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

项目总结 肿瘤微环境(TME)对膀胱肿瘤细胞转移信号的激活作用 对癌症的研究还不够深入。在临床上，Col I沉积增加与膀胱癌的进展有关(即 肿瘤分期增加)。我们发表的研究表明，I型胶原诱导膀胱肿瘤细胞侵袭和 通过盘状结构域受体1(DDR1)途径在肺中定植。然而，增加的钴沉积是已知的 导致营养匮乏，这对肿瘤的生长是不可持续的。肿瘤可以不断适应这些变化 通过下调蛋白质合成来降低恶劣环境--这是一种代谢代价高昂的动态平衡过程。 有趣的是，这种蛋白质合成的下调也被证明可以提高对失巢细胞的抵抗力。 由细胞外基质脱落引起的死亡，癌细胞在经历 转移。据我们所知，胶原蛋白由外向内的信号是否感觉营养缺乏以及此后 通过关注蛋白质合成来降低能量消耗还有待研究。有趣的是，我的飞行员 研究表明，蛋白质下调有两种独立但互补的非规范机制 合成，这涉及到Col I-DDR1相互作用。我现在提议审问这两种机制： 下调蛋白质合成和2)这种Col I-DDR1介导的蛋白质合成下调如何影响 肿瘤转移的效率。从这项提议的成功中获得的知识将产生更新的见解 Col I-DDR1相互作用促进膀胱癌细胞存活和转移的研究

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.