美国内布拉斯加大学Pankaj K. Singh及其课题组发现，癌症相关成纤维细胞（CAFs）产生的乙酸盐通过ACSS2-SP1-SAT1通路改变多胺代谢促进胰腺癌进展。该项研究成果发表在2024年3月1日出版的《自然-细胞生物学》上。

研究人员发现胰腺癌相关成纤维细胞通过分泌乙酸来调节肿瘤细胞的新陈代谢，通过沉默CAFs中的ATP柠檬酸裂解酶（ACLY）可以阻断乙酸的分泌。研究进一步发现，乙酰-CoA合成酶短链家族成员2（ACSS2）通过外源乙酸来动态调控癌细胞的表观基因组和转录组，从而促进癌细胞在酸性微环境中的生存。H3K27ac ChIP-seq和RNA-seq的分析比较表明，多胺平衡的改变是通过调控SAT1基因表达和SP1富集反应实现。

研究发现乙酸盐/ASS2介导的SP1 19位赖氨酸的乙酰化增加了SP1蛋白的稳定性和转录活性。遗传或药物抑制ACSS2-SP1-SAT1通路可减轻小鼠模型的肿瘤负荷。这些结果表明，来源于细胞基质的乙酸赋予了癌细胞新陈代谢的灵活性，使癌细胞能够通过ACSS2-SP1-SAT1通路在酸中毒条件下存活。

据了解，肿瘤细胞能否在恶劣的微环境中生存取决于其对环境中营养物质的利用。

附：英文原文

Title: Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2–SP1–SAT1 axis

Author: Murthy, Divya, Attri, Kuldeep S., Shukla, Surendra K., Thakur, Ravi, Chaika, Nina V., He, Chunbo, Wang, Dezhen, Jha, Kanupriya, Dasgupta, Aneesha, King, Ryan J., Mulder, Scott E., Souchek, Joshua, Gebregiworgis, Teklab, Rai, Vikant, Patel, Rohit, Hu, Tuo, Rana, Sandeep, Kollala, Sai Sundeep, Pacheco, Camila, Grandgenett, Paul M., Yu, Fang, Kumar, Vikas, Lazenby, Audrey J., Black, Adrian R., Ulhannan, Susanna, Jain, Ajay, Edil, Barish H., Klinkebiel, David L., Powers, Robert, Natarajan, Amarnath, Hollingsworth, Michael A., Mehla, Kamiya, Ly, Quan, Chaudhary, Sarika, Hwang, Rosa F., Wellen, Kathryn E., Singh, Pankaj K.

Issue&Volume: 2024-03-01

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.

DOI: 10.1038/s41556-024-01372-4

Source: https://www.nature.com/articles/s41556-024-01372-4