Molecular Oncology Programme

Melanoma Group

Group Leader:  María S. Soengas
Research highlights
CNIO Melanoma Group: Objectives and model systems

Melanomas are aggressive solid tumours and a prime example of how integrated basic and clinical research has significantly improved patient prognosis. Nevertheless, despite great success with targeted and immune-based therapies, sustained clinical responses are still limited. Moreover, the field lacks molecular markers of diagnosis, and the knowledge on how melanomas progress and metastasise is largely incomplete. In addition, one of the main hurdles to advance in this disease is the lack of animal models to monitor melanoma initiation and progression in vivo.

To this end, our Group focuses on three main areas of research (FIGURE 1):

  • Aim 1. Oncogenic pathways selectively deregulated in melanoma that may represent new diagnostic indicators.
  • Aim 2. Risk factors and prognostic markers.
  • Aim 3. Animal models that allow for non-invasive monitoring of pre-metastatic niches.
Lineage-specific oncogenic dependencies in melanoma

One of the long-term objectives of the Melanoma Group is to discover new melanoma drivers. We have previously identified a cluster of endolysosomal-associated genes that distinguish melanoma from over 35 additional malignancies (Alonso-Curbelo et al., Cancer Cell 2014; Alonso-Curbelo et al., Oncotarget 2015a and Oncotarget 2015b). Further analyses of lysosomal-dependent pathways also revealed unique features of autophagy genes (ATG5) in melanoma (García-Fernández et al., Autophagy 2016). Additional contributions of autophagy to melanoma cell survival and response to targeted therapy were generated in collaboration with the Ashani Weeraratna group at the Wistar Institute (USA) (Ndoye et al., Cancer Res 2017). Other melanoma-enriched regulatory mechanisms were identified by focusing on RNA binding proteins (RBPs). We selected RBPs (a family of over 950 members) because they are largely unexplored in melanoma, although this is a tumour characteristically associated with a plethora of changes in mRNA gene expression profiles. Performing a series of genome wide studies (i.e. genomic, transcriptomic, proteomic and interactomic analyses) we uncovered new roles of the RBPs CPEB4 and CUGBP1 in the modulation of mRNA stability, with unexpected targets involving master specifiers of the melanocyte lineage (Perez-Guijarro et al., Nat Commun 2016; Cifdaloz et al., Nat Commun 2017).

‘MetAlert’ mice for the visualisation of premetastatic niches in melanoma and as a platform for gene discovery and target validation

We have also made great progress regarding one of the most pressing needs in the melanoma field, namely, the mechanisms that enable melanoma cells to disseminate already from lesions of barely 1 mm in depth. In collaboration with Sagrario Ortega at the CNIO, we have generated a series of mouse models of melanoma that have the unique feature of revealing how these cells act ‘a distance’ from very early stages of tumour development, activating the lymphatic vasculature and preparing metastatic niches before their colonisation (Olmeda et al., Nature 2017; see the versatility of these mice for gene discovery and pharmacological analyses in FIGURE 1). Using these ‘MetAlert’ animals we found the growth factor MIDKINE as a new driver of lymphangiogenesis and melanoma metastasis (FIGURE 2, A). The physiological relevance of these data was validated in human clinical biopsies where MIDKINE expression correlated with poor patient prognosis (FIRGURE 2, B). This paper of Olmeda et al. was highlighted in Nature, Cancer Discovery, Developmental Cell and other scientific journals, and was awarded the Premio “Constantes y Vitales” by the Fundación AtresMedia for the Best Publication in Biomedical Research in 2017. This article was also considered as being among the Top 10 publications in Spain in 2017 by the news agency EFE. This publication, together with others from the Soengas Group, was recognised by the Estela Medrano Memorial Award by the Society of Melanoma Research, which honours the most influential female leaders in the melanoma field. In addition, clinical trials with the compound BO-112 performed by the biotechnology company Bioncotech Therapeutics were considered as being among the 14 Most Relevant Scientific Hits in 2017 by the SINC agency (the Spanish Information and Scientific News Service). BO-112 is a derivative of the polyplex BO-110 generated at the CNIO by the Soengas laboratory.