Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Gastroenterology. 2021 Jan;160(1):346-361.e24. doi: 10.1053/j.gastro.2020.09.010. Epub 2020 Sep 30.
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibroblast-rich desmoplastic stroma. Cancer-associated fibroblasts (CAFs) have been shown to display a high degree of interconvertible states including quiescent, inflammatory, and myofibroblastic phenotypes; however, the mechanisms by which this plasticity is achieved are poorly understood. Here, we aim to elucidate the role of CAF plasticity and its impact on PDAC biology.
To investigate the role of mesenchymal plasticity in PDAC progression, we generated a PDAC mouse model in which CAF plasticity is modulated by genetic depletion of the transcription factor Prrx1. Primary pancreatic fibroblasts from this mouse model were further characterized by functional in vitro assays. To characterize the impact of CAFs on tumor differentiation and response to chemotherapy, various coculture experiments were performed. In vivo, tumors were characterized by morphology, extracellular matrix composition, and tumor dissemination and metastasis.
Our in vivo findings showed that Prrx1-deficient CAFs remain constitutively activated. Importantly, this CAF phenotype determines tumor differentiation and disrupts systemic tumor dissemination. Mechanistically, coculture experiments of tumor organoids and CAFs showed that CAFs shape the epithelial-to-mesenchymal phenotype and confer gemcitabine resistance of PDAC cells induced by CAF-derived hepatocyte growth factor. Furthermore, gene expression analysis showed that patients with pancreatic cancer with high stromal expression of Prrx1 display the squamous, most aggressive, subtype of PDAC.
Here, we define that the Prrx1 transcription factor is critical for tuning CAF activation, allowing a dynamic switch between a dormant and an activated state. This work shows that Prrx1-mediated CAF plasticity has significant impact on PDAC biology and therapeutic resistance.
胰腺导管腺癌（PDAC）的特征是富含成纤维细胞的纤维母细胞性间质。已经表明，癌相关成纤维细胞（CAF）具有高度可转换状态，包括静止、炎症和肌成纤维细胞表型；然而，这种可塑性是如何实现的机制尚不清楚。在这里，我们旨在阐明 CAF 可塑性的作用及其对 PDAC 生物学的影响。
为了研究间充质可塑性在 PDAC 进展中的作用，我们通过基因敲除转录因子 Prrx1 来调节 CAF 可塑性，从而在 PDAC 小鼠模型中生成了 CAF 可塑性。进一步通过功能体外测定来对该小鼠模型中的原代胰腺成纤维细胞进行了表征。为了研究 CAF 对肿瘤分化和对化疗反应的影响，进行了各种共培养实验。在体内，通过形态、细胞外基质组成以及肿瘤扩散和转移来对肿瘤进行了表征。
我们的体内研究结果表明，Prrx1 缺陷型 CAF 持续保持激活状态。重要的是，这种 CAF 表型决定了肿瘤分化，并破坏了系统性肿瘤扩散。在机制上，肿瘤类器官和 CAF 的共培养实验表明，CAF 塑造了上皮-间充质表型，并赋予了由 CAF 衍生的肝细胞生长因子诱导的 PDAC 细胞对吉西他滨的耐药性。此外，基因表达分析表明，高基质表达 Prrx1 的胰腺癌患者表现出 PDAC 最具侵袭性的鳞状亚型。
在这里，我们定义了 Prrx1 转录因子对于调节 CAF 激活至关重要，允许在休眠和激活状态之间进行动态切换。这项工作表明，Prrx1 介导的 CAF 可塑性对 PDAC 生物学和治疗抵抗具有重大影响。
