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 本申请是为了响应被识别为 NOT-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。 阐明这种恶性癌症的生物学原理。 仍然是改善患者预后的关键 PDAC 的特点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 1 型胶原 (Col I)，通常是由两条 a1 链和一条 a2 链组成的异源三聚体，是肿瘤进展的过程。 PDAC 相关基质中发现的主要 ECM 蛋白，近年来已被证明发挥着重要作用 通过盘状蛋白结构域在调节肿瘤生长、进展和治疗反应中发挥重要作用 Karin 实验室发现受体酪氨酸激酶 1 (DDR1) 和 a3b1 整合素受体信号通路。 ECM 中不溶且完整的 Col I 原纤维被基质金属蛋白酶 (MMP) 裂解，形成可溶性 1/4 和 3/4 Col I 片段不同，Col I 原纤维会诱导 DDR1 降解并抑制 DDR1 的下游。 在效应器中，3/4 Col I 片段与 DDR1 结合，激活其酪氨酸激酶活性并刺激 PDAC 然而，Kalluri 实验室发现 PDAC 癌症。 细胞表观遗传学沉默 COL1A2 基因，产生少量 MMP 抗性 Col1a1 同源三聚体 仅由三个 a1 链组成，与癌症相关成纤维细胞通常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来改变免疫景观。 并通过a3b1整合素受体介导的致癌作用以自分泌方式刺激肿瘤生长 构成 PDAC ECM 大部分的切割和完整 Col I 异源三聚体的作用。 并通过 DDR1 对 Col I 同源三聚体起作用，通过 a3b1 整合素调节癌细胞生长，反之亦然 这是一个尚未得到解答的关键生物学和翻译问题。 我们对 PDAC 中 Col I 功能的理解存在差距，第一个目标集中于 Col Ia13 是否存在。 PDAC 细胞产生的同源三聚体可以在完整和/或存在的情况下激活或抑制 DDR1 信号传导 第二个目标是确定 Col Ia13 表达和 Col Ia1 缺失的 PDAC 细胞的表达方式。 对含有可裂解和不可裂解的 Col I 异源三聚体的 ECM 做出反应 破译机制。 PDAC ECM 中确定的 Col I 亚型之间的相互作用是设计成功基质的关键步骤 胰腺癌的靶向治疗。