1. Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.
- Author
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Niu N, Shen X, Wang Z, Chen Y, Weng Y, Yu F, Tang Y, Lu P, Liu M, Wang L, Sun Y, Yang M, Shen B, Jin J, Lu Z, Jiang K, Shi Y, and Xue J
- Subjects
- Humans, Mice, Animals, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Epigenesis, Genetic, Tumor Microenvironment, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology
- Abstract
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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