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Heterogeneity in melanoma metastasis and resistance to immune checkpoint blockade

19th national competition for scientific and technical research

Precision Medicine and Cancer

Senior Researcher : María S. Soengas y Yardena Samuels

Research Centre or Institution : Centro Nacional de Investigaciones Oncológicas. Madrid y el Weizman Institute of Science. Rehovot


This proposal was set to identify new tumor drivers and targets for therapeutic intervention in cutaneous melanoma, the most aggressive form of skin cancer. This was trivial, as melanomas accumulate the highest mutational rate described to date, and are notorious for a marked heterogeneity. Whether this heterogeneity is a byproduct of genomic alterations, or plays an active role in tumor progression is unclear. Work of the laboratory of Yardena Samuels suggested that heterogeneity (ITH), but not mutational load, correlated with immune-mediated tumor rejection. The Maria Soengas group, in turn, had data that supporting the growth factor MIDKINE as a main driver of immune suppression, with key roles in metastasis via neolymphangiogenesis.

We are glad to report great progress of both teams: Samuels and collaborators have now published that ITH (driven for example by UVB irradiation) is indeed a key determinant in immune evasion and resistance to immune checkpoint blockade (Wolf et al. Cell, 2019). They have also identified two components of the immunoproteasome (PSMB8 and PSMB9), as key mediators in the response to immune checkpoint inhibitors, with a better prognostic value than tumor mutational burden (Kalaora et al. Nat Commun, 2020). On the other hand, the Soengas group now definitively linked MDK to immunosuppression and immune resistance, in a study in revision in Nat Medicine (Cerezo-Wallis et al.), with very supportive comments from the referees and the editor. Moreover, they have outlined how a mouse model they had generated (termed MetAlert for its ability to follow melanoma progression in vivo), revealed new inhibitors of MDK and melanoma metastasis (Olmeda et al. BioRxv, 2019; Olmeda et al. Submitted to Science Translat Med).  The Soengas group is now assessing and targeting intratumoral heterogeneity in the MetAlert mice, using reagents of Samuels. Conversely, the Samuels laboratory is mining their transcriptomic datasets for MDK-related signaling cascades. We are very enthusiastic about these mutually-beneficial collaborations. 

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