IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
复制标题
DOI：
10.1158/2159-8290.cd-18-0710
复制
发表时间：
2019-03
期刊：
影响因子：
28.2
通讯作者：
Tuveson DA
中科院分区：
文献类型：
--
作者：
Biffi G;Oni TE;Spielman B;Hao Y;Elyada E;Park Y;Preall J;Tuveson DA
胰腺导管腺癌（PDAC）对治疗反应较差，并且组织学上包含少量嵌入致密促结缔组织增生基质内的肿瘤细胞。在基质内，癌症相关成纤维细胞 (CAF) 分泌趋向因子和细胞外基质成分，并与 PDAC 进展和化疗耐药有关。我们最近发现了两种不同的 CAF 亚型，其特征是肌纤维母细胞或炎症表型；然而，其多样性背后的机制及其在 PDAC 中的作用仍然未知。在这里，我们使用类器官和小鼠模型来鉴定 TGF-β 和 IL-1 作为促进 CAF 异质性的肿瘤分泌配体。我们发现 IL-1 诱导 LIF 表达和下游 JAK/STAT 激活以产生炎症 CAF，并证明 TGF-β 通过下调 IL-1R1 表达并促进分化为肌成纤维细胞来拮抗这一过程。我们的结果提供了一种机制，通过该机制在 PDAC 微环境中建立不同的成纤维细胞生态位，并阐明选择性靶向支持肿瘤生长的 CAF 的策略。
Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAFs) secrete tropic factors and extracellular matrix components, and have been implicated in PDAC progression and chemotherapy resistance. We recently identified two distinct CAF subtypes characterized by either myofibroblastic or inflammatory phenotypes; however, the mechanisms underlying their diversity and their roles in PDAC remain unknown. Here, we use organoid and mouse models to identify TGF-β and IL-1 as tumor-secreted ligands that promote CAF heterogeneity. We show that IL-1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs, and demonstrate that TGF-β antagonizes this process by downregulating IL-1R1 expression and promoting differentiation into myofibroblasts. Our results provide a mechanism through which distinct fibroblast niches are established in the PDAC microenvironment and illuminate strategies to selectively target CAFs that support tumor growth.