The non-canonical Collagen I-DDR1 signaling regulating protein synthesis during metastasis

非经典胶原蛋白 I-DDR1 信号在转移过程中调节蛋白质合成

基本信息

批准号：
10607947
负责人：
Mark E. Alonzo
金额：
$ 4.13万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-12-22 至 2026-12-21
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607947
关键词：
5&apos -AMP-activated protein kinase Affect Anoikis Binding Biological Bladder Neoplasm C-terminal Cancer Model Cancer Patient Cell Death Cell Nucleus Cell Survival Cell physiology Cells Clinical Collagen Collagen Receptors Deposition Down-Regulation EEF1A1 gene Elongation Factor Energy Metabolism Energy consumption Environment Extracellular Matrix Extravasation Goals Human Hypoxia Invaded Knowledge Malignant neoplasm of urinary bladder Mediating Metabolic Metastatic Neoplasm to the Lung Modeling Neoplasm Metastasis Nuclear Translocation Nutrient Oxygen Pathway interactions Pilot Projects Predisposition Primary Neoplasm Process Production Prognosis Promoter Regions Protein Biosynthesis Proteins Publishing Receptor Signaling Regulation Reporting Research Resistance Role Signal Transduction Testing Translational Regulation Translations Tumor Cell Invasion Tumor stage cancer cell deprivation detection of nutrient discoidin domain receptor 1 in vivo insight lung colonization lung metastatic metastatic process neoplastic cell nutrient deprivation overexpression pharmacologic protein expression response success tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY The activation of signaling tumor cells via the tumor micrenvironment (TME) to undergo metastasis in bladder cancer is understudied. Clinically, increased Col I deposition correlates with bladder cancer progression (i.e. increasing tumor stage). Our published study demonstrated that Col I induces bladder tumor cells to invade and colonize the lung through Discoidin Domain Receptor 1 (DDR1) pathway. Yet, increase Col deposition is known to cause nutrient deprivation which is unsustainable for tumor growth. Tumors can adapt to these increasingly harsh environment by downregulating protein synthesis – a metabolically expensive homeostatic process. Interestingly, this downregulation of protein synthesis has also been shown to promote resistance to anoikis, cell death resulting from extracellular matrix detachment, which cancer cells must overcome when they undergo metastasis. To our knowledge, whether collagen outside-in signaling senses nutrient deprivation and thereafter reduces energy expenditure by attentuating protein synthesis has yet to be investigated. Interestingly, my pilot studies show two independent, yet complementary non-canonical mechanisms of downregulating protein synthesis, which involves Col I-DDR1 interaction. I now propose to 1) interrogate these two mechanisms that downregulate protein synthesis and 2) how this Col I-DDR1 mediated downregulation of protein synthesis affects the efficiency of cancer metastasis. Knowledge gained from the success of this proposal will yield newer insights on Col I-DDR1 interaction in promoting cancer cell survival and metastasis in bladder cancer.

项目概要通过肿瘤微环境（TME）激活信号肿瘤细胞以进行膀胱转移临床上，Col I 沉积增加与膀胱癌进展相关（即我们发表的研究表明，Col I 诱导膀胱肿瘤细胞侵袭和生长。通过盘状蛋白结构域受体 1 (DDR1) 途径在肺部定植，但已知会增加 Col 沉积。导致肿瘤生长不可持续的营养匮乏，肿瘤可以越来越适应这些。通过下调蛋白质合成（一种代谢昂贵的稳态过程）来应对恶劣的环境。值得注意的是，这种蛋白质合成的下调也被证明可以促进对失巢凋亡、细胞细胞外基质脱离导致的死亡，这是癌细胞在经历细胞外基质脱离时必须克服的问题据我们所知，胶原蛋白由外而内的信号是否能感知营养缺乏及其后的情况。通过减弱蛋白质合成来减少能量消耗尚未得到研究。研究表明下调蛋白质的两种独立但互补的非典型机制合成，其中涉及 Col I-DDR1 相互作用，我现在建议 1）询问这两种机制。下调蛋白质合成以及 2) Col I-DDR1 介导的蛋白质合成下调如何影响从该提案的成功中获得的知识将产生新的见解。 Col I-DDR1 相互作用促进膀胱癌癌细胞存活和转移的研究。