekihiro, Sia, Daniela, Chen, Xin, Califano, Andrea, Schwabe, Robert F

المصدر: Cancer Cell. 39(6)

مصطلحات موضوعية: Genetics, Liver Disease, Cancer, Digestive Diseases - (Gallbladder), Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Aged, Animals, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Cancer-Associated Fibroblasts, Cholangiocarcinoma, Collagen Type I, Female, Hepatic Stellate Cells, Hepatocyte Growth Factor, Humans, Hyaluronan Synthases, Hyaluronic Acid, Male, Mice, Transgenic, Middle Aged, Proto-Oncogene Proteins c-met, Tumor Microenvironment, CellPhoneDB, HGF, KRAS, YAP, cholangiocarcinoma, immune, mechanosensitive, single cell, stiffness, tumor microenvironment, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5g02234jTest

المؤلفون: Bhattacharjee, Sonakshi, Hamberger, Florian, Ravichandra, Aashreya, Miller, Maximilian, Nair, Ajay, Affo, Silvia, Filliol, Aveline, Chin, LiKang, Savage, Thomas M, Yin, Deqi, Wirsik, Naita Maren, Mehal, Adam, Arpaia, Nicholas, Seki, Ekihiro, Mack, Matthias, Zhu, Di, Sims, Peter A, Kalluri, Raghu, Stanger, Ben Z, Olive, Kenneth P, Schmidt, Thomas, Wells, Rebecca G, Mederacke, Ingmar, Schwabe, Robert F

المصدر: Journal of Clinical Investigation. 131(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Digestive Diseases, Liver Disease, Aetiology, 2.1 Biological and endogenous factors, Animals, Cancer-Associated Fibroblasts, Cell Line, Tumor, Collagen Type I, Hepatic Stellate Cells, Humans, Liver Neoplasms, Experimental, Mechanotransduction, Cellular, Mice, Knockout, Neoplasm Metastasis, Collagens, Fibrosis, Hepatology, Oncology, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences

الوصف: Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6hm8b52qTest