When cancer cells metastasize to the brain, the diagnosis becomes terminal. In melanoma brain metastasis, patients are only given months to live. There is an urgent need to develop treatment strategies to improve clinical outcomes for these patients. Although immunotherapy has been successfully used to treat some types of cancers, its effectiveness is limited in many solid tumors, including brain metastasis. One reason for this is due to the accumulation of myeloid cells in the tumor. These myeloid cells come from bone marrow, and enter the circulation when tumors produce recruitment signals into the blood. One of the main functions of these myeloid cells is to suppress the killing activity of T cells, allowing the tumors to grow while evading the body’s natural immune system. In the brain, there are specialized myeloid cells called microglia. In brain tumors, these microglia are thought to have both unique and shared functions to the circulating myeloid cells. Therefore, a better understanding of these microglia and how they may contribute to brain tumor progression will lead to the development of new therapies. This study will investigate a biological signaling pathway that is found to be activated in microglia as a response to invading cancer cells. This pathway is part of the natural immune response exerted by microglia in many other nervous system diseases, such as Alzheimer’s and multiple sclerosis. In these other diseases, the activated microglia play a role in resolving inflammation, which has beneficial effects by reducing damage to the local organ. In cancer, however, this has the opposite effect and protects the tumor, allowing it to grow unchecked. In this study, we propose to investigate this pathway and its involvement in brain tumor progression. Completion of this project will establish targeting of microglia as a new therapeutic approach, in combination with immunotherapies, for brain metastasis patients.

Prolonged sun exposure combined with other multi-factorial cues can transform skin’s melanocytes into melanoma cells characterized by uncontrolled proliferation. If not removed on time, melanoma cells can quickly spread into other tissues and form lethal secondary tumors called metastasis. Several anti-melanoma drugs have been developed in the last decade, in particular immunotherapy to help our natural protective barrier or immune system to eradicate cancer cells. Immune system is a group of diverse cells able to activate biological responses to eliminate foreign organisms (i.e., viruses) or abnormal cells including cancer cells. However, melanoma cells can modify the expression of genes that confer them special “identities” allowing them to become invisible to the immune system. Therefore, a better characterization of these identities remains essential to define new therapeutic targets. Using complex bioinformatic analyses, we compared the expression of several genes among different tumors and normal tissues. Surprisingly, we identified a new gene named HOXD13 almost exclusively expressed in melanoma cells of patients non responsive to immunotherapy. Through genetically modified mice able to develop melanoma, we observed that HOXD13 activation confers to melanoma cells an invisible identity to the immune system. Using other molecular techniques, we demonstrate that HOXD13 activates two other genes named CD73 and NGFR which we suspect being the main actors of immune invisibility. Altogether, our studies will reveal whether HOXD13/CD73/NGFR axes inhibition could make melanoma cells more visible to the immune system and improving immunotherapy response with a direct relevance for the patients.

For decades, cancer initiation and progression are thought to occur gradually through small mutational changes in its DNA. After natural selection, winning variants that have accumulated sufficient fitness-conferring traits expand and spread, causing respectively primary tumor growth and metastases. More recent studies have discovered new mechanisms that allow cancer’s DNA or genome to undergo a large number of mutational changes all at once and survive this catastrophic event. This would therefore enable cancer cells to accelerate its evolution by rapidly generating large pools of variants for natural selection. We and others have discovered that such powerful genomic instability mechanisms (specifically referred to as chromothripsis or more generally as complex genomic rearrangements) are operative in advanced metastatic cutaneous melanomas, in particular those causing therapy resistance and death.

Here, we will test the hypothesis that these powerful genomic instability mechanisms are critically important evolutionary events in early (primary) melanoma. To address whether and how complex genomic instability mechanisms drive the growth of primary melanomas, fuel metastases in the same patients, and increase the aggressiveness of the disease course in the affected patients, we will achieve two non-trivial logistical and technical milestones to test this new conceptual paradigm of melanoma evolution. First, we will collect patient-matched primary and metastatic melanomas and normal tissues. Second, we will generate so-called whole-genome sequences from all these tissues. We will deploy a comprehensive suite of computational strategies to analyze a large volume of genomic data to understand how complex genomic rearrangements accelerate melanoma evolution. Moreover, our analysis will generate additional hypotheses pertaining to prognostic and predictive biomarkers as well as preventive and therapeutic targets. Analysis of preliminary data from over 30 patients support the notion that clones of melanoma with these complex alterations drive early and late disease frequently in patients with melanoma, including acral cutaneous, desmoplastic cutaneous, and mucosal melanomas. Within the two-year project period, we can feasibly achieve analysis over one hundred patients, including patients of under-represented minorities. With follow-up expansion, this project will seed an invaluable resource for the melanoma and cancer research community.