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
  • 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: [email protected].
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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