Functional Analysis of Uveal Melanoma Dormancy to Identify Antimetastatic Therapies

Cancer metastases is a leading cause for patient death that has been traditionally understudied compared with primary tumors. Disseminated cancer cells (DCCs) can leave the primary tumor reach distant organs like lungs or liver, and remain dormant for years, until some change 'awakens' DCCs causing metastasis (distant recurrences). Understanding the mechanisms of DCCs dormancy is critical to design durable therapies for cancer patients. Dormant DCCs lay in quiescence and cannot be eradicated by chemotherapy that kills dividing cells, as these cells do not multiply actively.

Uveal Melanoma (UM) is the most common adult eye cancer and a relevant model of prolonged cancer dormancy. 50% of UM patients, treated for primary tumors, succumb to liver metastases up to 15 years later. UM is of prevalence in the armed forces, and a key focus of this Department of Defense (DOD) Melanoma Research Program proposal. Standard therapies fail in UM and there are no specific therapies, highlighting an urgent need for effective treatments. Inhibiting mechanisms that promote UM dormant DCCs survival or that cause an irreversible dormant state will allow treatments to be effective in the long-term. Identifying these mechanisms will also provide prognostic markers to determine whether DCCs are or not dormant and will inform on outcome and therapy response. Importantly, this will help to detect minimal residual dormant disease after therapy, with the ultimate goal of eradicating it.

Our rationale is based on preliminary data from the lab suggesting that retinoic acid (RA) or vitamin A signaling may play a critical role in UM DCCs switch to become dormant. Vitamin A is highly abundant in the liver tissue, where these melanoma cells sleep and then eventually grow. We found that vitamin A regulated gene programs are upregulated UM single cells, which are low for proliferation markers compared with large and growing metastases. Our data indicates that TGFß2, a liver tissue factor that is also growth suppressor and key mediator in UM DCCs dormancy, is upregulated in UM single cells compared with growing metastasis. We propose that upon liver colonization, those DCCs able to sense TGFß2 and RA in the tumor microenvironment switch off growth while engaging dormancy. Our data indicates that TGFß2 liver microenvironment expression decreases with ageing and this could contribute to UM DCCs re-awakening and metastasis formation. In addition, we aim to understand how a frequent UM mutation that persistently activate genes for growth may be blocked by the TGFß2 and RA programs. As a whole we hypothesize that treating UM cells with dormancy-inducing factors (retinoids; to mimic vitamin A role) might prevent liver metastasis, and we postulate that the poor UM prognosis may be associated with the blockade of dormancy pathways. The researcher objectives for this DOD MRP are (1.1) to functionally identify TGFß2 transcriptional programs regulating UM DCCs dormancy in liver, (1.2) to link these programs to genetic alterations and (2) to test new dormancy-inducing therapies in UM DCCs.