CTHRC1+ fibroblasts and SPP1+ macrophages synergistically contribute to pro-tumorigenic tumor microenvironment in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer that accounts for over 90% of all pancreatic cancer cases. With a 5-year survival rate of only 13%, PDAC has proven to be extremely desmoplastic and immunosuppressive to most current therapies, including chemotherapy and surgical...

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Bibliographic Details
Published in:	Scientific reports Vol. 14; no. 1; pp. 17412 - 15
Main Authors:	Li, Evan, Cheung, Hoi Ching (Zoey), Ma, Shuangge
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 29-07-2024 Nature Publishing Group Nature Portfolio
Subjects:	631/114 631/67 Adenocarcinoma Animals Apolipoprotein E Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Carcinoma, Pancreatic Ductal - immunology Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cell Line, Tumor Chemotherapy Epithelial-Mesenchymal Transition Extracellular matrix Fibroblasts - metabolism Fibroblasts - pathology Humanities and Social Sciences Humans Immunosuppressive agents Macrophages Macrophages - immunology Macrophages - metabolism Medical prognosis Mice multidisciplinary Myeloid cells Pancreatic cancer Pancreatic Neoplasms - immunology Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Population studies Prognosis Science Science (multidisciplinary) Survival Therapeutic targets Transcriptomics Tumor microenvironment Tumor Microenvironment - immunology Tumor-Associated Macrophages - immunology Tumor-Associated Macrophages - metabolism Tumor-Associated Macrophages - pathology Tumors
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Summary:	Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer that accounts for over 90% of all pancreatic cancer cases. With a 5-year survival rate of only 13%, PDAC has proven to be extremely desmoplastic and immunosuppressive to most current therapies, including chemotherapy and surgical resection. In recent years, focus has shifted to understanding the tumor microenvironment (TME) around PDAC, enabling a greater understanding of biological pathways and intercellular interactions that can ultimately lead to potential for future drug targets. In this study, we leverage a combination of single-cell and spatial transcriptomics to further identify cellular populations and interactions within the highly heterogeneous TME. We demonstrate that SPP1 + APOE + tumor-associated macrophages (TAM) and CTHRC1 + GREM1 + cancer-associated myofibroblasts (myCAF) not only act synergistically to promote an immune-suppressive TME through active extracellular matrix (ECM) deposition and epithelial mesenchymal transition (EMT), but are spatially colocalized and correlated, leading to worse prognosis. Our results highlight the crosstalk between stromal and myeloid cells as a significant area of study for future therapeutic targets to treat cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-024-68109-z