Project description:To investigate the effect of Interferon-gamma signaling on gene expression in melanoma cells We performed gene expression analysis of mouse melanoma cell lines that have been treated with Interferon-gamma cytokine as compared with mock-treated controls.
Project description:We have study 15 melanoma metastasis obtained from 2 different patients. Five metastases were obtained from patient 1 after M-VAX treatment (2 regressing and 3 progressing). Ten were obtained from patient 2, five after interferon treatment (1 progressing and 4 regreesing) and another 5 after M-VAX treatment (1 progressing and 4 regressing) We have study 15 melanoma metastasis obtained from 2 different patients. Five metastases were obtained from patient 1 after M-VAX treatment (2 regressing and 3 progressing). Ten were obtained from patient 2, five after interferon treatment (1 progressing and 4 regreesing) and another 5 after M-VAX treatment (1 progressing and 4 regressing)
Project description:We analyzed baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). Analysis of whole transcriptome data showed that T cell infiltration and interferon-gamma signaling signatures corresponded most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. Clinical outcome differences were likely not due to differential melanoma cell responses to interferon-gamma, as 57 human melanoma cell lines exposed in vitro to this cytokine showed a conserved interferon-gamma transcriptome response unless they had mutations that precluded signaling from the interferon-gamma receptor. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream interferon-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
Project description:Melanoma is one of the most aggressive and treatment-resistant cancers. It represents the most life-threatening neoplasm of the skin, and its incidence has been increasing for the last three decades. Melanoma evolves from the local transformation of melanocytes to primary tumors, which can metastasize to multiple organs. Brain metastases represent one of the most significant causes of death in cutaneous melanoma patients. Despite aggressive multi-modality threapy, patients with melanoma brain metastasis have a median survival of less than a year, with a majority of these patients dying as a result of their intracranial disease. We aimed to find brain metastasis-specific molecular markers. To identify alterations in DNA methylation related to brain metastasis, we used Illumina 450K BeadChips to assess differentially methylated regions in melanocytes, primary melanomas, lymph node metastases, and brain metastases. Bisulphite-converted DNA from 40 specimens was hybridised to the Illumina Infinium 450k Human Methylation BeadChip.
Project description:Immunotherapy revolutionized the treatment of advanced melanoma. As the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of pre-immunotherapy tumor biopsies from melanoma patients that received PD-1 blockade (n=36) or adoptive cell therapy with tumor infiltrating lymphocytes (n=37). We identified two melanoma-intrinsic mutually exclusive gene programs, which are controlled by interferon-γ and MYC, and determine immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower interferon-γ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays under the control of JAK2 promoter demonstrated reduced activity in MYC-overexpressing cells, which was reversible upon mutagenesis of MYC E-box binding sites in the JAK2 promoter. Moreover, silencing of MYC or its co-factor MAX with siRNA increased JAK2 expression and interferon-γ responsiveness of melanomas, while concomitantly enhancing the effector functions of T-cells co-incubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a “metastasis aggressiveness gene expression signature” derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Keywords: disease state
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a “metastasis aggressiveness gene expression signature” derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Keywords: disease state analysis
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a “metastasis aggressiveness gene expression signature” derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Keywords: disease state