Metabolic determinants of metastatic heterogeneity: quantitative experiments and mathematical models

项目概要/摘要 确定器官特异性转移的原因至关重要；如果没有这些知识， 转移性癌症进展的预防和及时治疗可能仍然有限。拟议的 该项目旨在确定原发肿瘤的代谢梯度如何维持不同的谱系 特定的代谢适应，以及这些适应如何促进乳腺器官特异性转移 癌症。中心假设是 1) 代谢适应是种子（种子）之间匹配的关键。 播散性细胞）和转移性乳腺癌中的土壤（远端部位），2）代谢 原发肿瘤中的微环境驱动代谢多样化的亚群。假设已 制定基于 1) 已发表的详细描述代谢异质性的数据，并且代谢适应可以 促进转移，2）RNA表达、代谢组学和通量的初步数据和分析 测量结果揭示了不同组织的乳腺肿瘤细胞的不同代谢适应， 3) 初步数据显示转移谱系对缺氧和营养梯度的反应不同， 表明代谢微环境在维持同一体内不同亚群中的作用 原发肿瘤异质性。 所提出的目标将通过实验和计算的结合来实现 生物学。转移谱系的综合通量平衡模型将识别受干扰的代谢途径 每个血统。敲低或过度表达这些途径中的关键节点并评估体内趋向性 将决定代谢适应在器官特异性转移选择中的作用。的能力 原发肿瘤中的自发营养梯度影响具有不同谱系的空间分离 将使用定制的 MEMIC 组织模拟板来研究代谢适应。数学模型 将用于研究细胞系与其微环境之间的生态相互作用，从而导致 原发肿瘤中代谢不同的转移前亚群共存。 Joao Xavier 将为该项目和候选人的职业目标提供出色的指导 领导一个独立的研究项目，结合实践教学和自由 独立发现。当前的项目将为候选人未来的独立奠定基础 研究。培训计划还包括与共同发起人和合作者的会议，以促进 全面的教育并确保项目成功的可能性很高。环境位于 MSKCC 提供了对于完成拟议项目以及职业发展非常重要的进一步资源 当候选人过渡到独立职业时提供发展支持。

Project Summary/Abstract It is critically important to establish the causes of organ-specific metastasis; without this knowledge, prevention and timely treatment of metastatic cancer progression will likely remain limited. The proposed project aims to identify how metabolic gradients in the primary tumor can maintain diverse lineages with specific metabolic adaptations, and how these adaptations contribute to organ-specific metastasis in breast cancer. The central hypothesis is 1) that metabolic adaptations are key to the match between the seed (the disseminated cell) and the soil (the distal site) in metastatic breast cancer, and 2) that the metabolic microenvironment in a primary tumor drives metabolically diverse subpopulations. The hypothesis has been formulated based on 1) published data detailing metabolic heterogeneity and that metabolic adaptations can promote metastasis, 2) preliminary data and analysis of RNA expression, metabolomics, and flux measurements, revealing different metabolic adaptations in breast tumor cells that home to different tissues, and 3) preliminary data showing that metastatic lineages respond differently to hypoxia and nutrient gradients, indicating a role for the metabolic microenvironment in maintaining diverse subpopulations within the same heterogeneous primary tumor. The proposed aims will be accomplished using a combination of experimental and computational biology. Integrated flux balance models of metastatic lineages will identify perturbed metabolic pathways in each lineage. Knocking down or overexpressing key nodes in these pathways and assessing tropism in vivo will determine the role of metabolic adaptations in organ-specific metastatic selection. The ability of spontaneous nutrient gradients in the primary tumor to affect spatial segregation of lineages with distinct metabolic adaptations will be investigated using custom MEMIC tissue mimetic plates. Mathematical models will be used to study the ecological interactions between cell lines and their microenvironment that lead to coexistence of metabolically distinct pre-metastatic subpopulations in the primary tumor. Joao Xavier will provide excellent mentorship for this project and the candidate’s career goals of leading an independent research program, with a combination of hands-on teaching and freedom for independent discovery. The current project will form the foundation of the candidate’s future independent research. The training plan also includes meetings with a co-sponsor and collaborators, facilitating a comprehensive education and ensuring a high probability of success for the project. The environment at MSKCC provides further resources important for the completion of the proposed project, as well as career development support as the candidate transitions to an independent career.