Abstract
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 Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 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.
胰腺导管腺癌（PDAC）的肿瘤微环境（TME）包括癌症相关成纤维细胞（CAFs）的大量聚集，这是宿主对肿瘤细胞反应的一部分。人们对PDAC中转录多样的CAF群体的起源和功能仍知之甚少。肿瘤细胞内在基因突变和表观遗传失调可能会重塑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，具有肿瘤抑制功能。通过单细胞RNA测序，我们在SETD2缺陷型胰腺肿瘤中发现了一个以ABCA8a为标志的脂质负载CAF亚群。我们的研究结果表明，肿瘤内在SETD2缺失会通过H3K27Ac的异位增益释放BMP2信号，导致CAFs向富脂表型分化。然后，富含脂质的CAFs通过ABCA8a转运体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的异质性与肿瘤细胞的表观遗传失调联系起来，凸显了CAF与胰腺肿瘤细胞之间以前未被重视的新陈代谢相互作用。
