@article{32572b86b7314bb394283137cb2f535a,
title = "Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer",
abstract = "Stromal desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) involves significant accumulation of type I collagen (Col1). However, the precise molecular and mechanistic contribution of Col1 in PDAC progression remains unknown. Activated pancreatic stellate cells/αSMA+ myofibroblasts are major contributors of Col1 in the PDAC stroma. We use a dual-recombinase genetic mouse model of spontaneous PDAC to delete Col1 specifically in myofibroblasts. This results in significant reduction of total stromal Col1 content and accelerates the emergence of PanINs and PDAC, decreasing overall survival. Col1 deletion leads to Cxcl5 upregulation in cancer cells via SOX9. Increase in Cxcl5 is associated with recruitment of myeloid-derived suppressor cells and suppression of CD8+ T cells, which can be attenuated with combined targeting of CXCR2 and CCR2 to restrain accelerated PDAC progression in the setting of stromal Col1 deletion. Our results unravel the fundamental role of myofibroblast-derived Co1l in regulating tumor immunity and restraining PDAC progression.",
keywords = "B cells, T cells, extracellular matrix, fibroblasts, genetically engineered mouse models, myeloid-derived suppressor cells (MDSCs), pancreatic ductal adenocarcinoma (PDAC), tumor immunology, tumor microenvironment, type I collagen",
author = "Yang Chen and Jiha Kim and Sujuan Yang and Huamin Wang and Wu, {Chang Jiun} and Hikaru Sugimoto and LeBleu, {Valerie S.} and Raghu Kalluri",
note = "Funding Information: We thank D. Saur for providing the KPPF and R26 Dual mouse strain, C.G. Liu at the MD Anderson Cancer Center (MDACC) Sequencing and ncRNA Program for RNA-seq analysis, K.M. Ramirez, K. Clise-Dwyer, and R. Jewell at the Advanced Cytometry & Sorting Facility at South Campus of MDACC for flow cytometry (in part supported by NCI P30CA16672 ), E.J. Thompson, D.P. Pollock, and Y. Chen at the Advanced Technology Genomics Core for their assistance for the single-cell RNA sequencing analysis in part supported by NCI CA016672 (ATGC), the Genetically Engineered Mouse Facility team of MDACC for the generation of Col1a1 loxP/loxP mouse strain. We also thank Y. Fan and P.E. Phillips for their technical help with flow cytometry and immunohistochemistry/multispectral imaging, K.M. McAndrews for flow cytometry data analysis, J. Zhang, X. Song, and X. Mao for RNA-seq data processing, J.L. Carstens for TSA multispectral imaging, A.M. Zaske at the AFM core facility of UT Health Science Center for atomic force microscopy. This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) award RP150231 and NCI P01CA117969 . The current address of J.K. is the Department of Biological Sciences, North Dakota State University, Fargo, ND 58102, USA. Funding Information: We thank D. Saur for providing the KPPF and R26Dual mouse strain, C.G. Liu at the MD Anderson Cancer Center (MDACC) Sequencing and ncRNA Program for RNA-seq analysis, K.M. Ramirez, K. Clise-Dwyer, and R. Jewell at the Advanced Cytometry & Sorting Facility at South Campus of MDACC for flow cytometry (in part supported by NCI P30CA16672), E.J. Thompson, D.P. Pollock, and Y. Chen at the Advanced Technology Genomics Core for their assistance for the single-cell RNA sequencing analysis in part supported by NCI CA016672 (ATGC), the Genetically Engineered Mouse Facility team of MDACC for the generation of Col1a1loxP/loxP mouse strain. We also thank Y. Fan and P.E. Phillips for their technical help with flow cytometry and immunohistochemistry/multispectral imaging, K.M. McAndrews for flow cytometry data analysis, J. Zhang, X. Song, and X. Mao for RNA-seq data processing, J.L. Carstens for TSA multispectral imaging, A.M. Zaske at the AFM core facility of UT Health Science Center for atomic force microscopy. This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) award RP150231 and NCI P01CA117969. The current address of J.K. is the Department of Biological Sciences, North Dakota State University, Fargo, ND 58102, USA. Conceptualization: Y.C. and R.K; data curation: Y.C.; formal analysis: Y.C.; methodology: Y.C. J.K. S.Y. and C.-J.W.; investigation: Y.C. S.Y. H.S. and C.-J.W.; human PDAC sections and approvals: H.W.; single-cell RNA sequencing analysis: S.Y. and Y.C.; resources: R.K.; supervision: Y.C. H.W. S.Y. V.S.L. and R.K.; validation: Y.C.; writing ? original draft: Y.C. and R.K.; writing ? review & editing: Y.C. J.K. S.Y. H.W. C.-J.W, H.S. V.S.L. and R.K. The authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "12",
doi = "10.1016/j.ccell.2021.02.007",
language = "English (US)",
volume = "39",
pages = "548--565.e6",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}