New drivers of metastasis in melanoma that define poor prognosis in patients: In red, imaging by fluorescence microscopy of p62 in melanoma cells. Red foci correspond to large complexes of p62 with other proteins that potentiate the ability of these tumor cells to survive, proliferate and invade distal organs. /CNIO
The study has discovered that numerous processes involved in the metastasis of melanoma, which were thought to be independent from each other, have a global coordinator: the p62 protein
The publication also discovered the involvement of another protein, FERMT2, in metastasis, and suggests that both, FEMT2 and p62, could represent indicators of bad prognosis in melanoma patients
These findings have resulted from a comprehensive analysis of clinical biopsies, new animal models and the most cutting edge –omic studies and bioinformatic methodologies
Unlike other skin cancers – and without knowing really why – melanoma is one of the most aggressive tumours, with potential for metastasis from very early stages, when lesions are just millimetres thick. Most puzzling is that these metastases occur in an apparently chaotic way, as they involve many processes that occur simultaneously but do not appear to have an apparent relationship among them. Now, scientists from the Melanoma Group at the Spanish National Cancer Research Centre (CNIO), together with the University Hospital 12 de Octubre, have just found some order to this chaos, through a research study that proves that these metastatic processes do not occur through independent mercenaries, but they are coordinated by a general captain: the p62 protein.
Furthermore, the study discovers that one of these warriors controlled by p62 is FERMT2, a protein that had not been previously linked to metastasis in melanoma, and shows that both, FERMT2 and p62, could represent a marker for poor patient prognosis. These important findings are featured in the cover of the January 2019 issue of the prestigious journal Cancer Cell.
An unexpected result
“It is complicated to bring order within the mechanisms underlying melanoma progression, and particularly, to dissect the barcode that defines the aggressive behaviour of this tumour”, explains Marisol Soengas, Head of the Melanoma Group. This is because the melanoma cells accumulate an extremely high number of alterations in the RNA – the genetic material that enables proteins to be created. Furthermore, Soengas says that “there are more than 1,500 proteins that bind RNA and most of them have not been studied”.
Her Group had found that one of the characteristics that differentiate melanoma from other tumours is the regulation of a cell self-cleaning process called autophagy. Autophagy is a system that all cells, including tumour ones, eliminate components that they no longer need, and generate energy to continue growing.
The melanoma researchers at CNIO began then to explore p62, a protein commonly associated with autophagy in many malignancies. “We were interested in p62 because it had been described as one of the yin and yang of cancer, for its ability to favour or inhibit tumours depending on the context”, indicates Panagiotis Karras, the first author of the study. Analysing melanoma biopsies, it was observed that the greater the progression of the melanoma, the higher the p62 levels. However, through the use of animal models, it was verified that in this tumour, p62 is not decisive in autophagy.
To find the main function of p62 in melanoma, the researchers conducted a full -omic study, which also used the most cutting edge bioinformatic technologies. In this way, they performed the first detailed characterisation of p62 and its mode of action in melanoma, studying the expression of the genes involved in these processes (transcriptomics), the identity of the proteins involved (proteomics) and the interactions that occur between them (interactomics).
A coordinated, non-chaotic, metastasis of melanoma
Thanks to this comprehensive study, researchers discovered a new and unexpected function of p62: to control the half-life of other fact0rs involved in melanoma metastasis. Soengas continues: “Recruiting certain RNA-binding proteins, from the 1,500 described, p62 controls numerous proteins, which favour metastasis through such apparently independent processes as survival, metabolism, cell cycle or invasion. Now, we can see that these processes are not independent, but they have a common regulator”.
This work went even further by finding that other processes regulated by p62 may also affect the survival of patients. In this way, a new protein was identified, FERMT2, which correlates with a worse prognosis in metastatic melanomas. “For us pathologists, it was interesting to find that p62 and FERMT2 are increased in samples from patients with melanoma metastasis, because up to now, we did not have any good markers of tumour progression”, indicates José Luis Rodríguez-Peralto, Head of the Anatomical Pathology Department at the University Hospital 12 de Octubre in Madrid, co-author of this paper.
The next step for the researchers will be to try to validate these results in a higher number of biopsies, and to further investigate this melanoma barcode that separates it from other aggressive tumours.
This research has been funded by the Spanish Ministry of Science, Innovation and Universities, the Spanish Association Against Cancer (AECC), a L’Oreal-Paris USA-Melanoma Research Alliance Team Science Award for Women in Scientific Research, the Worldwide Cancer Research, the TV3 Maratò, the Fundación La Caixa, the Mutua Madrileña Foundation, the Carlos III Institute of Health, and the Spanish Ministry of Health, Consumer Affairs and Social Welfare.
p62/SQSTM1 fuels melanoma progression by opposing mRNA decay of a selective set of pro-metastatic factors. Panagiotis Karras, Erica Riveiro-Falkenbach, Estela Cañón, Cristina Tejedo, Tonantzin G. Calvo, Raúl Martínez-Herranz, Direna Alonso-Curbelo, Metehan Cifdaloz, Eva Perez- Guijarro, Gonzalo Gómez-López, Pilar Ximenez-Embun, Javier Muñoz, Diego Megias, David Olmeda, Jorge Moscat, Pablo L. Ortiz-Romero, Jose L. Rodríguez-Peralto, María S. Soengas (Cancer Cell, 2018). DOI: https://doi.org/10.1016/j.ccell.2018.11.008