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

癌细胞产生的胶原蛋白 1 同源三聚体对微环境胶原蛋白 1 片段激活 DDR1 信号传导的影响。

• 批准号: 10831212
• 负责人: Michael Karin
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831212
• 关键词: Address; Affect; Alleles; Binding; Biogenesis; Biological; Biology; Blood Vessels; COL1A2 gene; Cancer Cell Growth; Cancer Etiology; Cells; Collaborations; Collagen; Collagen Receptors; Collagen Type I; Complex; DOK1 gene; Deposition; Desmoplastic; Elements; Epigenetic Process; Extracellular Matrix; Extracellular Matrix Proteins; Fiber; Fibrillar Collagen; Fibroblasts; Fibrosis; Future; Goals; Growth; Immune; Infiltration; Integrins; Laboratories; Laboratory Finding; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Matrix Metalloproteinases; Mediating; Metabolism; Metalloproteases; Mitochondria; NF-kappa B; Nutrient; Oncogenic; Pancreatic Ductal Adenocarcinoma; Pancreatic Endocrine Carcinoma; Patients; Play; Protein Tyrosine Kinase; Reagent; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Technology; Time; Tumor Promotion; United States; Variant; autocrine; cancer cell; cellular engineering; design; discoidin receptor; experimental study; improved; insoluble fiber; interest; islet; mortality; mutant; pancreatic ductal adenocarcinoma cell; patient prognosis; prevent; receptor; response; restraint; survival prediction; therapeutic development; therapeutic target; treatment response; tumor; tumor growth; tumor metabolism; tumor microbiome; tumor progression

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.

摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（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， 是美国癌症死亡率的第三大原因。阐明这种恶性癌症的生物学 仍然是改善患者预后的关键。PDAC的特征是复杂的促纤维增生基质 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。1型胶原（Col I）通常是由两条α 1和一条α 2链组成的异源三聚体， 在PDAC相关基质中发现的主要ECM蛋白，近年来，已被证明在PDAC相关基质中起作用。 通过盘状结构域调节肿瘤生长、进展和治疗反应的重要作用 受体酪氨酸激酶1（DDR 1）和α 3b 1整联蛋白受体信号通路。卡琳实验室发现， ECM中的不溶性和完整的Col I原纤维被基质金属蛋白酶（MMP）切割以形成可溶性的胶原蛋白。 和100个Col I片段。不像完整的Col I纤维，其诱导DDR 1降解并抑制DDR 1的下游 作为效应物，H2 Col I片段结合DDR 1，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，Kadui实验室发现，PDAC癌症 细胞表观遗传沉默COL 1A 2基因，产生少量MMP抗性Col 1a 1同源三聚体 与通常由癌症相关的成纤维细胞产生的异源三聚体不同， (CAF)在PDAC基质中。同源三聚体通过改变肿瘤微生物组改变免疫景观 并通过α 3 β 1整联蛋白受体介导的致癌作用以自分泌方式刺激肿瘤生长 发信号。构成PDAC ECM的大部分的裂解的和完整的Col I异源三聚体的作用 并通过DDR 1作用于Col I同源三聚体，通过α 3 β 1整联蛋白调节癌细胞生长，反之亦然 是一个关键的生物学和翻译问题，尚未得到解答。该提案针对 在我们的理解的差距，我在PDAC功能使用两个目标。第一个目标集中在Ia 13上校是否 由PDAC细胞产生的同源三聚体可以在完整和/或非完整的PDAC存在下激活或抑制DDR 1信号传导。 裂解的Col I异源三聚体。第二个目的是确定表达Col Ia 13和Col Ia 1-null的PDAC细胞如何 响应于含有可裂解和不可裂解的Col I异源三聚体的ECM。解读机械论 在PDAC ECM中鉴定的Col I亚型之间的相互作用是设计成功基质的关键步骤， 针对胰腺癌的治疗