1. Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer
- Author
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Ligorio, Matteo, Sil, Srinjoy, Malagon-Lopez, Jose, Nieman, Linda T, Misale, Sandra, Di Pilato, Mauro, Ebright, Richard Y, Karabacak, Murat N, Kulkarni, Anupriya S, Liu, Ann, Vincent Jordan, Nicole, Franses, Joseph W, Philipp, Julia, Kreuzer, Johannes, Desai, Niyati, Arora, Kshitij S, Rajurkar, Mihir, Horwitz, Elad, Neyaz, Azfar, Tai, Eric, Magnus, Neelima KC, Vo, Kevin D, Yashaswini, Chittampalli N, Marangoni, Francesco, Boukhali, Myriam, Fatherree, Jackson P, Damon, Leah J, Xega, Kristina, Desai, Rushil, Choz, Melissa, Bersani, Francesca, Langenbucher, Adam, Thapar, Vishal, Morris, Robert, Wellner, Ulrich F, Schilling, Oliver, Lawrence, Michael S, Liss, Andrew S, Rivera, Miguel N, Deshpande, Vikram, Benes, Cyril H, Maheswaran, Shyamala, Haber, Daniel A, Fernandez-Del-Castillo, Carlos, Ferrone, Cristina R, Haas, Wilhelm, Aryee, Martin J, and Ting, David T
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Rare Diseases ,Genetics ,Digestive Diseases ,Stem Cell Research ,Pancreatic Cancer ,Cancer ,Stem Cell Research - Nonembryonic - Human ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Cancer-Associated Fibroblasts ,Carcinoma ,Pancreatic Ductal ,Cell Proliferation ,Coculture Techniques ,Epithelial-Mesenchymal Transition ,Female ,HEK293 Cells ,Heterografts ,Humans ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Mitogen-Activated Protein Kinases ,Pancreatic Neoplasms ,RNA-Seq ,STAT3 Transcription Factor ,Stromal Cells ,Transfection ,Tumor Microenvironment ,mass spectrometry ,pancreatic cancer ,pancreatic ductal adenocarcinoma ,single cell RNA-sequencing ,single cell spatial analysis ,stromal microenvironment ,tumor architecture ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.
- Published
- 2019