Investigating Epigenomic Reprogramming in Human Melanoma Development
Abstract
Scientific Objective and Rationale: Skin melanoma is a tumor of pigment cells (melanocytes) that start as atypical moles (dysplastic nevi) and quickly progress into aggressive malignant melanoma. The majority of melanoma cells contain mutation in BRAF gene (BRAFV600E), which makes the basis of current anti-BRAFV600E drug treatment given to the melanoma patients. Surprisingly, more than 80% of benign nevi (typical moles) also contain same mutation but rarely turn into melanomas, suggesting a possible role of mechanisms beyond genetic mutations (epigenetic mechanisms) in melanoma development. Developmentally, melanocytes are derived from a short-lived embryonic stem cell population called neural crest stem cells. Recent evidence suggests that when melanocytes turn cancerous, they activate a developmental program similar to embryonic neural crest cells. In addition, melanoma cells also utilize molecular machinery of neural crest cells to spread to different parts of the body (metastasis) and in acquiring resistance against anti-BRAFV600E drugs. Taken together, these observations suggest that melanocytes possibly de-differentiate into neural crest cell-like state during melanoma initiation and this neural crest-like state further drives melanoma progression. I have hypothesized that epigenomic reprogramming drives transition of melanocyte towards a more na?ve developmental state(s) and in presence of BRAFV600E mutation this developmental state can be conducive to melanomagenesis. As human neural crest cells are inaccessible embryonic cells, I have established an in vitro model of neural crest cells derived from human embryonic stem cells and from neural crest cells, melanocyte precursor cells, and mature melanocytes in a step-wise manner. Initial results of my study suggests that molecular profile of patient-derived melanoma cells is very similar to human embryonic stem cell-derived neural crest cells and melanocyte precursor cells in agreement with my hypothesis. However, more studies are required to fully characterize to what extent melanoma indeed represents epigenetic reprogramming of the fully mature melanocyte state to a more na?ve developmental state(s). Furthermore, studies are required to conclusively demonstrate that such epigenetic rewiring (reprogramming) can endow normal melanocytes with tumorigenic potential in the presence of melanoma permissive environment (BRAFV600E mutation). These are the most basic questions that have significant implications in understanding melanoma initiation, progression, metastasis, and quickly acquired resistance against melanoma treatment. This Peer Reviewed Cancer Research Program (PRCRP) Horizon Award will help me pursue these studies in a fully committed manner and provide the necessary training for my career development. Principal Investigator Career Goals: My long-term career goal is to establish myself as an independent cancer researcher with focus on cancer stem cell biology. This PRCRP Horizon Award will help substantially in my training, which includes learning several interdisciplinary approaches such as next-generation sequencing, computational biology, molecular biology, stem cell biology, melanoma tumor biology, and in vivo imaging. My mentor, Dr. Joanna Wysocka, is one of the leading experts in epigenetics and chromatin biology field and has advanced the understanding of neural crest stem cells biology, and my collaborator, Dr. Irving Weissman, is a renowned cancer stem cell biologist. Guidance and expertise of top-notch scientists coupled with availability of state-of-the-art facilities of both Stanford Cancer Institute and Stanford Stem Cell Institute (located in the same building as the Wysocka laboratory) will help me complete this project in an expeditious manner while simultaneously providing me with a unique fertile environment where I can grow as a holistic cancer researcher. Military Relevance: Melanoma is the most aggressive form of skin c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710246
Entities
People
- Vivek K Bajpai
Organizations
- Stanford University
- United States Army