MECHANOMETMOT: Understanding the crosstalk between mechano-sensing and metabolic reprogramming during tumour dissemination

转移是大多数癌症死亡的原因。异常的细胞迁移和侵袭是转移性播散的基础，而癌细胞与周围细胞外基质（ECM）之间的相互作用指导这些过程。迁移的癌细胞感知并将物理线索转化为细胞内信号，从而引发基因表达的变化。这些线索也可以改变细胞的新陈代谢。然而，ECM信号如何被细胞骨架整合并转化为细胞迁移所需的代谢变化尚不清楚。我推测，外部物理力量导致代谢适应最佳的三维（3D）迁移和成功转移。在这项提案中，我将采取高度创新和多学科的方法，结合生物化学，分子和细胞生物学，基于NMR/MS的代谢组学和数字病理学。我将对癌细胞进行广泛的基于NMR/MS的代谢组学和脂质组学分析，以揭示癌细胞生长和侵入3D胶原基质时失调的代谢途径。揭示代谢途径的关键侵略性癌细胞找到他们的弱点;2.了解这些细胞如何响应于模拟人体组织和/或疾病阶段的ECM的3D基质的物理化学变化来改变侵袭性特征和代谢;3.研究促侵袭酶/代谢转录调节因子和机械转换器在肿瘤侵袭前沿和转移病灶中的表达改变，最终目标是揭示控制癌症侵袭的特定代谢途径，这可能为特异性靶向转移细胞的新治疗铺平道路。

Metastasis is responsible for most cancer deaths. Abnormal cell migration and invasion underlie metastatic dissemination while interactions between cancer cells and the surrounding extracellular matrix (ECM) guide these processes. Migrating cancer cells sense and translate physical clues into intracellular signals, which trigger changes in gene expression. Such cues can also alter cellular metabolism. Nevertheless, how ECM signals are integrated by the cytoskeleton and translated into metabolic changes needed for cell migration is unclear. I hypothesize that external physical forces lead to metabolic adaptations for optimal 3Dimensional (3D) migration and successful metastasis. In this proposal, I will undertake a highly innovative and multidisciplinary approach, combining biochemistry, molecular and cellular biology, NMR/MS-based metabolomics and digital pathology. I will perform extensive NMR/MS- based metabolomics and lipidomics analyses of cancer cells to uncover metabolic pathways that are dysregulated in cancer cells growing and invading into 3D collagen matrices.This project has three aims:1. to uncover metabolic pathways key for aggressive cancer cells to find their vulnerabilities;2. to understand how these cells modify invasive traits and metabolism in response to physicochemical changes of the 3D matrices, which mimic ECM of human tissues and/or disease stages;3. to investigate altered expression of pro-invasive enzymes/transcriptional regulators of metabolism and mechano- transducers in the invasive fronts of tumours and in the metastatic lesions.The ultimate goal is to reveal specific metabolic pathways controlling cancer invasiveness, which may pave the way for novel treatments that target specifically metastatic cells.