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

JAK 和 RIPK2 抑制对 CAF 和癌细胞串扰的影响

• 批准号: 10817517
• 负责人: Naim Ur Rashid
• 金额: $ 1.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817517
• 关键词: Affect; Cells; Fibroblasts; Heterogeneity; Malignant Neoplasms; Parents; Patient-Focused Outcomes; Patients; Phosphotransferases; Proteomics; RIPK2 gene; Resistance; Role; Signal Transduction; Tumor Subtype; cancer cell; neoplastic cell; response; small molecule inhibitor; treatment response; tumor; tumor progression

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.

摘要 使用去卷积方法，我们已经确定了肿瘤内在亚型（基底和经典）和基质 PDAC中的亚型（激活和正常）。患者预后取决于肿瘤和间质 亚型，这表明了解肿瘤-间质相互作用及其如何影响 治疗反应。我们已经表明，癌症相关成纤维细胞（CAF）是癌症的贡献细胞。 激活基质。类似地，我们发现i/myCAF可以差异化地培养基础与经典亚型细胞系， 我们的研究结果为我们的中心假设提供了强有力的支持，即CAFs和肿瘤细胞之间存在相互作用， 一起可能改变肿瘤的进展和反应，这使得我们了解肿瘤的异质性变得至关重要。 基质，特别是CAF，它们与肿瘤的相互作用，用于肿瘤-基质环境特异性治疗 反应我们和其他研究小组已经表明，基底亚型肿瘤患者对标准的 一线治疗此外，我们的无偏蛋白质组学筛选的最新结果表明，基础和 经典亚型肿瘤富含特异性激酶。这一多样性补充项目扩大了目标1 在父U 01中。我们已经鉴定了两种靶向JAK和RIPK 2的小分子抑制剂， 由于CAF的存在而变得敏感。该项目将确定JAK和RIPK 2信号传导在细胞凋亡中的作用。 CAF和肿瘤细胞之间的串扰以及靶向JAK和RIPK 2在所选肿瘤和CAF中的作用 子类型行。