Intratumoral Heterogeneity and Plasticity in Basal-Like Breast Cancers

项目摘要 三阴性乳腺癌(TNBC)是一种侵袭性、预后差的恶性肿瘤，占10- 全世界20%的乳腺癌病例。肿瘤对化疗的耐药性是患者面临的主要障碍 对于TNBCs，由于TNBCs缺乏传统的可用药靶点，患者主要依赖化疗 治疗选项。肿瘤内的异质性和肿瘤细胞的可塑性被认为是导致对 化疗。基底细胞样乳腺癌(BLBC)是一种分子亚型，约占TNBCs的70%，是 具有高度异质性和遗传多样性的肿瘤细胞的特点。BLBC肿瘤的发病机制 细胞对化疗产生抗药性的情况还知之甚少。我假设肿瘤细胞之间的可塑性 表型状态，特别是基底样和间充质状态，会导致肿瘤对 化疗。 本工作旨在鉴定BLBC亚群间可塑性的遗传调控因素，并验证 无论靶向试剂是阻断还是启动这种可塑性，都会导致肿瘤化疗敏感性的改变。至 为此，我的第一个目标是确定不同细胞亚群的功能和基因组特征 用流式细胞术和单细胞RNA测序(scRNA-seq)检测小鼠和人的肿瘤细胞模型 在活体内。我将使用基因表达和网络分析来确定每种基因可能的调控因素 子群体，并使用CRISPR基因敲除对这些进行经验检验。在第二个目标中，我计划测试 染色质重塑抑制剂能够阻断BLBC肿瘤的EMT，从而增加肿瘤对 化疗。这项工作有望确定潜在的内在和治疗诱导的肿瘤调节因子。 可塑性，这可能对开发改进的治疗方案具有治疗意义 耐化疗的TNBCs。

Project Summary Triple Negative Breast Cancer (TNBC) is an aggressive malignancy with a poor prognosis that accounts for 10- 20% of breast cancer cases worldwide. Tumor resistance to chemotherapy is a major obstacle facing patients with TNBCs, as TNBCs lack conventional druggable targets and patients rely on chemotherapy as the main treatment option. Intra-tumoral heterogeneity and tumor cell plasticity are thought to contribute to resistance to chemotherapy. Basal-like breast cancer (BLBC) is a molecular subtype that makes up ~70% of TNBCs, and is characterized by high heterogeneity and genetically diverse tumor cells. The mechanism by which BLBC tumor cells develop resistance to chemotherapy is poorly understood. I hypothesize that plasticity between tumor cell phenotypic states, specifically basal-like and mesenchymal states, leads to changes in tumor sensitivity to chemotherapy. This work aims to identify the genetic regulators of plasticity between subpopulations of BLBCs and to test whether targeted agents blocking or initiating this plasticity can lead to changes in tumor chemo-sensitivity. To do this, my first aim is to identify the functional and genomic characteristics of distinct cellular subpopulations in BLBCs by flow cytometry and single cell RNA-sequencing (scRNA-seq), using murine and human TNBC models in vivo. I will use gene expression and network analyses to identify possible genetic regulators of each subpopulation, and test these empirically using CRISPR knockouts. In the second aim, I plan to test whether chromatin remodeling inhibitors are able to block EMT in BLBC tumors and thereby increase tumor sensitivity to chemotherapy. This work is expected to identify potential inherent and therapy-induced regulators of tumor plasticity, which could have therapeutic implications in developing improved treatment regimens for patients with chemo-resistant TNBCs.