Periodic Reporting for period 1 - MetaMelNiche (Deciphering the melanoma-niche cell interplay to identify novel treatments for metastatic melanoma)
Período documentado: 2023-09-01 hasta 2025-08-31
Problem to be addressed:
The overarching aim of MetaMelNiche is to define the impact of signals from the cancer cell niche on melanoma dissemination in vivo, with the long-term goal of discovering drug targets and developing new pharmacologic strategies against metastatic melanoma. The influence of the cancer cell niche on cancer cell adhesion and migration has only recently become a subject of investigation, and in non-epithelial tumours like melanoma, that do not arise from well-structured organs, these mechanisms remain largely obscure. Previous research has mostly focused on cell-intrinsic properties of cancer cells, whilst the impact of signals from the cancer cell niche on melanoma dissemination in vivo and in melanoma patients has been largely unexplored. MetaMelNiche, for the first time, fills this gap: I have used state-of-the-art techniques to define the impact of signals from the cancer cell niche on melanoma dissemination in vivo, with the long-term goal of discovering drug targets and developing new pharmacologic strategies against metastatic melanoma.
Why is it important for society?
Despite significant progress in the treatment and management of patients with cancer, metastatic tumours remain hard to treat and highly lethal. In the case of melanoma, the most aggressive form of skin cancer, the 5-year survival rate drops from almost 100% for localized tumours that can be removed by surgery to only 50% in the presence of metastases, despite the effectiveness of immunotherapies and targeted therapies. MetaMelNiche will generate invaluable insights into the mechanisms by which signals from the cancer cell niche impact the dissemination capacity of melanoma cells and may provide new opportunities for therapeutic intervention against metastatic tumours.
What are the objectives?
1) Elucidate and target the mechanism by which IGF1 modulates adherens junction formation and cell migration in melanoma through pathway analyses in human melanoma cell lines and genetic and pharmacologic manipulation in zebrafish models.
2) Identify and study interactions between melanoma cells and their niche by scRNA-seq analysis followed by modelling in zebrafish and in human reconstructed skin coupled with advanced live-cell imaging.
The overarching aim of MetaMelNiche is to define the impact of signals from the cancer cell niche on melanoma dissemination in vivo, with the long-term goal of discovering drug targets and developing new pharmacologic strategies against metastatic melanoma. The influence of the cancer cell niche on cancer cell adhesion and migration has only recently become a subject of investigation, and in non-epithelial tumours like melanoma, that do not arise from well-structured organs, these mechanisms remain largely obscure. Previous research has mostly focused on cell-intrinsic properties of cancer cells, whilst the impact of signals from the cancer cell niche on melanoma dissemination in vivo and in melanoma patients has been largely unexplored. MetaMelNiche, for the first time, fills this gap: I have used state-of-the-art techniques to define the impact of signals from the cancer cell niche on melanoma dissemination in vivo, with the long-term goal of discovering drug targets and developing new pharmacologic strategies against metastatic melanoma.
Why is it important for society?
Despite significant progress in the treatment and management of patients with cancer, metastatic tumours remain hard to treat and highly lethal. In the case of melanoma, the most aggressive form of skin cancer, the 5-year survival rate drops from almost 100% for localized tumours that can be removed by surgery to only 50% in the presence of metastases, despite the effectiveness of immunotherapies and targeted therapies. MetaMelNiche will generate invaluable insights into the mechanisms by which signals from the cancer cell niche impact the dissemination capacity of melanoma cells and may provide new opportunities for therapeutic intervention against metastatic tumours.
What are the objectives?
1) Elucidate and target the mechanism by which IGF1 modulates adherens junction formation and cell migration in melanoma through pathway analyses in human melanoma cell lines and genetic and pharmacologic manipulation in zebrafish models.
2) Identify and study interactions between melanoma cells and their niche by scRNA-seq analysis followed by modelling in zebrafish and in human reconstructed skin coupled with advanced live-cell imaging.
Transcriptomic, proteomic, and functional assays in human melanoma cell lines showed that IGF1R inhibition alters the translation of adhesion-related genes and identifies key downstream effectors of IGF1R signaling.
Established and validated a standardized workflow for dissociating human melanoma tissue, encapsulating single cells, and performing scRNA-seq, including data analysis.
Collaborated with the bioinformatics platform to establish a data analysis pipeline to identify functionally implicated cell–cell interactions in human melanoma.
Established the models to validate the functional implication of cell-cell interactions in vitro using human melanoma and stromal cell lines.
Validated the implication of identified cell-cell interactions in melanoma progression.
Established and validated a standardized workflow for dissociating human melanoma tissue, encapsulating single cells, and performing scRNA-seq, including data analysis.
Collaborated with the bioinformatics platform to establish a data analysis pipeline to identify functionally implicated cell–cell interactions in human melanoma.
Established the models to validate the functional implication of cell-cell interactions in vitro using human melanoma and stromal cell lines.
Validated the implication of identified cell-cell interactions in melanoma progression.
Generated a novel single-cell RNA-seq dataset from melanoma patient samples.
Developed and implemented a pipeline enabling the identification of functionally relevant cell–cell interactions between melanoma and tumour microenvironment cells.
Established co-culture models of human melanoma and stromal cell lines to experimentally validate the functional significance of cell–cell interactions.
Established a skin reconstruction model that enables long-term live-cell imaging to study the behaviour of melanoma and stromal cells.
Developed and implemented a pipeline enabling the identification of functionally relevant cell–cell interactions between melanoma and tumour microenvironment cells.
Established co-culture models of human melanoma and stromal cell lines to experimentally validate the functional significance of cell–cell interactions.
Established a skin reconstruction model that enables long-term live-cell imaging to study the behaviour of melanoma and stromal cells.