Biology subjects

Licht, J.

Publications and source records attributed to Licht, J..

5 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↗

bioRxiv2025

GDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases

Uveal melanoma (UM) results in fatal liver metastasis, yet little is known about the interactions between UM and host cells in the tumor microenvironment that promote this distinctive proclivity. Here, we used single cell (sc)-RNA-Seq analysis of UM-hepatic stellate cell (HSC) co-cultures to demonstrate that HSCs enriched for UM cell states that expressed genes implicated in cell survival, metabolic reprogramming and angiogenesis. A lead candidate driver of HSC reprogramming was the TGF-{beta} family member GDF15, which was associated with a metastatic UM phenotype. Silencing of BAP1 in UM cells led to increased GDF15 expression and accumulation of H3K27ac marks at the GDF15 promoter. Treatment of HSCs with GDF15 led to increased expression extracellular matrix proteins, inflammatory cytokines and angiogenic factors, including IL-8. Both exogenous GDF15, IL-8 and conditioned media from UM-HSC co-cultures increased endothelial cell network formation in vitro, an effect that was blocked by anti-GDF15 antibodies. In multiple models of metastatic UM, silencing of GDF15 inhibited the outgrowth of metastatic lesions, associated with reduced deposition of extracellular matrix and recruitment of endothelial cells. UM liver metastasis development is dependent upon GDF15-mediated remodeling of the liver microenvironment leading to an angiogenic response and matrix deposition that supports tumor growth.

cancer biology↗

bioRxiv2023

Recruitment of FBXO22 for Targeted Degradation of NSD2

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here, we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain of function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 in a covalent and reversible manner to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.

biochemistry↗

bioRxiv2022

Inability to make facial expressions dampens emotion perception.

Humans rely heavily on facial expressions for social communication to convey their thoughts and emotions and to understand them in others. One prominent but controversial view is that humans learn to recognize the significance of facial expressions by mimicking the expressions of others. This view predicts that an inability to make facial expressions (e.g., facial paralysis) would result in reduced perceptual sensitivity to others facial expressions. To test this hypothesis, we developed a diverse battery of sensitive emotion recognition tasks to characterize emotion perception in individuals with Moebius Syndrome (MBS), a congenital neurological disorder that causes facial palsy. Using computer-based emotion detection tasks we systematically assessed emotion perception thresholds for static and dynamic face and body expressions. We found that while MBS individuals were able to perform challenging perceptual control tasks, they were less efficient at extracting emotion from facial expressions, compared to matched controls. Exploratory analyses of fMRI data from a small group of MBS participants suggested potentially reduced engagement of the amygdala in MBS participants during expression processing relative to matched controls. Collectively, these results support the role of facial mimicry and consequent facial feedback and motor experience in the perception of others expressions.

neuroscience↗

bioRxiv2022

HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a NCSC gene expression signature and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. scRNA-seq analyses showed that HDAC8 expression was correlated with the NCSC cell state in clinical MBM specimens. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion and resistance to stress. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.

cancer biology↗