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Cell
06 27, 2019;178 (1): 160-175.e27.

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 Tai, Neelima 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
Author Information
  1. Matteo Ligorio: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  2. Srinjoy Sil: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  3. Jose Malagon-Lopez: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  4. Linda T Nieman: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  5. Sandra Misale: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  6. Mauro Di Pilato: Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
  7. Richard Y Ebright: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  8. Murat N Karabacak: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA.
  9. Anupriya S Kulkarni: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  10. Ann Liu: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  11. Nicole Vincent Jordan: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  12. Joseph W Franses: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  13. Julia Philipp: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  14. Johannes Kreuzer: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  15. Niyati Desai: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  16. Kshitij S Arora: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  17. Mihir Rajurkar: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  18. Elad Horwitz: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  19. Azfar Neyaz: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  20. Eric Tai: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  21. Neelima K C Magnus: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  22. Kevin D Vo: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  23. Chittampalli N Yashaswini: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  24. Francesco Marangoni: Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
  25. Myriam Boukhali: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  26. Jackson P Fatherree: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  27. Leah J Damon: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  28. Kristina Xega: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  29. Rushil Desai: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  30. Melissa Choz: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  31. Francesca Bersani: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  32. Adam Langenbucher: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  33. Vishal Thapar: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  34. Robert Morris: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  35. Ulrich F Wellner: Clinic of Surgery, UKSH Campus Lübeck, Germany.
  36. Oliver Schilling: Institute of Pathology, University Medical Center Freiburg, Germany.
  37. Michael S Lawrence: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  38. Andrew S Liss: Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  39. Miguel N Rivera: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  40. Vikram Deshpande: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
  41. Cyril H Benes: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  42. Shyamala Maheswaran: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  43. Daniel A Haber: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  44. Carlos Fernandez-Del-Castillo: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  45. Cristina R Ferrone: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  46. Wilhelm Haas: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  47. Martin J Aryee: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aryee.martin@mgh.harvard.edu.
  48. David T Ting: Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu.
PMID: 31155233 DOI: 10.1016/j.cell.2019.05.012

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.

Keywords

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

MeSH Term

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

Chemicals

STAT3 Transcription Factor
STAT3 protein, human
Mitogen-Activated Protein Kinases
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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Stromal Microenvironment Shapes Intratumoral Architecture Pancreatic Cancer.mass spectrometry pancreatic cancer pancreatic ductal adenocarcinoma single cell RNA-sequencing single cell spatial analysis stromal microenvironment tumor architecture" style="background-color: #f5f5f5">