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.

项目摘要 乳腺癌是一种异质疾病，部分解释了预后，治疗反应的差异， 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），这是预后的，可以预测对荷尔蒙和her2靶向的反应性 疗法。在这些亚型中，TNBC的预后较差，缺乏靶向疗法。这 TNBC的致死性在很大程度上归因于其侵略性和抵抗传统治疗学，尤其是 作为转移。 TNBC表现出大量的肿瘤间和肿瘤内异质性，具有表型和 单个肿瘤中存在的分子肿瘤细胞亚群。已知细胞的罕见亚群 对化学疗法和靶向疗法具有内在耐药性称为肿瘤发射细胞（TICS）（又称癌症） 干细胞）。抽动具有自我更新和概括克隆衍生的蜂窝等级的能力 产生新的肿瘤。转移性启动细胞（MIC），被认为是源自抽动的，潜在的类似 表型的特性，但也能够在遥远的部位播种肿瘤。当前的化学疗法 靶向大部分病变，但在许多情况下，不能有效消除导致转移性复发 初次治疗后的几年。细胞表面标记和信号记者已用于研究抽动。 但是，这样的标记要么是抽搐独有的，要么在表型上稳定，也没有建立的方法 谱系痕迹在发生细胞状态时会发生变化。结果，研究抽动是重要的 挑战。为了解决这个问题，我们开发了一种新型的他莫昔芬诱导的，CRE重组酶依赖性的， STAT3信号特异性慢病毒谱系追踪（LT）系统，该系统将使我们能够识别原发性肿瘤中的抽动， 探究其行为和表型，并确定候选遗传脆弱性。中央 该提议的假设是某些TNBC肿瘤中的STAT3信号传导TICS的子集代表 MIC，具有独特的转录程序，可以针对消除抽动和 改善对化疗的反应。在AIM 1中，我们将阐明STAT3信号传导是否代表 麦克风人口。在AIM 2中，我们将确定原发性肿瘤中的STAT3信号抽动是否明确 可以针对预防肿瘤进展的基因。该提案的结果将产生积极的影响 在现场，它将揭示STAT3信号抽动在转移中的作用并确定遗传脆弱性 这可能是针对消除抽动和改善化学疗法反应的目标。新的识别 消除TIC种群的治疗靶标可以改善TNBC患者的临床结果。