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

MECHANOMETMOT：了解肿瘤传播过程中机械传感和代谢重编程之间的串扰

• 批准号: EP/X033392/1
• 负责人: Vittoria Graziani
• 金额: $ 24.26万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX033392%2F1
• 关键词: MECHANOMETMOT; Understanding; crosstalk; between; mechano

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.

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扩散的基础，而癌细胞与周围细胞外基质 (ECM) 之间的相互作用则引导这些过程。迁移的癌细胞感知物理线索并将其转化为细胞内信号，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。我假设外部物理力会导致代谢适应，以实现最佳的 3D 迁移和成功转移。在本提案中，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 胶原基质中失调的代谢途径。该项目有三个目标：1。揭示侵袭性癌细胞发现其弱点的关键代谢途径；2．了解这些细胞如何响应 3D 矩阵的物理化学变化来改变侵入性特征和代谢，模拟人体组织和/或疾病阶段的 ECM；3.研究肿瘤侵袭前沿和转移病灶中促侵袭酶/代谢转录调节因子和机械传感器的表达变化。最终目标是揭示控制癌症侵袭性的特定代谢途径，这可能为专门针对转移细胞的新疗法铺平道路。