Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

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

Research output: Contribution to journalArticle

49 Scopus citations

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. Clinical outcomes for pancreatic cancer are impacted by intra-tumoral tissue architecture as defined by single-cell analyses and high content digital imaging.

Original languageEnglish (US)
Pages (from-to)160-175.e27
JournalCell
Volume178
Issue number1
DOIs
StatePublished - Jun 27 2019
Externally publishedYes

Keywords

  • mass spectrometry
  • pancreatic cancer
  • pancreatic ductal adenocarcinoma
  • single cell RNA-sequencing
  • single cell spatial analysis
  • stromal microenvironment
  • tumor architecture

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ligorio, M., Sil, S., Malagon-Lopez, J., Nieman, L. T., Misale, S., Di Pilato, M., Ebright, R. Y., Karabacak, M. N., Kulkarni, A. S., Liu, A., Vincent Jordan, N., Franses, J. W., Philipp, J., Kreuzer, J., Desai, N., Arora, K. S., Rajurkar, M., Horwitz, E., Neyaz, A., ... Ting, D. T. (2019). Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. Cell, 178(1), 160-175.e27. https://doi.org/10.1016/j.cell.2019.05.012