Project 3: The role of microenvironmental metabolites on metastatic progression

项目摘要 代谢程序在转移过程中特别相关，因为它是一个低效的过程，包括几个代谢程序。 在一个实施方案中，该方法包括连续步骤，其中仅小比例的循环肿瘤细胞产生转移性病变。的 低效率主要归因于宿主器官环境，其对癌症施加代谢限制 细胞事实上，由于肿瘤细胞的生长，癌细胞经常在远处器官环境中缺乏营养和氧气。 血管系统不好为了在转移级联过程中耐受不利的营养条件， 细胞需要大量的代谢重组，使它们能够在原发和转移部位生长。 此外，癌细胞在代谢上相互作用，并与正常细胞类型或上调 替代途径来克服环境中的这些代谢限制。养分整合 癌细胞中具有代谢适应特征的局部环境的可用性是关键， 了解癌细胞如何与周围细胞和细胞外营养物质相互作用。此外如 癌细胞在新器官部位的重新增殖为有效的抗肿瘤治疗带来了挑战 尽管有这些策略，但有一个未得到满足的基本和临床需求，即更好地了解这些策略之间的分子相互作用。 转移部位和肿瘤细胞。因此，在本提案中，我们将检验远距离器官部位 从而施加癌细胞需要克服以进行转移性定殖的代谢限制。为了解决这一问题， 我们将采用一种全面的无偏见的方法，结合多种遗传，转录组学和 代谢组学技术。这些方法将使我们能够剖析癌症的代谢异质性 细胞和其他类型的细胞在遥远的器官网站。在第一个目标中，我们将系统地绘制代谢图， 使用基于CRISPR的损失和获得的乳腺癌细胞在肺和肝定植期间的依赖性 功能的方法。在我们的初步工作中，我们已经确定了参与的潜在候选人 乳腺癌转移到肺部在第二个目标中，我们将研究小生境细胞的作用， 细胞特异性代谢组学和单细胞测序方法在多种转移模型中的应用 接受治疗Birsoy实验室最近率先使用以代谢为重点的CRISPR筛选来研究 癌症模型中细胞代谢的多个方面。Cao和Saeed Tavazoie实验室在以下方面拥有专业知识： 单细胞转录组学和计算生物学。通过整合基因表达谱和代谢组学 通过这种多学科合作努力产生的信息，我们的工作将为识别 在转移性定植过程中以及在对转移性定植的反应中可能被激活或抑制的途径。 疗法

Project Summary Metabolic programs are particularly relevant during metastasis as it is an inefficient process comprising several consecutive steps, with only a small proportion of circulating tumor cells generating a metastatic lesion. The inefficiency is largely attributable to the host organ environments, which impose metabolic limitations on cancer cells. Indeed, cancer cells are frequently starved for nutrients and oxygen in distant organ environments due to poor vasculature. To endure unfavorable nutrient conditions during the metastatic cascade, disseminated tumor cells require substantial metabolic rewiring that enables them to grow at the primary and metastatic sites. Additionally, cancer cells metabolically interact with each other and with normal cell types or upregulate alternative pathways to overcome these metabolic limitations in their environment. Integration of nutrient availability from the local environment with metabolic adaptation signatures in cancer cells is key to understanding how cancer cells interact with the surrounding cells and extracellular nutrients. Furthermore, as re-population of cancer cells at a new organ site creates challenges for effective anti-tumor therapeutic strategies, there is an unmet basic and clinical need to better understand the molecular interplay between the metastatic site and tumor cells. Therefore, in this proposal, we will test the hypothesis that distant organ sites impose metabolic restrictions that cancer cells need to overcome for metastatic colonization. To address this, we will employ a comprehensive unbiased approach that combines multiple genetic, transcriptomic and metabolomics techniques. These approaches will enable us to dissect the metabolic heterogeneity of cancer cells and other cell types in distant organ sites. In the first aim, we will systematically map metabolic dependencies of breast cancer cells during colonization of the lung and liver using CRISPR-based loss and gain of function approaches. In our preliminary work, we have already identified potential candidates that are involved in breast cancer metastasis to lung. In the second aim, we will investigate the role of niche cells by combining cell-specific metabolomics and single-cell sequencing approaches in multiple metastasis models and in response to therapy. The Birsoy lab has recently pioneered the use of metabolism focused CRISPR screens to study multiple aspects of cellular metabolism in cancer models. The Cao and Saeed Tavazoie labs have expertise in single cell transcriptomics and computational biology. By integrating gene expression profiles and metabolomic information generated by this collaborative multidisciplinary effort, our work will provide entry points for identifying pathways that may be activated or repressed during the course of metastatic colonization and in response to therapy.