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

项目总结 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(ESR1；PGR/-，HER2， 和三重阴性(TNBC))，它们可以预测预后并预测对激素和HER2靶向的反应 治疗。在这些亚型中，TNBC预后较差，缺乏靶向治疗。这个 TNBC的致命性在很大程度上归因于它的侵袭性和对传统疗法的耐药性，尤其是 作为转移瘤。TNBC显示出显著的瘤内和瘤内异质性，表型和 单个肿瘤内存在分子上不同的肿瘤细胞亚群。一种罕见的已知细胞亚群 对化疗和靶向治疗具有内在抵抗力的人被称为肿瘤启动细胞(TICS)(又名。癌症 干细胞)。抽搐具有自我更新和概括克隆派生的细胞层次结构的能力 产生一种新的肿瘤。肿瘤转移启动细胞(MICs)，被认为是源于抽搐，具有类似的 抽搐的表型特征，但也能够在远处种植肿瘤。现代化疗方法 靶向病变的大部分，但在许多情况下，并不能有效消除导致转移复发的抽搐 在最初治疗数年后。细胞表面标记物和信号转导已被用于研究抽动。 然而，这样的标记既不是TICS独有的，也不是表型稳定的，也没有既定的方法 在经历细胞状态变化时，对痕迹抽搐进行谱系分析。因此，学习TICS一直是一项重要的 挑战。为了解决这个问题，我们开发了一种新的三苯氧胺可诱导的、依赖Cre重组酶的， STAT3信号特异性慢病毒谱系追踪(LT)系统，将使我们能够识别原发肿瘤中的抽搐， 探索他们的行为和表型，并确定候选的遗传易感性。中环 这一提议的假设是，在一些TNBC肿瘤中，STAT3信号抽动的子集代表 MICS，它拥有一个独特的转录程序，可以有针对性地消除抽搐和 提高对化疗的反应。在目标1中，我们将澄清STAT3信令TIC是否代表 麦克风种群。在目标2中，我们将确定STAT3信号传导通路在原发肿瘤中是否表达不同 可以靶向阻止肿瘤进展的基因。这项提议的结果将产生积极影响 因为它将揭示STAT3信号抽动在转移中的作用并确定遗传脆弱性 这可能是为了消除抽搐和改善化疗反应。新产品的识别 消除TIC人群的治疗目标可以改善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.