The effect of cancer cell produced collagen 1 homotrimers on DDR1 signaling activation by microenvironmental collagen 1 fragments.

摘要 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 23-045.胰腺导管腺癌(PDAC)占胰腺恶性肿瘤的90%以上。 美国癌症死亡的第三大原因。阐明这种恶性癌症的生物学机制 仍然是改善患者预后的关键。PDAC的特征是复杂的促结缔组织间质。 主要由成纤维细胞和细胞外基质(ECM)组成，可以抑制或促进 肿瘤进展。I型胶原(Col I)，通常是由两个a1和一个a2链组成的杂三聚体，是 在PDAC相关间质中发现的主要ECM蛋白，近年来已被证明在 盘状结构域在调节肿瘤生长、进展和治疗反应中的重要作用 受体酪氨酸激酶1(DDR1)和a3b1整合素受体信号通路。卡林实验室发现 基质金属蛋白酶(MMPs)裂解ECM中不溶的、完整的I型胶原纤维，形成可溶的1/4。 和1/4列的碎片。与完整的I型胶原纤维不同，它诱导DDR1D降解，并抑制DDR1下游的S 效应器，？Col I片段与DDR1结合，激活其酪氨酸激酶活性并刺激PDAC 代谢、线粒体生物发生和肿瘤生长。然而，卡鲁里实验室发现，PDAC癌症 细胞表观沉默COL1A2基因以产生少量抗基质金属蛋白酶的Col1a1同源三聚体 仅由三条A1链组成，不同于通常由癌症相关成纤维细胞产生的异源三聚体 (Caf)在PDAC基质中。同源三聚体通过改变肿瘤微生物群来改变免疫格局 并通过3b1整合素受体介导的致癌作用以自分泌方式刺激肿瘤生长。 发信号。在PDAC ECM中占大多数的裂解和完整的Col I杂三聚体的作用 并通过DDR1作用于Col I同源三聚体，通过A3b1整合素调节癌细胞生长，反之亦然 是一个关键的生物学和翻译问题，尚未得到回答。这项建议解决了 我们对使用两个目标的PDAC中的Col I功能的理解存在差距。第一个目标是Col Ia13是否 PDAC细胞产生的同源三聚体在完整和/或 裂解的Col I杂三聚体。第二个目的确定Col Ia13表达和Col Ia1缺失的PDAC细胞 对含有可切割和不可切割的Col I杂三聚体的ECM作出反应。破译机械论 在PDAC ECM中确定的Col I亚型之间的相互作用是设计成功的间质的关键步骤。 胰腺癌的靶向治疗。

Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Pancreatic Ductal Adenocarcinoma (PDAC) accounts for over 90% of pancreatic malignancies and is the third leading cause of cancer mortality in the United States. Elucidating the biology of this pernicious cancer remains the key to improving prognosis for patients. PDAC is characterized by a complex desmoplastic stroma composed largely of fibroblasts and extracellular matrix (ECM), that can function to either restrain or promote tumor progression. Type 1 Collagen (Col I), typically a heterotrimer consisting of two a1 and one a2 chains, is the major ECM protein found in the PDAC-associated stroma, and in recent years, has been proven to play an important role in regulating tumor growth, progression, and response to therapy through the discoidin domain receptor tyrosine kinase 1 (DDR1) and a3b1 integrin receptor signaling pathways. The Karin lab discovered that insoluble and intact Col I fibrils in the ECM are cleaved by matrix metalloproteinases (MMPs) to form soluble ¼ and ¾ Col I fragments. Unlike intact Col I fibrils, which induce DDR1 degradation and inhibit DDR1’s downstream effectors, the ¾ Col I fragment binds to DDR1, activates its tyrosine kinase activity and stimulates PDAC metabolism, mitochondrial biogenesis, and tumor growth. The Kalluri lab, however, discovered that PDAC cancer cells epigenetically silence the COL1A2 gene to produce small amounts of MMP-resistant Col1a1 homotrimers consisting solely of three a1 chains, unlike the heterotrimer normally produced by cancer associated fibroblasts (CAF) in the PDAC stroma. The homotrimer changes the immune landscape by altering the tumor microbiome and stimulates tumor growth in an autocrine manner through a3b1 integrin receptor mediated oncogenic signaling. The effect of cleaved and intact Col I heterotrimers that constitute a majority of the PDAC ECM and act via DDR1 on Col I homotrimer modulation of cancer cell growth via a3b1 integrin and vice versa is a critical biological and translational question that is yet to be answered. This proposal addresses the gap in our understanding of Col I function in PDAC using two aims. The first aim focuses on whether Col Ia13 homotrimers produced by PDAC cells can activate or inhibit DDR1 signaling in the presence of intact and/or cleaved Col I heterotrimers. The second aim determines how Col Ia13 expressing and Col Ia1-null PDAC cells respond to ECM containing cleavable and non-cleavable Col I heterotrimers. Deciphering the mechanistic interplay between the Col I subtypes identified in the PDAC ECM is a critical step in designing successful stroma- targeting treatments for pancreatic cancer.