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.

项目总结