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Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape

黑色素瘤进展和治疗逃避中基质微环境的重新编程

基本信息

批准号：
10656454
负责人：
Yuhang Zhang
金额：
$ 35.6万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656454
关键词：
Ablation Acceleration Automobile Driving BRAF gene Biological Process Biology Bypass Cancer Control Cell Line Coin Complex Data Development Drug resistance Extracellular Matrix Fibroblasts Genes Genetic Genetic Transcription Goals Growth Human Immune checkpoint inhibitor In Vitro Knowledge MAP Kinase Gene MEK inhibition MEKs Magic Malignant Neoplasms Mediating Melanoma Cell Metastatic Melanoma Modeling Molecular Molecular Target Mus Nuclear Outcome Pathway interactions Patient-Focused Outcomes Patients Penetration Pharmaceutical Preparations Phenotype Population Proliferating Protein Secretion Proteins Recurrence Recurrent tumor Relapse Research Resistance Role Series Signal Pathway Signal Transduction Stromal Cells TCF7L2 gene Testing Therapeutic Therapeutic Agents Tumor Promotion beta catenin carcinogenesis cell growth cellular targeting design drug resistance development drug-sensitive experimental study improved in vivo inhibitor inhibitor therapy innovation melanoma mouse model multidisciplinary mutant neoplastic cell new therapeutic target novel novel strategies novel therapeutics periostin programs raf Kinases resilience response targeted treatment therapy outcome transcriptome transcriptome sequencing tumor tumor microenvironment

项目摘要

Although the approval of novel targeted therapy drugs, such as BRAF inhibitors (BRAFi), MEK inhibitors (MEKi), and immune checkpoint inhibitors, has revolutionized melanoma treatment, long-term outcomes are still disappointing for many patients because of the development of drug resistance. A major contributing factor to tumor resilience and relapse is the presence of a “plastic” microenvironment, which is comprised of heterogeneous stromal cell populations embedded in a dense and stiff extracellular matrix (ECM). Particularly, the ECM not only functions as a barrier to drug penetration and distribution and also provides structural and adaptive signals, which can induce therapeutic escape pathways in melanoma cells. Genetically stable cancer- associated fibroblasts (CAFs) are known to be a notorious ECM-remodeling machine in the tumor stroma. We have discovered that the number of CAFs with nuclear β-catenin in the melanoma stroma increases significantly after the patients are treated with BRAFi/MEKi. We have established that increased nuclear β-catenin in CAFs is induced by BRAFi but not MEKi. Nevertheless, how BRAFi stimulates CAFs to reprogram their biological functions via hyperactivated nuclear β-catenin activity remains to be understood. We have obtained compelling data demonstrating that targeted depletion of β-catenin in CAFs ablates their ability to remodel the tumor microenvironment, downregulates abnormal BRAF/MAPK/ERK signaling in melanoma cells, and suppresses melanoma cell drug resistance in vitro and in vivo. RNA-Seq data show that β-catenin is essential for CAF to remodel the ECM by coining the CAF transcriptome. We have identified the β-catenin/TCF4 target gene periostin (POSTN) as an important matricellular protein secreted by CAFs to promote BRAFi resistance. The central hypothesis is that decoding and targeting the ECM-remodeling CAFs has the potential to create a drug-sensitive microenvironment that sensitizes melanoma cells to therapeutic agents and increase their response rate. In Aim 1, we will elucidate the pro-activation pathway(s) by which BRAFi stimulates CAFs to mediate melanoma drug resistance phenotypes. We will assess the role of hyperactivated nuclear β-catenin in the function of CAFs in melanoma. In Aim 2, we will determine whether the β-catenin-TCF4 transcriptional complex is the signaling hub that controls CAF-driven ECM remodeling and BRAFi/MEKi resistance. We will evaluate whether disrupting the β-catenin-TCF4 interaction in CAFs will sensitize BRAF-mutant melanoma cells to BRAFi/MEKi in vivo. In Aim 3, we will determine the roles of CAF-derived POSTN in melanoma cell growth and resistance to BRAFi/MEKi. We will investigate signaling pathways that are activated by POSTN in melanoma cells to promote their proliferation and resistance to BRAFi. The expected outcomes are to be an in-depth mechanistic characterization of the complex interactions among CAFs, BRAFi, and the ECM microenvironment that promote the growth and drug resistance in BRAF-mutant melanoma cells. The knowledge obtained will open the possibility of developing a “magic bullet” that could destroy the tumor niche to improve targeted therapy and optimize patient outcomes.

尽管新的靶向治疗药物，如BRAF抑制剂（BRAFi）， MEK抑制剂（MEKi），