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.

抽象的 该申请是为了响应特殊利益通知（NOSI）而提交 23-045。胰腺导管腺癌（PDAC）占胰腺恶性肿瘤的90％以上，IS 美国癌症死亡率的第三个主要原因。阐明这种恶性癌的生物学 仍然是改善患者预后的关键。 PDAC的特征是复杂的脱肿瘤基质 主要由成纤维细胞和细胞外基质（ECM）组成，可以限制或促进 肿瘤进展。 1型胶原蛋白（Col I），通常是由两个A1和一个A2链组成的异构体 在PDAC相关的基质中发现的主要ECM蛋白，近年来已被证明可以发挥作用 通过盘状结构域控制肿瘤生长，进展和对治疗的反应中的重要作用 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 ECM中的不溶性和完整的Col I原纤维被基质金属蛋白酶（MMP）裂解以形成可溶性¼ 和¾col I碎片。与完整的Col I原纤维不同，它会诱导DDR1降解并抑制DDR1的下游 效果，¾col 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。但是，卡卢里实验室发现PDAC癌 细胞表观遗传沉默Col1a2基因产生少量抗MMP的COL1A1同构鉴定 与通常由癌症相关的成纤维细胞产生的异质三合一的三个A1链组成 （CAF）在PDAC基质中。同型聚合物通过改变肿瘤微生物组改变免疫景观 并通过A3B1整合素受体介导的致癌蛋白受体以自分泌方式刺激肿瘤生长 信号。构成PDAC ECM大部分的分裂和完整的Col I异三聚体的效果 并通过DDR1对癌细胞生长的Col I同颗粒调制通过A3B1整合素进行起作用，反之亦然 是一个尚未回答的关键生物学和翻译问题。该提议解决了 使用两个目标，我们对PDAC中Col I功能的理解差距。第一个目的重点是IA13上校 PDAC细胞产生的同构元在完整和/或存在的情况下会激活或抑制DDR1信号传导 裂解Col I异三聚体。第二个目标决定了Col IA13如何表达和Col Ia1-null PDAC细胞 破译机械 PDAC ECM中确定的Col I子类型之间的相互作用是设计成功的基质 - 靶向胰腺癌的治疗方法。