Project 3: The role of microenvironmental metabolites on metastatic progression

项目3：微环境代谢物对转移进展的作用

• 批准号: 10493343
• 负责人: Kivanc Birsoy
• 金额: $ 31.69万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493343
• 关键词: 4T1; Address; Affinity; Area; Breast; Breast Cancer Cell; Breast cancer metastasis; CRISPR screen; CRISPR/Cas technology; Cancer Model; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colon Carcinoma; Computational Biology; Dependence; Distant; Environment; Enzymes; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Screening; Goals; Knowledge; Liver; Lung; MC38; Maps; Metabolic; Metabolic stress; Metabolism; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Methods; Microscopy; Modeling; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Non-Malignant; Normal Cell; Nutrient; Organ; Organelles; Oxygen; Pathway interactions; Population; Process; Role; Site; System; Techniques; Testing; Therapeutic; Tissues; Work; base; cancer cell; cancer heterogeneity; cell type; epigenome; experience; extracellular; gain of function; genetic approach; in vivo; innovation; loss of function; lung colonization; metabolomics; multi-photon; multidisciplinary; multiple omics; neoplastic cell; photoactivation; programs; single cell sequencing; small molecule; transcriptome; transcriptomics; treatment response; tumor

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.

项目摘要 代谢程序在转移过程中尤其相关，因为它是一个低效的过程，包括几个 连续的步骤，只有一小部分循环中的肿瘤细胞产生转移灶。这个 低效很大程度上归因于宿主器官环境，这对癌症施加了新陈代谢限制。 细胞。事实上，在遥远的器官环境中，癌细胞经常缺乏营养和氧气，原因是 血管系统不好。在转移性级联、播散性肿瘤期间忍受不利的营养条件 细胞需要大量的新陈代谢重新布线，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，并与正常类型的细胞或上调表达 在其环境中克服这些新陈代谢限制的替代途径。营养物质的整合 从当地环境中获得具有代谢适应特征的癌细胞是关键 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，由于 癌细胞在新器官部位的重新聚集给有效的抗肿瘤治疗带来了挑战 策略，有一个尚未得到满足的基本和临床需要，以更好地了解之间的分子相互作用 转移部位和肿瘤细胞。因此，在这个提议中，我们将检验这样一个假设，即遥远的器官位置 施加新陈代谢限制，癌细胞需要克服这些限制才能转移定植。为了解决这个问题， 我们将采用一种全面的、公正的方法，将多种基因、转录和 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。 远端器官部位的细胞和其他类型的细胞。在第一个目标中，我们将系统地绘制代谢图 应用基于CRISPR的丢失和获得研究乳腺癌细胞在肺和肝脏定植期间的依赖性 函数方法的一部分。在我们的初步工作中，我们已经确定了涉及的潜在候选人 在乳腺癌转移到肺中的作用。在第二个目标中，我们将通过结合 细胞特异性代谢组学和单细胞测序方法在多转移模型和反应中的应用 去接受治疗。Birsoy实验室最近率先使用新陈代谢CRISPR筛查进行研究 癌症模型中细胞代谢的多个方面。曹和赛义德·塔瓦佐伊实验室在 单细胞转录学和计算生物学。通过整合基因表达谱和代谢组 由这一多学科协作努力产生的信息，我们的工作将为确定 在转移定植过程中可能被激活或抑制的通路 心理治疗。