The action of DDR2 in cancer-associated fibroblasts promotes ovarian cancer metastasis through increased arginase-1 activity.

DDR2 在癌症相关成纤维细胞中的作用通过增加精氨酸酶 1 活性促进卵巢癌转移。

• 批准号: 10606021
• 负责人: Favour Ayomide Akinjiyan
• 金额: $ 3.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606021
• 关键词: Abdomen; Anabolism; Architecture; Arginine; Biological Assay; Cancer Patient; Cell Proliferation; Cells; Chemoresistance; Collagen; Data; Deposition; Development; Diffusion; Environment; Enzymes; Extracellular Matrix; Female Genital Diseases; Fibrillar Collagen; Fibroblasts; Future; Greater sac of peritoneum; Growth; Human; In Vitro; Knock-out; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Manuscripts; Mass Spectrum Analysis; Mediating; Mesenchymal; Mesothelial Cell; Mesothelium; Metabolic; Molecular; Mus; Neoplasm Metastasis; Omentum; Organ; Ornithine; Ornithine Decarboxylase; Ovarian; Pattern; Peritoneal; Physicians; Play; Polyamines; Production; Proline; Receptor Protein-Tyrosine Kinases; Regulation; Role; Scientist; Serous; Source; Stage at Diagnosis; Stromal Cells; Stromal Neoplasm; Testing; Therapeutic Intervention; Training; Tumor Burden; Tumor Cell Invasion; arginase; cancer cell; discoidin domain receptor 2; in vivo; intraperitoneal; mRNA sequencing; malignant breast neoplasm; metastatic process; mouse model; neoplastic cell; novel; novel therapeutics; ovarian neoplasm; overexpression; paracrine; receptor binding; response; small hairpin RNA; therapeutic development; treatment response; tumor; tumor growth; tumor microenvironment

SPECIFIC AIMS Ovarian cancer is the most lethal gynecological disease. 70-80% of ovarian cancer patients are diagnosed at stage III or IV when peritoneal metastasis has already occurred. The unique metastasis pattern in ovarian cancer involves the detachment of tumor cells, diffusion through the intraperitoneal space and attachment to the mesothelial layer lining the omentum and abdominal organs. Both increased collagen deposition and extracellular matrix (ECM) stiffening (due to altered collagen architecture) by stromal cells can create a pro- metastatic environment. Paracrine action of tumor growth-inducing molecules like polyamines can also promote metastasis. Identifying mechanisms that underlie collagen deposition and polyamine synthesis will allow better understanding of metastasis and thus further development of therapeutic interventions. One putative candidate for regulating metastasis is the fibrillar collagen-binding receptor tyrosine kinase Discoidin Domain Receptor-2 (DDR2). DDR2 expression is increased in the stroma of high grade serous ovarian cancer (HGSOC) patients and this increase is, alone, associated with shorter survival and worse response to therapy. We found that there were fewer intraperitoneal tumors when DDR2-expressing tumor cells were injected into the peritoneal cavity of syngeneic Ddr2-/- mice vs WT mice. To understand molecular reasons for this difference I performed targeted mRNA sequencing of tumors from Ddr2 WT and Ddr2-/- mice and found that expression of Arginase-1 was highly down-regulated in tumors from Ddr2-/- mice. Moreover, I found that shRNA depletion of DDR2 in WT ovarian omental cancer-associated fibroblasts also significantly decreased Arginase- 1 expression and activity. A major metabolic function of Arginase-I in cells is to promote arginine degradation into ornithine, which is a source of proline for collagen synthesis and polyamines that can impact cellular proliferation. Based upon these, and other, compelling preliminary data I propose to test the hypothesis: DDR2-regulated Arginase-1 expression in ovarian cancer omental CAFs promotes metastasis by impacting collagen production and ECM organization as well as polyamine synthesis. I will test this hypothesis by pursuing two specific aims: Aim 1: Determine the role of intracellular Arginase-1 in omental cancer-associated fibroblasts on collagen synthesis and architecture. Aim 2: Determine the role of intracellular Arginase-1 on polyamine-mediated tumor cell metastasis. These studies will uncover novel mechanisms by which DDR2 regulates arginase-1 in omental CAFs and how arginase-1 promotes metastasis through increased collagen deposition and polyamine synthesis. As DDR2 has been implicated in lung, pancreatic, and breast cancer, my findings may have broad implications in other cancers. This project will encourage my scientific growth as a physician scientist-in-training.

具体目标 卵巢癌是最致命的妇科疾病。70%-80%的卵巢癌患者是在 已经发生腹膜转移的III期或IV期。卵巢癌独特的转移方式 包括肿瘤细胞的分离，通过腹膜腔扩散并附着于 间皮层衬里于大网膜和腹部器官。都增加了胶原沉积和 基质细胞使细胞外基质(ECM)变硬(由于胶原结构改变)可以产生有利于 转移环境。多胺等肿瘤生长诱导分子的旁分泌作用也可以促进 转移。识别胶原沉积和多胺合成的基础机制将允许更好的 了解转移情况，从而进一步发展治疗干预措施。 纤维状胶原结合受体酪氨酸激酶可能是调节肿瘤转移的候选基因之一。 盘状结构域受体-2(DDR2)。DDR2在高级别浆液性卵巢间质中的表达增加 癌症(HGSOC)患者，这种增加单独与较短的生存期和较差的反应有关 心理治疗。我们发现，当注射表达DDR2的肿瘤细胞时，腹膜内肿瘤较少 经同基因DDR2-/-小鼠与WT小鼠的腹膜腔注射。要了解这一现象的分子原因 Difference I对DDR2 WT和DDR2-/-小鼠的肿瘤进行了靶向mRNA测序，发现 精氨酸酶-1在DDR2-/-小鼠肿瘤中的表达高度下调。此外，我发现shRNA WT卵巢癌相关成纤维细胞中DDR2的缺失也显著降低了精氨酸酶- 1表达和活性。精氨酸酶-I在细胞中的主要代谢功能是促进精氨酸的降解 转化为鸟氨酸，鸟氨酸是合成胶原蛋白和多胺的一种来源，可以影响细胞 扩散。 基于这些和其他令人信服的初步数据，我建议检验这一假设：DDR2受调控 精氨酸酶-1在卵巢癌大网膜CAF中的表达通过影响胶原生成促进转移 和ECM组织以及多胺的合成。我将通过追求两个具体目标来检验这一假设： 目的1：确定细胞内精氨酸酶-1在大网膜癌相关成纤维细胞中对胶原的作用 综合与建筑。目的2：确定细胞内精氨酸酶-1在多胺介导的肿瘤中的作用 细胞转移。这些研究将揭示DDR2调节大网膜精氨酸酶-1的新机制 以及精氨酸酶-1如何通过增加胶原沉积和多胺合成来促进转移。 由于DDR2与肺癌、胰腺癌和乳腺癌有关，我的发现可能具有广泛的影响。 在其他癌症中。这个项目将鼓励我作为一名正在培训的内科科学家的科学成长。