Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts
Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts
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DOI：
10.7554/elife.50663
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发表时间：
2019-11-01
期刊：
影响因子：
7.7
通讯作者：
Verma, Amit
中科院分区：
文献类型：
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作者：
Bhagat, Tushar D.;Von Ahrens, Dagny;Verma, Amit
尽管胰腺导管腺癌（PDAC）与纤维化间质相关，但调节癌症相关成纤维细胞（CAF）形成的分子途径尚未得到很好的阐明。对患者来源的和新生产生的CAF的表观基因组分析表明，胞嘧啶甲基化的广泛丧失与包括CXCR 4在内的各种炎性转录物的过表达相关。肿瘤细胞与CAF的共培养导致侵袭力增加，但通过抑制CXCR 4而消除。代谢物追踪显示，肿瘤细胞产生的乳酸导致间充质干细胞（MSC）内α-酮戊二酸（aKG）的产生增加。反过来，aKG介导的脱甲基酶泰特酶的活化导致MSC从头分化为CAF期间胞嘧啶甲基化降低和羟甲基化增加。肿瘤细胞与TET缺陷的MSC的共注射抑制体内肿瘤生长。因此，在PDAC中，肿瘤介导的乳酸通量与CAF形成期间观察到的广泛的表观基因组重编程相关。
Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.