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

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.
Ningning Niu 1,  Xuqing Shen 1,  Zheng Wang 2,  Yueyue Chen 1,  Yawen Weng 1,  Feier Yu 1,  Yingying Tang 1,  Ping Lu 1,  Mingzhu Liu 1,  Liwei Wang 3,  Yongwei Sun 4,  Minwei Yang 4,  Baiyong Shen 5,  Jiabin Jin 5,  Zipeng Lu 6,  Kuirong Jiang 6,  Yufeng Shi 7,  Jing Xue 8
Affiliations

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.

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