Periodic Reporting for period 1 - METMEL (Long range-acting drivers of premetastatic niches in melanoma)
Periodo di rendicontazione: 2017-04-01 al 2019-03-31
Melanoma is the 5th most common tumor in females and the 6th in males and it is the tumour with the fastest rising incidence worldwide. Advanced melanomas are of concern because they represent 80% of skin-cancer related deaths (over 26000 deaths in 2020 in Europe alone) (Globocan 2020). The aggressiveness of this cancer type is reflected by the fact that that seemingly thin primary lesions (≥2 mm in depth) can already bear high risk of dissemination to lymph nodes that drain the tumour (sentinel lymph nodes) and ultimately, to distal sites. A series of treatments have been approved in the recent years, particularly involving immunotherapy. However, a significant fraction of these patients are or will become resistant. Therefore, a main unmet need in the field is a better understanding of the the first steps of the metastatic spread of melanoma.
Our group and others have demonstrated that melanoma cells act “at a distance”, preparing pre-metastatic niches before they colonized them. Soluble and vesicle-associated proteins secreted by malignant cells and/or their stroma have been proposed to facilitate tumor cell dissemination. We found that a key factor favouring these pre-metastatic sites is the growth factor Midkine (MDK). However, blockade of MDK reduced, but did not completely abrogate metastasis. Therefore, this proposal was set to identify other other long-range acting factors promoting metastasis in addition or in parallel to Midkine in the establishment of pre-metastatic niches.
Our group and others have demonstrated that melanoma cells act “at a distance”, preparing pre-metastatic niches before they colonized them. Soluble and vesicle-associated proteins secreted by malignant cells and/or their stroma have been proposed to facilitate tumor cell dissemination. We found that a key factor favouring these pre-metastatic sites is the growth factor Midkine (MDK). However, blockade of MDK reduced, but did not completely abrogate metastasis. Therefore, this proposal was set to identify other other long-range acting factors promoting metastasis in addition or in parallel to Midkine in the establishment of pre-metastatic niches.
focused our studies on a particular candidate, whose expression levels correlate with poorer prognosis and overall survival in melanoma patients. Key malignant features of the melanoma cells in vitro such as cell proliferation, invasion and migration are not influenced by the candidate levels. Additionally, both in vitro and in vivo studies failed to report a significant contribution of this gene to tumour driven-lymphangiogenesis. However, bioinformatic analyses of TCGA data for melanoma patients showed that high levels of the candidate correlate with significant alterations in the immune cells infiltration of the tumours, potentially favouring an immunosuppressive environment that would promote metastasis. We therefore focused on studying the influence of the candidate in the tumour microenvironment in melanoma using immunocompetent systems. Analysis of xenograft growth indicates that the candidate downregulation significantly hinders tumour growth in vivo. Importantly, the candidate downregulation correlates with an in increase in CD8 T cells and a decrease in the number of pro-tumoral macrophages. In vitro, we showed that STC2 increases the expression of immunosuppressive markers in macrophages.
These results have been exploited and disseminated via scientific seminars and via presentation in several scientific conferences. A manuscript is at early stages of drafting.
These results have been exploited and disseminated via scientific seminars and via presentation in several scientific conferences. A manuscript is at early stages of drafting.
The data linking the candidate to an immunosuppressive environment in the tumour are particularly relevant since immunotherapy is the treatment that has allowed to achieve remission rates never seen in melanoma before. Additionally, the candidate is a soluble secreted protein. For all of this, we could envision two plausible scenarios:
• Use of the monitoring of the candidate levels in blood as a biomarker for poor prognosis/poor response to immunotherapy.
• Design of a targeted therapy for the candidate, such as a specific antibody or a ligand trap, that would bind it in circulation and could be used in combination with ICB to increase response to immunotherapy.
• Use of the monitoring of the candidate levels in blood as a biomarker for poor prognosis/poor response to immunotherapy.
• Design of a targeted therapy for the candidate, such as a specific antibody or a ligand trap, that would bind it in circulation and could be used in combination with ICB to increase response to immunotherapy.