Biology subjects

Posorske, B.

Publications and source records attributed to Posorske, B..

3 recordsLinked to original sources

bioRxiv2025

A multi-step immune-competent genetic mouse model reveals phenotypic plasticity in uveal melanoma

Uveal melanoma (UM) is a highly aggressive intraocular malignancy with limited therapeutic options for metastatic disease. Existing transgenic UM mouse models inadequately recapitulate human disease progression, while transplant models lack immune competence for studying the tumor immune microenvironment and therapeutic interventions. To address these limitations, we developed a genetically engineered mouse model incorporating stepwise genetic alterations implicated in human UM progression. Spatiotemporally controlled expression of mutant GNAQQ209L from the endogenous locus induced choroidal nevi with limited penetrance. Concomitant BAP1 deletion enhanced nevus formation, while further MYC activation led to fully penetrant intraocular tumors with metastatic potential. Single-cell RNA sequencing revealed malignant cells segregated into Melanocytic and Neural Crest-like subpopulations characterized by distinct transcriptional and biosynthetic programs. Trajectory analyses inferred dedifferentiation from the Melanocytic toward the Neural Crest-like state during tumor progression. Comparison to human UM revealed commonalities with highly aggressive Class 2 UM, including gene expression signatures and copy number gains affecting genes that map to human chromosome 8q beyond the activated MYC allele, suggesting cooperative effects of multiple drivers in this chromosomal region. The tumor microenvironment featured immunosuppressive macrophage populations and exhausted T cells, closely resembling human UM. This physiologically relevant, immune-competent model provides a platform for investigating UM biology, functionally characterizing candidate driver genes, and developing immune-based therapeutic strategies. SIGNIFICANCE STATEMENTWe developed a mouse model that resembles the genetic progression and phenotypic plasticity of human UM. This spatially controlled model confirms the critical role of driver mutations in GNAQ and BAP1, proposes MYC as a promoter of malignant transformation in coordination with other chromosome 8q genes, and reveals UM progression through distinct cellular states. This model offers an urgently needed preclinical platform for understanding the immunogenomics of UM and for testing immune and targeted treatments for this lethal cancer.

cancer biology↗

bioRxiv2024

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG[~]MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation. Significance statementMITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.

cancer biology↗

bioRxiv2024

MAPK-mediated PHGDH induction is essential for melanoma formation and represents an actionable vulnerability

ABSTRACTOverexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. While PHGDH amplification explains PHGDH overexpression in a subset of melanomas, we find that PHGDH levels are universally increased in melanoma cells due to oncogenic BRAFV600E promoting PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, PHGDH expression was critical for melanomagenesis as depletion of PHGDH in genetic mouse models blocked melanoma formation. Despite BRAFV600E- mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction, creating a potential vulnerability whereby melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction. Indeed, we show that this combination promoted cell death in vitro and attenuated melanoma growth in vivo. This study identified a melanoma cell-specific PHGDH-dependent vulnerability.

cancer biology↗