Rationale: Despite recent progress in treatment of melanoma, the metastatic form of the disease remains highly drug- resistant and frequently fatal. The reactivation of tumor-suppressive pathways constitutes an under-explored research avenue and presents a strategic opportunity to develop novel therapeutic interventions for this devastating disease. The explosion of data from genome-wide analysis technologies has produced a wealth of information on the genomic landscape of tumors, including mutation hotspots and copy-number alterations. Here I propose to utilize these data and analyze the functional relevance of candidate tumor- suppressor genes for melanoma formation. Research:
The aims of this project are: 1) to assess the tumor-suppressive potential of ARID2, a gene encoding a chromatin regulator frequently mutated in human melanomas, and to analyze its mechanism of action, and 2) to identify the tumor-suppressor gene in a region of chromosome 10 frequently lost in human melanomas and to decipher its associated signaling pathway. I will use the zebrafish as a model organism to study the in vivo effect of gene knock-out on tumor initiation. The zebrafish is particularly suited for these studies because zebrafish embryos are genetically malleable, their large numbers provide statistical power to tumor-incidence curves and a reliable fish melanoma model is readily available. I have developed a technique for tissue-specific inactivation of genes in the zebrafish based on the CRISPR technology of genome-editing that I recently published in Developmental Cell. I will use it to evaluate the loss- of-function phenotype of candidate tumor-suppressor genes in zebrafish melanoma. The preliminary data I have obtained demonstrates the feasibility of this approach. Finally, I will investigate the cellular and molecular mechanisms of action of the identified tumor-suppressors. I expect that this research plan will yield crucial new insights into tumor-suppressive pathways in melanoma and result in the development of novel therapeutic approaches. Career plan: My long-term career goal is to lead a world-class laboratory in the forefront of cancer biology with a particular focus on the development of innovative therapies based on the analysis of tumor- suppressive mechanisms. I intend to use both the mouse and the zebrafish as investigation tools and preclinical models. To complement my knowledge of mouse models of cancer acquired during my PhD, I will carry out the mentored phase of this Award as a postdoctoral Research Fellow in the laboratory of Dr. Leonard Zon, a renowned zebrafish researcher who has made seminal contributions to the fields of developmental hematopoiesis and cancer biology. I have designed an ambitious research career development plan to achieve my immediate goals for the mentored period: 1) expand my advanced scientific and technical knowledge, and 2) prepare my transition to independence. Building on my strong background of studying cell signaling mechanisms, I will gain expertise in zebrafish techniques and perfect my cellular and molecular biology as well as biochemistry skills. Under the mentorship of Dr. Zon and a prestigious advisory committee, I will follow a structured training program to enhance my professional abilities to establish and run my own laboratory. The division of Hematology/Oncology at Boston Children's Hospital and the Harvard Medical School will provide me with the ideal environment to fully benefit from this Award and become a successful independent scientist.
Melanoma is a devastating form of skin cancer. Oncogene targeted therapies have recently led to tremendous progress in the treatment of melanoma but the prognosis of the metastatic disease remains poor. Most patients relapse within 6 months of treatment and the 5-year survival rate in cases presenting distant spread is still below 20%. By using a zebrafish model of melanoma to reactivate tumor-suppressive pathways, this proposal aims to develop novel therapeutic strategies.
|Ablain, Julien; Xu, Mengshu; Rothschild, Harriet et al. (2018) Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science 362:1055-1060|