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Targeting the epithelial to mesenchymal transition-mediated chemoresistance in breast cancer

靶向乳腺癌中上皮间质转化介导的化疗耐药性

基本信息

批准号：
9891022
负责人：
Dingcheng Gao
金额：
$ 34.54万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-28 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891022
关键词：
Ablation Address Animal Model Apoptosis Apoptotic Blood Circulation Breast Breast Cancer Treatment Breast Cancer therapy CRISPR library CRISPR screen Cell Proliferation Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Development Distant Drug resistance E-Cadherin Epithelial Epithelium Event Family Fluorescence Future Genes Genetic Genetic Recombination Guide RNA Human IL6 gene Impairment Libraries Mammary Neoplasms Mediating Mesenchymal Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Mouse Mammary Tumor Virus Neoplasm Metastasis Organ Paracrine Communication Pathway interactions Patient-derived xenograft models of breast cancer Pharmacology Phenotype Pre-Clinical Model Primary Neoplasm Process Regimen Resistance Resistance development Series Snails System Therapeutic Transcription Repressor Transgenic Model Transitional Cell Transitional Cell Neoplasm Tumor Cell Invasion autocrine base cadherin 8 cancer therapy chemotherapy design differential expression drug development drug metabolism epithelial to mesenchymal transition improved in vivo malignant breast neoplasm neoplastic cell new therapeutic target novel overexpression paracrine pre-clinical programs public health relevance screening slug stemness transcription factor transcriptome transdifferentiation tumor progression

项目摘要

DESCRIPTION (provided by applicant) Despite significant advances in the treatment, development of resistance to conventional chemotherapy remains an unresolved problem. Consequently an in-depth understanding of the mechanisms underlying the development of chemoresistance is of utmost importance for improving the therapeutic regimens. Recent evidence indicates that epithelial to mesenchymal transition (EMT), the transdifferentiation program involved in tumor invasion and metastasis, may also contribute to chemoresistance. However, the importance of EMT in vivo is fiercely debated due to the inability of tracking EMT events during tumor progression. To solve this critical issue, we have established a novel EMT lineage tracing system in breast cancer by combining multiple transgenic models (MMTV-PyMT/Fsp1-Cre/Rosa26-GRFP). In this model, mesenchymal- specific Cre-mediated recombination initiates a permanent switch of fluorescent markers in tumor cells undergoing EMT, which enable us to track the EMT tumor cells throughout the breast tumor progression. The initial studies with this model found that within a predominantly epithelial primary tumor, a small portion (approx. 2%) of tumor cells underwent EMT. Strikingly, these EMT cells did not give rise to metastasis as the metastases were mainly comprised of non-EMT tumor cells (no fluorescence switch). Importantly, we discovered that EMT tumor cells significantly contributed to lung metastasis after chemotherapy. The EMT tumor cells survived chemotherapy due to reduced proliferation, apoptotic tolerance, and elevated expression of chemoresistance- related genes. Inhibiting EMT by overexpressing miR-200 family abrogated this resistance. These results provide direct evidence of EMT in chemoresistance and open the window to investigate EMT-targeting strategies as a means to overcome chemoresistance in breast cancer. In this proposal, we will take advantage of the EMT lineage tracing model, to further investigate a series of rationally guided anti-EMT approaches such as targeting EMT-induced autocrine/paracrine signals (Aim 1) and EMT-promoting transcription factors (Aim 2). We will use both genetic and pharmacological approaches to evaluate their importance in EMT-mediated chemoresistance. Moreover, based on our preliminary transcriptome analysis we will generate a CRISPR gRNA library targeting the differentially expressed genes in EMT tumor cells. The EMT lineage tracing model will provides a unique platform for the CRISPR screen to identify novel therapeutic targets for the EMT-mediated chemoresistance (Aim 3). At the end, we will validate our findings in human breast cancer and evaluate efficacy of combination therapies in a series of metastatic breast cancer patient-derived xenograft (PDX) models (Aim 4). We envision that this mechanism-based targeting of EMT- mediated chemoresistance will constitute feasible strategies for breast cancer therapy.