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Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer.


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.

SUBMITTER: Ligorio M 

PROVIDER: S-EPMC6697165 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer.

Ligorio Matteo M   Sil Srinjoy S   Malagon-Lopez Jose J   Nieman Linda T LT   Misale Sandra S   Di Pilato Mauro M   Ebright Richard Y RY   Karabacak Murat N MN   Kulkarni Anupriya S AS   Liu Ann A   Vincent Jordan Nicole N   Franses Joseph W JW   Philipp Julia J   Kreuzer Johannes J   Desai Niyati N   Arora Kshitij S KS   Rajurkar Mihir M   Horwitz Elad E   Neyaz Azfar A   Tai Eric E   Magnus Neelima K C NKC   Vo Kevin D KD   Yashaswini Chittampalli N CN   Marangoni Francesco F   Boukhali Myriam M   Fatherree Jackson P JP   Damon Leah J LJ   Xega Kristina K   Desai Rushil R   Choz Melissa M   Bersani Francesca F   Langenbucher Adam A   Thapar Vishal V   Morris Robert R   Wellner Ulrich F UF   Schilling Oliver O   Lawrence Michael S MS   Liss Andrew S AS   Rivera Miguel N MN   Deshpande Vikram V   Benes Cyril H CH   Maheswaran Shyamala S   Haber Daniel A DA   Fernandez-Del-Castillo Carlos C   Ferrone Cristina R CR   Haas Wilhelm W   Aryee Martin J MJ   Ting David T DT  

Cell 20190530 1


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 tr  ...[more]

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