Characterization of Transgenic Zebrafish (Danio rerio) Lines Expressing Variants of ICER (Inducible cAMP Response Element); Implications for Melanoma Pathogenesis
Presentation Type
Poster
Faculty Advisor
Carlos Molina
Access Type
Event
Start Date
26-4-2024 9:45 AM
End Date
26-4-2024 10:44 AM
Description
Cutaneous melanoma, the deadliest form of skin cancer, presents significant challenges in treatment despite recent advancements in immune checkpoint inhibitors and targeted therapies. The majority of melanomas harbor BRAF gene mutations, particularly the BRAFV600E alteration, leading to constitutive activation of the MAPK pathway. While BRAF and MEK inhibitors have demonstrated efficacy, resistance mechanisms remain a challenge, primarily involving reactivation of the MAPK pathway through various alternative means. Emerging evidence implicates cAMP signaling, with studies revealing a cyclic-AMP-dependent melanocytic signaling network. Our investigation focuses on the Inducible cAMP Early Repressor (ICER), a dominant negative cAMP pathway regulator. Previous work from our lab demonstrates its absence in cancer cells, despite no impact on ICER gene expression. The absence is a result of post-translational modification through the proteasome. In this work we explore ICER's regulation through phosphorylation and ubiquitination, elucidating a cross-talk mechanism between the cAMP and MAPK pathways. Specifically, we observe reduced tumor progression and increased lifespan in zebrafish expressing a ubiquitin-deficient ICER variant, suggesting its role in melanoma pathogenesis. Additionally, we observed reduced expression of genes involved in the MAPK pathway, in the ubiquitin-deficient form of ICER compared to zebrafish expressing wild-type ICER. The data also suggests some reduction in gene expression involved in Oxidative Phosphorylation, which may contribute to the reduction in tumorigenesis in this group, though more work is needed to better understand this result. Our findings highlight the potential of targeting ICER to overcome resistance and improve melanoma treatment outcomes.
Characterization of Transgenic Zebrafish (Danio rerio) Lines Expressing Variants of ICER (Inducible cAMP Response Element); Implications for Melanoma Pathogenesis
Cutaneous melanoma, the deadliest form of skin cancer, presents significant challenges in treatment despite recent advancements in immune checkpoint inhibitors and targeted therapies. The majority of melanomas harbor BRAF gene mutations, particularly the BRAFV600E alteration, leading to constitutive activation of the MAPK pathway. While BRAF and MEK inhibitors have demonstrated efficacy, resistance mechanisms remain a challenge, primarily involving reactivation of the MAPK pathway through various alternative means. Emerging evidence implicates cAMP signaling, with studies revealing a cyclic-AMP-dependent melanocytic signaling network. Our investigation focuses on the Inducible cAMP Early Repressor (ICER), a dominant negative cAMP pathway regulator. Previous work from our lab demonstrates its absence in cancer cells, despite no impact on ICER gene expression. The absence is a result of post-translational modification through the proteasome. In this work we explore ICER's regulation through phosphorylation and ubiquitination, elucidating a cross-talk mechanism between the cAMP and MAPK pathways. Specifically, we observe reduced tumor progression and increased lifespan in zebrafish expressing a ubiquitin-deficient ICER variant, suggesting its role in melanoma pathogenesis. Additionally, we observed reduced expression of genes involved in the MAPK pathway, in the ubiquitin-deficient form of ICER compared to zebrafish expressing wild-type ICER. The data also suggests some reduction in gene expression involved in Oxidative Phosphorylation, which may contribute to the reduction in tumorigenesis in this group, though more work is needed to better understand this result. Our findings highlight the potential of targeting ICER to overcome resistance and improve melanoma treatment outcomes.