ArticleNature cell biology2024
Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
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Article in Nature cell biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 59 papers.
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59citing papers in PubMed
16.4field-weighted citation impact, top 1% of its field
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Who cites it
59 citing papers in PubMed, 70 citations in OpenAlex.
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- Guanylate-binding protein 2 (GBP2) drives pancreatic cancer cell proliferation by promoting cell cycle progression via the SP1/SKP2/P27 axis.Journal of translational medicine · 2026Article
- Advances in Lipid Metabolism Reprogramming in Hepatocellular Carcinoma.Journal of clinical and translational hepatology · 2026Review
- MYCN-driven metabolic remodelling of the tumour microenvironment in neuroblastoma: implications for stromal biology and CAF heterogeneity.Cancer metastasis reviews · 2026Review
- KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.Cancer research · 2026Article
- Cancer-Associated Fibroblast-Derived Sphingosine-1-Phosphate Activates a MALL-SDC4 Axis to Facilitate Perineural Invasion in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Cancer-Associated Fibroblasts Functions as Multifunctional Architects of the Tumor Stroma and Represent Emerging Therapeutic Vulnerabilities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- An Insulin-Exosome-TNFAIP8 Axis Drives Stromal Fibrosis and Therapeutic Resistance in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Acetyl-coenzyme A synthetase 2-mediated acetyl-coenzyme A accumulation promotes mitophagy and tumor growth via increased H3K27ac in hepatitis B virus-related hepatocellular carcinoma.Clinical and molecular hepatology · 2026Article
- Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment.Molecular cancer · 2026Review
- DNMT2-m5C-ACLY Axis Promotes Lenvatinib Resistance in Hepatocellular Carcinoma Through Histone Acetylation-Mediated Notch Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Integrative analysis of polyamine-associated genes reveals a prognostic and immunological signature in esophageal squamous cell carcinoma.Discover oncology · 2026Article
- Short-chain fatty acids in the tumor microenvironment: from molecular mechanisms to cancer therapy.Theranostics · 2026Review
- Metabolic programming in tooth development: a regulatory network from energy substrates to signaling instructions.Frontiers in cell and developmental biology · 2026Review
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
37 authors at 7 institutions in 3 countries.
Divya Murthy *Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0001-6492-1894
Kuldeep S Attri *Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0002-0668-5245
Surendra K Shukla *Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Ravi ThakurEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0003-2505-9757
Nina V ChaikaEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Chunbo HeEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Dezhen WangEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Kanupriya JhaDepartment of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India.
Aneesha DasguptaEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Ryan J KingEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0003-2081-3327
Scott E MulderEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Joshua SouchekEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Teklab GebregiworgisDepartment of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.ORCID http://orcid.org/0000-0002-1489-4813
Vikant RaiEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0001-6286-2341
Rohit PatelEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0001-8432-4616
Tuo HuEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Sandeep RanaEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Sai Sundeep KollalaEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Camila PachecoEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Paul M GrandgenettEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Fang YuDepartment of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0003-2243-5788
Vikas KumarDepartment of Cell Biology, Genetics and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
Audrey J LazenbyDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
Adrian R BlackEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0003-1560-6921
Susanna UlahannanDepartment of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.ORCID http://orcid.org/0000-0002-7234-2283
Ajay JainDepartment of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Barish H EdilDepartment of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
David L KlinkebielDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0001-9963-8909
Robert PowersDepartment of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.ORCID http://orcid.org/0000-0001-9948-6837
Amarnath NatarajanEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0001-5067-0203
Michael A HollingsworthEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.ORCID http://orcid.org/0000-0002-5255-8888
Kamiya MehlaEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
Quan LyDepartment of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
Sarika ChaudharyDepartment of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Greater Noida, Uttar Pradesh, India.ORCID http://orcid.org/0000-0003-4821-7017
Rosa F HwangDepartment of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kathryn E WellenDepartment of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-2281-0042
Pankaj K SinghEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. pankaj-singh@ouhsc.edu.ORCID http://orcid.org/0000-0001-8903-0131
University of Nebraska Medical Center · USUniversity of Oklahoma Health Sciences Center · USBennett University · INUniversity of Nebraska–Lincoln · USNebraska Medical Center · USThe University of Texas MD Anderson Cancer Center · USUniversity of Pennsylvania · US
Funding
Proteomics CoreP20GM103447 · NIGMS · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI David W Dyer · 2012 to 2026
$60.2MUNMC/EPPLEY CANCER CENTER SUPPORT GRANTP30CA036727 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI James Eudy · 1985 to 2026
$55.0MTissue Pathology Shared ResourceP30CA225520 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI ROBERT S. MANNEL · 2018 to 2026
$27.1MTarget Validation CoreP20GM121316 · NIGMS · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI ADRIAN R BLACK · 2018 to 2026
$23.5MTargeted mass spectrometry approaches to understand CART processing and recepter interactionsP20GM113126 · NIGMS · UNIVERSITY OF NEBRASKA LINCOLN · PI GUO, JIANTAO · 2016 to 2025
$20.8MTissue CoreP50CA127297 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI BATRA, SURINDER K. · 2008 to 2018
$17.1MTissue Core-UNMC Rapid Autopsy ProgramU54CA274329 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Paul M Grandgenett · 2022 to 2026
$7.8MCHEMICAL CARCINOGENESIS &CANCER BIOLOGYT32CA009476 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI Jennifer D. Black · 1988 to 2026
$6.2MTargeting Tumor-Stromal Metabolic Cross-Talk in Pancreatic CancerR01CA163649 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Pankaj Kumar Singh · 2012 to 2026
$5.4MRedox Biology CenterP30GM103335 · NIGMS · UNIVERSITY OF NEBRASKA LINCOLN · PI BECKER, DONALD F · 2012 to 2016
$4.3MMitochondrial calcium signaling in pancreatic cancer metastasis and progressionR01CA256911 · NCI · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI Pankaj Kumar Singh, Shengyu Yang · 2022 to 2026
$3.2MMolecular Basis of ME2-mediated Tumor Suppression in Pancreatic CancerR01CA270234 · NCI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI Pankaj Kumar Singh · 2022 to 2026
$2.2MNCI NIH HHS P30 CA036727NCI NIH HHS P30 CA225520NCI NIH HHS P50 CA127297NCI NIH HHS R01 CA163649NCI NIH HHS R01 CA256911NCI NIH HHS R01 CA270234NCI NIH HHS R37 CA276924NCI NIH HHS R50 CA211462NCI NIH HHS T32 CA009476NCI NIH HHS U54 CA274329NIGMS NIH HHS P20 GM103447NIGMS NIH HHS P20 GM113126NIGMS NIH HHS P20 GM121316NIGMS NIH HHS P30 GM103335
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 SP1 protein 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.
Indexed as
Cancer-Associated FibroblastsPancreatic NeoplasmsAcetatesAnimalsCell Line, TumorMicePolyaminesTumor MicroenvironmentAcetatesPolyamines
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