Molecular mechanisms regulating LMO2+ metastasis initiating cells

转移仍然是女性乳腺癌患者死亡的主要原因。虽然它是公认的 肿瘤细胞是异质性的，肿瘤内的少数群体具有肿瘤起始和转移性， 尽管这些能力，但人类乳腺癌中转移起始细胞（MIC）的身份仍存在争议。直到 我们可以识别这些细胞并研究调节它们的分子途径， 治疗策略将受到阻碍。本提案的长期目标是了解 外源性分子信号调节MIC。最近，使用乳腺癌单细胞RNA测序数据， 癌症患者样本和复杂的计算方法，我们确定了一个不成熟的人口， 乳腺癌中表达造血干细胞转录衔接子和T细胞癌基因的细胞， LMO2。本提案的目的是确定LMO 2促进转移的分子机制。 我们假设LMO 2+细胞是乳腺癌中的一群MIC，它们响应于 炎症和LMO 2是调节这一过程的关键适配器。我们的假设是基于 结果表明Lmo 2+细胞是转移性的，预测患者的无远处复发存活率差， LMO 2敲低减少多种人类肿瘤模型中的转移，并且LMO 2是STAT 3所需的 IL-6和TNF-α激活。这一建议的基本原理是，α识别信号的 转移中的LMO 2将阐明对治疗干预开放的MIC中的靶点。以强为导 初步数据，我们的建议将1。确定炎症诱导的转移是否需要LMO 2。 2.确定LMO 2-STAT 3轴调控的详细分子信号传导。3.确定LMO 2+是否 细胞利用血管拟态转移。拟议的研究是重要的，因为它将使 设计靶向乳腺癌MIC的治疗策略。以往的研究表明， 的MIC依赖于已建立的谱系标记。这项研究是创新的，因为我们 集中于从单细胞RNA测序中不可知地鉴定的LMO 2 + MIC群体， 乳腺癌患者样本。拟议的研究将大大提高我们对中等收入国家的认识 并为治疗转移性乳腺癌的新策略奠定基础。

Metastasis remains the primary cause of death in women with breast cancer. While it is well established that tumor cells are heterogeneous and minority populations within the tumor have tumor-initiating and metastatic capabilities, the identity of metastasis initiating cells (MICs) in human breast cancer remains controversial. Until we can identify these cells and study the molecular pathways regulating them, the development of new therapeutic strategies will be hindered. The long-term goal of this proposal is to understand the intrinsic and extrinsic molecular signaling regulating MICs. Recently, using single-cell RNA sequencing data from breast cancer patient samples and sophisticated computational approaches we identified an immature population of cells in breast cancer that express hematopoietic stem cell transcriptional adaptor and the T-cell oncogene, LMO2. The objective of this proposal is to determine the molecular mechanism of LMO2 in promoting metastasis. We hypothesize that LMO2+ cells are a population of MICs in breast cancer that are activated in response to inflammation and LMO2 is a key adaptor that regulates this process. Our hypothesis is based on our preliminary results that demonstrate that Lmo2+ cells are metastatic, predict poor distant recurrence-free survival in patients, LMO2 knockdown reduces metastasis in multiple human tumor models, and LMO2 is required for STAT3 activation in response to IL6 and TNFα. The rationale underlying this proposal is that αidentifying the signaling of LMO2 in metastasis will elucidate targets in MICs that are open to therapeutic intervention. Guided by strong preliminary data, our proposal will 1. Determine whether LMO2 is required for inflammation-induced metastasis. 2. Determine the detailed molecular signaling regulated by LMO2-STAT3 axis. 3. Determine whether LMO2+ cells utilize vascular mimicry to metastasize. The proposed research is significant because it will enable the design of therapeutic strategies targeting MICs in breast cancer. Previous research studies on the identification of MICs have relied on established lineage markers. The proposed research is innovative because we are focusing on a population of LMO2+ MICs that were agnostically identified from single-cell RNA sequencing in breast cancer patient samples. The proposed research will substantially enhance our understanding of MICs and lay the foundation for novel strategies to treat metastatic breast cancer.