Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer
Acidic fibroblast growth factor underlies microenvironmental regulation of MYC in pancreatic cancer
复制标题
DOI：
10.1084/jem.20191805
复制
发表时间：
2020-08-01
影响因子：
15.3
通讯作者：
Sherman, Mara H.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Sohinee;Oon, Chet;Sherman, Mara H.
尽管MYC作为致癌RAS的效应子具有关键作用，但缺乏在RAS驱动的癌症中靶向MYC活性的策略。在肺癌和胰腺癌的基因工程小鼠模型中，致癌KRAS不足以驱动肿瘤发生，而适度MYC过表达的增加驱动了强大的肿瘤形成，这表明RAS途径以外的机制在MYC调节和RAS驱动的肿瘤发生中起着关键作用。在这里，我们表明，酸性成纤维细胞生长因子（FGF 1）来源于癌症相关的成纤维细胞（CAFs）与癌细胞自主信号合作，以增加MYC水平，启动子占用和活性。FGF 1对于MYC蛋白稳定性的旁分泌调节是必要的和足够的，通过AKT和GSK-3 β信号传导以增加MYC半衰期。患者标本揭示了肿瘤区室中基质CAF含量和MYC蛋白水平之间的强相关性，并将CAF鉴定为肿瘤微环境中FGF 1的特异性来源。总之，我们的研究结果表明，MYC是协调调节细胞自主和微环境信号，并建立CAF衍生的FGF 1作为一种新的旁分泌调节致癌转录。
Despite a critical role for MYC as an effector of oncogenic RAS, strategies to target MYC activity in RAS-driven cancers are lacking. In genetically engineered mouse models of lung and pancreatic cancer, oncogenic KRAS is insufficient to drive tumorigenesis, while addition of modest MYC overexpression drives robust tumor formation, suggesting that mechanisms beyond the RAS pathway play key roles in MYC regulation and RAS-driven tumorigenesis. Here we show that acidic fibroblast growth factor (FGF1) derived from cancer-associated fibroblasts (CAFs) cooperates with cancer cell-autonomous signals to increase MYC level, promoter occupancy, and activity. FGF1 is necessary and sufficient for paracrine regulation of MYC protein stability, signaling through AKT and GSK-3 beta to increase MYC half-life. Patient specimens reveal a strong correlation between stromal CAF content and MYC protein level in the neoplastic compartment, and identify CAFs as the specific source of FGF1 in the tumor microenvironment. Together, our findings demonstrate that MYC is coordinately regulated by cell-autonomous and microenvironmental signals, and establish CAF-derived FGF1 as a novel paracrine regulator of oncogenic transcription.