Melanoma Immunotherapy Modeling

Melanoma is an extraordinarily heterogeneous and aggressive tumor with high propensity to metastasize and resist to current treatments, leading to most skin cancer-related deaths. Despite the revolutionary advances of immunotherapy in the last decades, more than one third of melanoma patients at late stages and around 60% of those with brain metastasis still do not benefit from any treatment. Our group´s research is centered on understanding the molecular mechanisms driving metastasis and immunotherapy resistance with the ultimate goal of discovering robust biomarkers and develop preventive and therapeutic strategies to improve melanoma patient outcomes. 

To address this, we use a unique panel of melanoma mouse models representing human etiology and genetic diversity, as well as single cell derived clonal sublines and brain metastatic cell lines that we recently generated. Our preclinical platform exhibits diverse pathological and molecular characteristics, distinct immune infiltrate profiles, and a wide range of responses to immune checkpoint inhibitors, allowing to study immunotherapy resistance mechanisms in fully immunocompetent conditions. 

We focus our research on three aspects: 
1)    Intratumoral heterogeneity (ITH), with especial interest on melanoma plasticity dynamics and the impact on the tumor microenvironment (TME) to understand its role in immune evasion and immunotherapy resistance. 
2)    The mechanisms of brain colonization, in particular melanoma crosstalk with stromal and immune cells leading to TME remodeling and determining the response to immunotherapy.
3)    Discover targetable drivers of immune evasion to develop strategies that prevent brain metastasis and overcome immunotherapy resistance. 

Our group employs a multidisciplinary approach that includes the generation of single-cell multi-omics mouse data sets, development of computation tools and comparative analysis of patient cohorts, gene inactivation and drug screens in 2D and 3D co-culture systems and preclinical therapeutic studies.

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