Tumor Cell-Intrinsic Epigenetic Dysregulation Shapes Cancer-Associated Fibroblasts Heterogeneity to Metabolically Support Pancreatic Cancer

Intrinsic Epigenetic Dysregulation in Tumor Cells Shapes Cancer-Associated Fibroblasts Heterogeneity to Metabolically Support Pancreatic Cancer

Authors Ningning Niu, Qingshen Xu, Wang Zheng, …, Kurong Jiang, Fengshi Yu, Xue Xu Jing published an article titled “Intrinsic Epigenetic Dysregulation in Tumor Cells Shapes Cancer-Associated Fibroblasts Heterogeneity to Metabolically Support Pancreatic Cancer” in Cancer Cell on May 13, 2024. This paper elucidates how the loss of SETD2 within tumor cells guides the differentiation of cancer-associated fibroblasts (CAFs) into a lipid-rich subpopulation through epigenetic reprogramming and activation of the BMP signaling pathway, thereby providing metabolic fuel to tumor cells and promoting tumor progression.

Academic Background

Pancreatic cancer, especially Pancreatic Ductal Adenocarcinoma (PDAC), is one of the deadliest solid tumors with causes involving molecular changes in tumor cells and alterations in the tumor microenvironment (TME). In the TME, a large number of CAFs play important roles in tumor initiation, metastasis, metabolic reprogramming, immune escape, and drug resistance. However, it is unclear how intrinsic gene mutations and epigenetic dysregulation in tumor cells affect the heterogeneity and function of CAFs. As a critical histone H3K36 trimethyltransferase, SETD2 has been found to be mutated or deleted in various cancers, which has profound implications for the development of individualized treatment plans.

Research Origin

This study was conducted by the team of Ningning Niu, Qingshen Xu, Wang Zheng, and others, with members from Shanghai Jiao Tong University School of Medicine, The First Affiliated Hospital of Xi’an Jiaotong University in Shaanxi, The First Affiliated Hospital of Nanjing Medical University, Tongji University, and other research institutions. The article was published in Cancer Cell on May 13, 2024.

Research Process

The study initially analyzed SETD2 deficiency and its role in tumor metabolism through Gene Set Enrichment Analysis (GSEA). Subsequently, using single-cell RNA sequencing (scRNA-seq), a lipid-rich CAF subpopulation was identified in mouse models, which provides energy for mitochondrial oxidative phosphorylation (oxphos) in tumor cells via ABCA8A-mediated lipid transport.

1. Gene Set Enrichment Analysis: Analysis through TCGA and QCMG databases revealed enhanced oxidative phosphorylation in pancreatic cancer under the combined effect of SETD2 deficiency and KRAS mutation.

2. Single-Cell RNA Sequencing: Further confirmed the enhancement of oxidative phosphorylation in SETD2-deficient pancreatic tumors in mice. UMAP analysis revealed multiple cell clusters, including different marked acinar and duct cells, and CAFs.

3. Identification of Lipid-Rich CAFs: Lipid-rich CAFs marked by ABCA8A were significantly increased in SETD2-deficient pancreatic tumors. These CAFs support the metabolic needs of tumor cells through oxidative phosphorylation via lipid metabolism characteristics revealed by gene set analysis.

4. Lipid Transport Mechanism: Confirmed ABCA8A’s key role in lipid transport. Co-culture experiments and lipid pulse tracking demonstrated that ABCA8A-overexpressing CAFs could efficiently transfer lipids to tumor cells, promoting their oxphos metabolism.

Main Results

1. Enhanced Oxidative Phosphorylation: Significant enhancement of oxidative phosphorylation in SETD2-deficient pancreatic tumors was confirmed by single-cell sequencing.

2. Lipid-Rich CAF Subpopulation: CAFs marked by ABCA8A significantly increased under SETD2-deficient conditions, supporting tumor cell oxidative phosphorylation through lipid metabolism.

3. Key Proteins in Lipid Transport: ABCA8A played a crucial role in lipid transport, with CAFs mediating lipid transfer to tumor cells via high-density lipoprotein (HDL) particles, supporting their growth.

4. Clinical Relevance Analysis: In human pancreatic cancer (hPDAC) patients, low H3K36me3 expression was closely associated with higher proportions of ABCA8+FAP+ CAFs and increased tumor cell oxidative phosphorylation.

Conclusion and Significance

This study reveals the mechanism by which epigenetic dysregulation in tumor cells reprograms CAF heterogeneity to support tumor metabolic needs, emphasizing the key role of SETD2 deficiency in pancreatic cancer metabolic reprogramming. It suggests that oxphos-targeting therapeutic strategies might offer new treatment opportunities for pancreatic cancer patients with SETD2 deficiency.

Research Highlights

1. Revealing Epigenetic Dysregulation Impact on CAFs: This study systematically demonstrates how SETD2 deficiency leads to the differentiation of CAFs into a lipid-rich subpopulation through abnormal deposition of H3K27ac.

2. Identification and Characterization of New CAF Subpopulation: Using scRNA-seq technology, the study identifies and characterizes a lipid-rich CAF subpopulation and reveals its crucial role in tumor metabolism.

3. Proposing New Therapeutic Strategy: The research suggests that oxphos-targeting therapy could be particularly effective for pancreatic cancer patients with SETD2 deficiency, providing a new approach for future clinical treatments.

Additional Information

Research data and codes can be accessed through the following link https://doi.org/10.1016/j.ccell.2024.03.005. Detailed experimental methods and statistical analyses are further described in the appendix. This study was supported by multiple scientific grants and utilized several key laboratories and pathology resources. Special thanks to all the participants for their contributions and collaboration.

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This study provides a deeper understanding of metabolic regulation and the tumor microenvironment in pancreatic cancer, potentially reshaping the clinical treatment landscape for pancreatic cancer in the future.