Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer

Ningning Niu; Xuqing Shen; Zheng Wang; Yueyue Chen; Yawen Weng; Feier Yu; Yingying Tang; Ping Lu; Mingzhu Liu; Liwei Wang; Yongwei Sun; Minwei Yang; Baiyong Shen; Jiabin Jin; Zipeng Lu; Kuirong Jiang; Yufeng Shi; Jing Xue

doi:10.1016/j.ccell.2024.03.005

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer

Cancer Cell. 2024 Apr 4:S1535-6108(24)00090-4. doi: 10.1016/j.ccell.2024.03.005. Online ahead of print.

Authors

Ningning Niu¹, Xuqing Shen¹, Zheng Wang², Yueyue Chen¹, Yawen Weng¹, Feier Yu¹, Yingying Tang¹, Ping Lu¹, Mingzhu Liu¹, Liwei Wang³, Yongwei Sun⁴, Minwei Yang⁴, Baiyong Shen⁵, Jiabin Jin⁵, Zipeng Lu⁶, Kuirong Jiang⁶, Yufeng Shi⁷, Jing Xue⁸

Affiliations

¹ State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
³ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Research Institute of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
⁷ Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
⁸ State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jingxue@sjtu.edu.cn.

PMID: 38579725
DOI: 10.1016/j.ccell.2024.03.005

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.

Keywords: OXPHOS; Pancreatic cancer; SETD2; cell communication; epigenetic dysregulation; lipid-laden CAF.