Identifying and Targeting STAT3 Tumor-Initiating Cells in Triple-Negative Breast Cancer

项目摘要 乳腺癌是一种异质性疾病，这在一定程度上解释了预后，治疗反应， 和患者之间的转移。乳腺癌分为组织学亚型（ESR 1 +;PGR+/-，HER 2+， 和“三阴性”（TNBC）），其是预后性的，并预测对激素和HER 2靶向药物的反应性。 治疗在这些亚型中，TNBC与更差的预后相关，并且缺乏靶向治疗。的 TNBC的致命性主要归因于其侵袭性和对传统疗法的抗性，特别是 作为转移。TNBC显示出显著的肿瘤间和肿瘤内异质性，表型和 单个肿瘤内存在的分子上不同的肿瘤细胞亚群。一种罕见的细胞亚群 对化疗和靶向治疗具有内在抗性的细胞被称为肿瘤起始细胞（TIC）（a.k.a.癌 干细胞）。TIC具有自我更新和重演克隆来源的细胞层级的能力， 产生新的肿瘤。转移起始细胞（MIC），被认为是来源于TIC，具有类似的 这些细胞具有TIC的表型特性，但也能够在远处部位接种肿瘤。目前的化疗 靶向病灶的大部分，但在许多情况下，不能有效消除导致转移复发的TIC 在初次治疗后几年。细胞表面标志物和信号报告分子已被用于研究TIC。 然而，这些标记物既不是TIC所特有的，也不是表型稳定的，并且没有建立的方法 追踪TIC的细胞状态变化。因此，研究TIC一直是一个重要的 挑战.为了解决这个问题，我们开发了一种新的他莫昔芬诱导型，Cre重组酶依赖型， STAT 3信号传导特异性慢病毒谱系追踪（LT）系统将使我们能够识别原发性肿瘤中的TIC， 以探测他们的行为和表型，并确定候选人的遗传弱点。中央 该提议的假设是，在一些TNBC肿瘤中的STAT 3信号转导TIC的子集代表了 MIC具有独特的转录程序，可以靶向消除TIC， 改善对化疗反应。在目标1中，我们将阐明STAT 3信号转导TIC是否代表 MIC人口。在目标2中，我们将确定原发性肿瘤中STAT 3信号转导TIC是否表达不同的STAT 3信号转导途径。 这些基因可以被靶向以防止肿瘤进展。这一提案的结果将产生积极影响 因为它将揭示STAT 3信号TIC在转移中的作用，并识别遗传脆弱性 可以靶向消除TIC并改善化疗反应。查明新 消除TIC群体的治疗靶标可以改善TNBC患者的临床结果。

PROJECT SUMMARY Breast cancer is a heterogeneous disease, which partly explains differences in prognosis, treatment response, and metastasis between patients. Breast cancer is classified into histological subtypes (ESR1+;PGR+/-, HER2+, and “triple-negative” (TNBC)), which are prognostic and predict responsiveness to hormonal and HER2-targeted therapies. Of these subtypes, TNBC is associated with a worse prognosis and lacks a targeted therapy. The lethality of TNBC is largely attributed to its aggressiveness and to resistance to traditional therapeutics, especially as metastases. TNBC show substantial inter- and intratumoral heterogeneity, with phenotypically and molecularly distinct tumor cell subpopulations existing within a single tumor. A rare subpopulation of cells known to have intrinsic resistance to chemo- and targeted therapies are called tumor-initiating cells (TICs) (a.k.a. cancer stem cells). TICs have the ability to self-renew and recapitulate clonally-derived cellular hierarchies upon generation of a new tumor. Metastasis-initiating cells (MICs), thought to be derived from TICs, possess similar phenotypic properties to TICs, but are also capable of seeding tumors at distant sites. Current chemotherapies target the bulk of a lesion, but in many cases, do not effectively eliminate TICs resulting in metastatic recurrence years after initial treatment. Cell surface markers and signaling reporters have been used to study TICs. However, such markers are neither unique to TICs nor phenotypically stable, and there is no established method to lineage trace TICs as they undergo cell state changes. As a result, studying TICs has been a significant challenge. To address this issue, we have developed a novel Tamoxifen-inducible, Cre recombinase-dependent, STAT3 signaling-specific lentiviral lineage-tracing (LT) system that will allow us to identify TICs in primary tumors, to probe their behaviors and phenotypes, and to identify candidate genetic vulnerabilities. The central hypothesis of this proposal is that a subset of STAT3 signaling TICs in some TNBC tumors represent MICs, which possess a distinct transcriptional program that can be targeted to eliminate TICs and improve response to chemotherapy. In Aim 1, we will clarify whether STAT3 signaling TICs represent the MIC population. In Aim 2 we will determine whether STAT3 signaling TICs in the primary tumor express distinct genes that can be targeted to prevent tumor progression. The results of this proposal will have a positive impact on the field as it will uncover the role of STAT3 signaling TICs in metastasis and identify genetic vulnerabilities that may be targeted to eliminate TICs and improve chemotherapy response. The identification of new therapeutic targets that eliminate the TIC population can improve clinical outcomes for TNBC patients.