Borges, S. | Search bioRxiv

bioRxiv2026

LMNA Haploinsufficiency in Human iPSC-Derived Cardiac Organoids Reveals Early Fibrotic Signaling as a Therapeutically Targetable Process

LMNA mutations are a major cause of dilated cardiomyopathy (DCM), with haploinsufficiency representing a common pathogenic mechanism. Yet the earliest disease-initiating events remain poorly defined. Here, we identify a novel intronic splice-site variant, c.937-1G>A, that disrupts pre-mRNA processing and induces nonsense-mediated mRNA decay, resulting in LMNA haploinsufficiency. Using induced pluripotent stem cells (iPSCs) generated from the patients peripheral blood mononuclear cells (PBMCs), we differentiated into self-patterning human cardiac organoids to model early LMNA-DCM in a multicellular human context. Single-nucleus transcriptomics revealed unexpectedly broad remodeling across major cardiac cell types beyond cardiomyocytes. Functionally, LMNA-mutant organoids exhibited impaired contractility, altered calcium handling, and increased arrhythmic activity. These changes were accompanied by early profibrotic activation, including increased reactive oxygen species (ROS), periostin (POSTN) secretion, and CTGF expression. Treatment with the antifibrotic drug nintedanib attenuated this response. Together, these findings show that LMNA haploinsufficiency initiates global pathogenic remodeling at an unexpectedly early developmental stage.

cell biology↗

bioRxiv2024

Identification of targetable epigenetic vulnerabilities in uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM remains highly resistant to therapy and is almost invariably fatal. The strongest genetic drivers of UM metastasis are loss-of-function mutations in tumor suppressor BAP1, an epigenetic regulator that serves as the ubiquitin hydrolase subunit of the polycomb repressive deubiquitinase (PR-DUB) complex, and a key player in global epigenetic regulation. Inactivation of BRCA Associated Protein 1 (BAP1) has been shown to induce widespread epigenetic alterations across multiple model systems. To identify novel therapeutic strategies, we investigated whether targeting the epigenome could reveal new vulnerabilities in UM. We performed high-throughput compound screening using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. Interestingly, we observed significant heterogeneity in the efficacy of different BET inhibitors in UM. While previous clinical trials with two BET inhibitors have failed to show efficacy in UM, our findings highlight substantial differences in the potency of specific BET inhibitors for this malignancy. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and completely prevented detectable metastases in the bones, spinal cord, and brain. Unexpectedly, RNA sequencing revealed a strong transcriptional overlap between BET inhibition and histone deacetylase (HDAC) inhibition--an approach currently under clinical evaluation for UM treatment. Both BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuronal differentiation-like phenotype in UM cells. Together, our findings demonstrate that UM cells exhibit a distinct vulnerability to BET inhibition and establish BET inhibitors as promising candidates for further clinical evaluation for metastatic UM.

cancer biology↗