Cancer-Associated Fibroblast-Derived Acetate Promotes Pancreatic Cancer Development by Altering Polyamine Metabolism via the ACSS2–SP1–SAT1 Axis

Authors

• Divya Murthy, University of Nebraska Medical Center
• Kuldeep S. Attri, University of Nebraska Medical Center
• Surendra K. Shukla, University of Nebraska Medical Center, University of Oklahoma Health Sciences Center
• Ravi Thakur, University of Nebraska Medical Center, University of Oklahoma Health Sciences Center
• Nina V. Chaika, University of Nebraska Medical Center
• Chunbo He, University of Nebraska Medical Center
• Dezhen Wang, University of Nebraska Medical Center
• Kanupriya Jha, Bennett University
• Aneesha Dasgupta, University of Nebraska Medical Center
• Ryan J. King, University of Nebraska Medical Center
• Scott E. Mulder, University of Nebraska Medical Center
• Joshua Souchek, University of Nebraska Medical Center
• Teklab Gebregiworgis, University of Nebraska-Lincoln, University of Western Ontario
• Vikant Rai, University of Nebraska Medical Center
• Rohit Patel, University of Nebraska Medical Center
• Tuo Hu, University of Nebraska Medical Center
• Sandeep Rana, University of Nebraska Medical Center
• Sai Sundeep Kollala, University of Nebraska Medical Center
• Camila Pacheco, University of Nebraska Medical CenterFollow
• Paul M. Grandgenett, University of Nebraska Medical CenterFollow
• Fang Yu, University of Nebraska Medical CenterFollow
• Vikas Kumar, University of Nebraska Medical Center
• Audrey J. Lazenby, University of Nebraska Medical CenterFollow
• Adrian R. Black, University of Nebraska Medical CenterFollow
• Susanna Ulhannan, University of Oklahoma Health Sciences Center
• Ajay Jain, University of Oklahoma Health Sciences Center
• Barish H. Edil, University of Oklahoma Health Sciences Center
• David L. Klinkebiel, University of Nebraska Medical Center
• Robert Powers, University of Nebraska-LincolnFollow
• Amarnath Natarajan, University of Nebraska Medical CenterFollow
• Michael A. Hollingsworth, University of Nebraska Medical CenterFollow
• Kamiya Mehla2,, University of Nebraska Medical Center
• Quan Ly, University of Nebraska Medical CenterFollow
• Sarika Chaudhary, Bennett University
• Rosa F. Hwang, The University of Texas MD Anderson Cancer Center
• Kathryn E. Wellen, University of Pennsylvania Perelman School of Medicine
• Pankaj K. Singh, University of Nebraska Medical Center, University of Oklahoma Health Sciences Center

Document Type

Article

Date of this Version

3-1-2024

Citation

Nature Cell Biology 26 (April 2024), pp. 613–627.

doi: 10.1038/s41556-024-01372-4

Comments

Open access

Abstract

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP–seq and RNA–seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2–SP1–SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2–SP1–SAT1 axis.