The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in -deficient pancreatic tumors. Our findings reveal that tumor-intrinsic loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

中文翻译：

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肿瘤细胞内在的表观遗传失调塑造了癌症相关成纤维细胞的异质性，从而在代谢上支持胰腺癌

胰腺导管腺癌 (PDAC) 中的肿瘤微环境 (TME) 涉及癌症相关成纤维细胞 (CAF) 的大量积累，作为宿主对肿瘤细胞反应的一部分。 PDAC 中转录多样性 CAF 群体的起源和功能仍然知之甚少。肿瘤细胞内在基因突变和表观遗传失调可能重塑 TME；然而，它们对 CAF 异质性的影响仍然难以捉摸。 SETD2 是一种组蛋白 H3K36 三甲基转移酶，具有肿瘤抑制因子的作用。通过单细胞 RNA 测序，我们在缺乏的胰腺肿瘤中鉴定出由 ABCA8a 标记的富含脂质的 CAF 亚群。我们的研究结果表明，肿瘤内在损失通过 H3K27Ac 的异位增益释放 BMP2 信号传导，导致 CAF 向富含脂质的表型分化。然后，充满脂质的 CAF 通过 ABCA8a 转运蛋白为线粒体氧化磷酸化提供脂质，从而促进肿瘤进展。总之，我们的研究将 CAF 异质性与肿瘤细胞的表观遗传失调联系起来，强调了 CAF 和胰腺肿瘤细胞之间以前未被认识到的代谢相互作用。