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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要代谢程序在转移过程中尤其重要，因为这是一个低效的过程，包括多个过程连续步骤，只有一小部分循环肿瘤细胞产生转移性病变。这低效率很大程度上归因于宿主器官环境，这对癌症施加了代谢限制细胞。事实上，由于以下原因，癌细胞经常在远处器官环境中缺乏营养和氧气：脉管系统不良。为了在转移级联、播散性肿瘤过程中忍受不利的营养条件细胞需要大量的代谢重新布线，使它们能够在原发部位和转移部位生长。此外，癌细胞之间以及与正常细胞类型的代谢相互作用或上调克服环境中这些代谢限制的替代途径。营养整合局部环境中具有癌细胞代谢适应特征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繁殖给有效的抗肿瘤治疗带来了挑战策略，有一个未满足的基本和临床需求，以更好地理解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，我们将检验以下假设：远处器官位点施加癌细胞转移定植所需克服的代谢限制。为了解决这个问题，我们将采用综合、公正的方法，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远处器官部位的其他细胞类型。在第一个目标中，我们将系统地绘制代谢图使用基于 CRISPR 的损失和增益研究乳腺癌细胞在肺和肝脏定植过程中的依赖性的函数方法。在我们的前期工作中，我们已经确定了参与的潜在候选人乳腺癌转移至肺部。在第二个目标中，我们将通过结合研究利基细胞的作用多种转移模型和响应中的细胞特异性代谢组学和单细胞测序方法来治疗。 Birsoy 实验室最近率先使用代谢聚焦 CRISPR 筛选进行研究癌症模型中细胞代谢的多个方面。 Cao 和 Saeed Tavazoie 实验室拥有以下方面的专业知识：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协作努力产生的信息，我们的工作将为识别在转移定植过程中可能被激活或抑制的途径以及响应治疗。