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

识别和靶向三阴性乳腺癌中的 STAT3 肿瘤起始细胞

• 批准号: 10604782
• 负责人: Eric Philip Souto
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-03 至 2025-12-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604782
• 关键词: Address; Behavior; CRISPR/Cas technology; Cell Line; Cell Proliferation; Cell physiology; Cell surface; Cells; Cellular biology; Classification; Clinical; Confocal Microscopy; Critical Pathways; Development; Disease; Distant; Drug resistance; DsRed; ERBB2 gene; ESR1 gene; Enterobacteria phage P1 Cre recombinase; Epithelium; Excision; Fatty acid glycerol esters; Flow Cytometry; Fluorescence-Activated Cell Sorting; Gene Expression Profile; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Harvest; Histologic; Hormonal; Human; Intraperitoneal Injections; Knock-out; Label; Lesion; Malignant Neoplasms; Mammospheres; Mediating; Metastatic/Recurrent; Methods; Modeling; Molecular; Mus; Neoplasm Metastasis; Outcome; Palpable; Pathway interactions; Patients; Phenotype; Play; Population; Primary Neoplasm; Prognosis; Property; Recurrence; Reporter; Resistance; Role; STAT3 gene; Signal Transduction; Site; System; Tamoxifen; Testing; Therapeutic; Transplantation; Tumor Promotion; Work; cancer stem cell; candidate identification; chemotherapy; genetic manipulation; improved; malignant breast neoplasm; mortality; neoplastic cell; new therapeutic target; novel; overexpression; patient derived xenograft model; predict responsiveness; pressure; prevent; prognostic; programs; rare cancer; response; self-renewal; single-cell RNA sequencing; stem cell biology; targeted treatment; treatment response; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor initiation; tumor progression; tumor xenograft

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.

项目概要 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、 以及患者之间的转移。乳腺癌分为组织学亚型（ESR1+；PGR+/-、HER2+、 和“三阴性”(TNBC))，它们具有预后作用并预测对激素和 HER2 靶向药物的反应 疗法。在这些亚型中，TNBC 与较差的预后相关，并且缺乏靶向治疗。这 TNBC 的致死率很大程度上归因于其侵袭性和对传统疗法的抵抗，尤其是 作为转移。 TNBC 显示出显着的瘤间和瘤内异质性，具有表型和 单个肿瘤内存在分子上不同的肿瘤细胞亚群。已知的罕见细胞亚群 对化疗和靶向治疗具有内在抵抗力的细胞称为肿瘤起始细胞 (TIC)（又名癌症） 干细胞）。 TIC 具有自我更新和重现克隆衍生细胞层次结构的能力 新肿瘤的产生。转移起始细胞 (MIC)，被认为源自 TIC，具有相似的功能 TIC 的表型特性，但也能够在远处种植肿瘤。目前的化疗 靶向大部分病灶，但在许多情况下，不能有效消除导致转移复发的 TIC 初次治疗后数年。细胞表面标记物和信号报告基因已被用于研究 TIC。 然而，此类标记物既不是 TIC 独有的，也不是表型稳定的，并且没有既定的方法 当 TIC 经历细胞状态变化时，对它们进行谱系追踪。因此，研究 TIC 已成为一项重要的工作。 挑战。为了解决这个问题，我们开发了一种新型他莫昔芬诱导型、Cre 重组酶依赖性、 STAT3 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， 探究他们的行为和表型，并识别候选基因漏洞。中央 该提议的假设是，某些 TNBC 肿瘤中 STAT3 信号传导 TIC 的一个子集代表 MIC，具有独特的转录程序，可以有针对性地消除 TIC 和 改善对化疗的反应。在目标 1 中，我们将阐明 STAT3 信号传导 TIC 是否代表 MIC 人口。在目标 2 中，我们将确定原发肿瘤中的 STAT3 信号传导 TIC 是否表达不同的 可以靶向预防肿瘤进展的基因。该提案的结果将产生积极影响 它将揭示 STAT3 信号传导 TIC 在转移中的作用并识别遗传脆弱性 可能有针对性地消除 TIC 并改善化疗反应。新的鉴定 消除 TIC 人群的治疗目标可以改善 TNBC 患者的临床结果。