The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis

Lu Han, Yongxia Wu, Kun Fang, Sean Sweeney, Ulyss K. Roesner, Melodie Parrish, Khushbu Patel, Tom Walter, Julia Piermattei, Anthony Trimboli, Julia Lefler, Cynthia D. Timmers, Xue-Zhong Yu, Victor X. Jin, Michael T. Zimmermann, Angela J. Mathison, Raul Urrutia, Michael C. Ostrowski () and Gustavo Leone ()
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Lu Han: Medical University of South Carolina
Yongxia Wu: Medical University of South Carolina
Kun Fang: Medical College of Wisconsin
Sean Sweeney: Medical University of South Carolina
Ulyss K. Roesner: Medical University of South Carolina
Melodie Parrish: Medical University of South Carolina
Khushbu Patel: Medical University of South Carolina
Tom Walter: Medical University of South Carolina
Julia Piermattei: Medical University of South Carolina
Anthony Trimboli: Medical College of Wisconsin
Julia Lefler: Medical University of South Carolina
Cynthia D. Timmers: Medical University of South Carolina
Xue-Zhong Yu: Medical University of South Carolina
Victor X. Jin: Medical College of Wisconsin
Michael T. Zimmermann: Medical College of Wisconsin
Angela J. Mathison: Medical College of Wisconsin
Raul Urrutia: Medical College of Wisconsin
Michael C. Ostrowski: Medical University of South Carolina
Gustavo Leone: Medical College of Wisconsin

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.

Date: 2023
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DOI: 10.1038/s41467-022-34464-6

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