Cutaneous melanoma is a highly complex solid tumor that arises from melanocytes located predominantly at the junction of the epidermis and dermis. Despite the advancements in novel targeted and immune therapies are providing hope, there is still a long way to go to find the cure for metastatic melanoma. Tumor cells develop both intrinsic and acquired mechanisms of resistance within a permissive and promotive host microenvironment, which consists of a heterogeneous mix of non-cancer cells, including endothelial cells, immune cells, and fibroblasts, embedded in a tumor-specific extracellular matrix (ECM). Genetically stable fibroblasts that surround and infiltrate the melanoma stroma, often termed as cancer-associated fibroblasts (CAFs), remodel the ECM and secrete chemical factors, which altogether constitute the backbone of a protective ?paradise? that allows a small population of melanoma cells to escape therapy. Nevertheless, how CAFs remodel the microenvironment and induce adaptive responses in melanoma cells to allow them to escape BRAF inhibitor-induced apoptosis via tumor-stroma interactions remain to be understood. The central hypothesis is that improved targeted therapy will only be achieved if microenvironment-derived adaptive signals that promote tumor metastasis and drug resistance can be suppressed. This hypothesis is based on preliminary data demonstrating that targeted ablation of ?-catenin in CAFs remodeled the tumor microenvironment and had significant anti-melanoma activities in vitro and in vivo, and nuclear YAP translocation is functionally associated with ?-catenin activity in melanoma-associated CAFs. In addition, YAP is highly expressed in the nuclei of CAFs in human and mouse melanomas.
In aim 1, we will investigate the mechanism underlying CAF-derived signals in promoting ECM remodeling and aggressive tumor phenotypes. We will identify the YAP interactome using novel proteomics-based approaches to determine how YAP signaling contribute to CAF phenotype, the remodeling of the tumor microenvironment and melanoma cell growth and migration.
In aim 2, we will characterize the molecular mechanism underlying CAF-induced metabolic pathway changes in melanoma to resist BRAF and MEK inhibitors.
In aim 3, we will assess the anti- tumor effects of targeted ablation of YAP in CAFs on melanoma growth and BRAF inhibitor resistance using an in vivo fluorescent mouse model of human BRAF; PTEN melanoma and a human melanoma xenograft model. The expected outcomes are to be a mechanistic characterization of CAF-mediated response and resistance of BRAF-mutant melanoma to BRAF and MEK inhibitors and an improved understanding of the benefits of CAF targeting with BRAF inhibitors in treating BRAF-driven melanoma. Research findings can potentially be translated to the development of new combination therapy and improve RAF- and MEK targeted therapies. Meanwhile, the project will play a significant role in strengthening the education and research environment of the College of Pharmacy and exposing undergraduate and graduate students to meritorious cancer research.
The current challenge in melanoma therapy is partly due to an incomplete understanding of the key influence of the tumor microenvironment in melanoma progression and the occurrence of resistance. The proposed studies will exploit the molecular mechanisms underlying the ECM-remodeling and pro-tumorigenic functions of melanoma-associated CAFs, and assess the therapeutic benefit of CAF targeting in suppressing BRAF-driven melanoma growth and overcoming BRAF inhibitor resistance. This knowledge is of great importance to developing innovative therapeutic approaches for improved targeted therapy with better patient survival.
