Ligorio and Sil et al. found that coculture of pancreatic ductal adenocarcinoma (PDAC) cells with stromal cancer-associated fibroblasts (CAFs) enriched proliferative (PRO) and epithelial-mesenchymal transition (EMT) markers and gene signatures in vitro and increased tumor growth and metastatic burden in vivo. CAF-conditioned media activated PRO/EMT phenotype and MAPK and STAT3 signaling pathways; TGF-β1 was implicated in driving this process. In human PDAC, quantitative digital microscopy at the glandular level revealed increased PRO/EMT phenotype in tumors with a high stromal component and correlations with disease prognosis.
Contributed by Alex Najibi
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.
Author Info: (1) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Cancer Center, Massachus
Author Info: (1) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (3) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. (4) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (5) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (6) Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (8) 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) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (10) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (15) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (16) 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) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (18) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (19) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (20) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (21) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (22) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (23) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (24) Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. (25) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (26) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (27) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (28) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (29) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (30) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (32) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (33) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. (34) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (35) Clinic of Surgery, UKSH Campus Lubeck, Germany. (36) Institute of Pathology, University Medical Center Freiburg, Germany. (37) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (38) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (39) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. (40) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. (41) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (42) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (43) 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) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (45) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (46) Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. (47) 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) 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.
