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

项目摘要 通过肿瘤微转移（TME）激活信号肿瘤细胞进行膀胱转移 癌症研究不足。临床上，增加的Col I沉积与膀胱癌进展相关（即， 增加肿瘤分期）。我们发表的研究表明，Col I诱导膀胱肿瘤细胞侵入， 通过盘状结构域受体1（DDR 1）途径定殖于肺。然而，已知增加的Col沉积 导致营养缺乏，这对肿瘤生长是不可持续的。肿瘤可以越来越多地适应这些 通过下调蛋白质合成-一个代谢昂贵的稳态过程。 有趣的是，这种蛋白质合成的下调也被证明可以促进对失巢凋亡的抵抗，细胞凋亡， 细胞外基质脱落导致的死亡，癌细胞在经历 转移据我们所知，胶原蛋白由外向内信号传导是否感知营养缺乏， 通过减弱蛋白质合成来降低能量消耗的方法还有待研究。有趣的是，我的飞行员 研究表明，两种独立但互补的非经典机制下调蛋白质 合成，其涉及Col I-DDR 1相互作用。我现在建议1）询问这两种机制， 下调蛋白质合成和2）这种Col I-DDR 1介导的蛋白质合成下调如何影响 癌症转移的效率。从这一建议的成功中获得的知识将产生更新的见解 Col I-DDR 1相互作用在膀胱癌中促进癌细胞存活和转移。

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.