Effect of JAK and RIPK2 inhibition on CAF and cancer cell crosstalk

摘要 使用去卷积方法，我们已经确定了肿瘤固有亚型(基础和经典)和间质。 PDAC中的亚型(激活和正常)。患者的预后取决于肿瘤和间质。 亚型，这表明了解肿瘤-间质相互作用及其影响是至关重要的 治疗反应。我们已经证明，癌症相关成纤维细胞(CAF)是在 激活的间质。类似地，我们发现I/myCAF可能对基本亚型系和经典亚型系进行差异教育 我们的发现有力地支持了我们的中心假设，即CAF和肿瘤细胞具有相互作用 共同可能改变肿瘤的进展和反应，这使得我们理解 间质，特别是CAF，它们与肿瘤的相互作用，用于肿瘤间质背景特异性治疗 回应。我们和其他小组已经证明，患有基底亚型肿瘤的患者对标准 一线治疗。此外，我们无偏见蛋白质组学筛查的最新结果表明，基础和 典型的亚型肿瘤富含特定的激酶。该多样性补充项目在目标1上扩展 在母公司U01中。我们已经确定了两种针对JAK和RIPK2的小分子抑制剂，它们是 由于CAF的存在而变得敏感。该项目将确定JAK和RIPK2信号在 CAF与肿瘤细胞之间的串扰及靶向JAK和RIPK2在部分肿瘤和CAF中的作用 子类型线。

Abstract Using deconvolution approaches, we have identified tumor-intrinsic subtypes (basal and classical) and stroma subtypes (activated and normal) in PDAC. Patient outcome is dependent on both the tumor and stroma subtype, suggesting that it is critically important to understand tumor-stroma interactions and how they affect treatment response. We have shown that cancer associated fibroblasts (CAFs) are the contributory cells in activated stroma. Similarly, we find that i/myCAF may differentially educate basal vs. classical subtype lines Our findings provide strong support for our central hypothesis that CAFs and tumor cells have interactions that together may alter tumor progression and response, making it critical that we understand the heterogeneity of the stroma, and specifically CAFs, their interaction with the tumor, for tumor-stroma context specific treatment response. We and other groups have shown that patients with basal subtype tumors are resistant to standard first-line therapies. In addition, recent results from our unbiased proteomics screen have shown that basal and classical subtype tumors are enriched in specific kinases. This diversity supplement project expands on Aim 1 in the parent U01. We have identified two small molecule inhibitors targeting JAK and RIPK2 that are sensitized by the presence of CAFs. The project will determine the role of JAK and RIPK2 signaling in the crosstalk between CAFs and tumor cells and the role of targeting JAK and RIPK2 in selected tumor and CAF subtype lines.