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.