Onder druk: hoe lncRNA's de tolerantie voor geneesmiddelen beïnvloeden

Owing to its remarkable heterogeneity and plasticity, melanoma is a paradigm for studying therapy resistance. Despite advances in targeted therapies and immunotherapies, durable responses remain limited due to the persistence of a subset of tumour cells, known as drug-tolerant persisters (DTPs) or minimal residual disease (MRD), that drive relapse. Biophysical cues within the tumour microenvironment critically shape tumour development and therapy response. Among these, we demonstrate that osmotic stress, encountered during proliferation and therapeutic pressure, drives phenotypic switching toward dedifferentiated states and biases relapse toward non-genetic adaptation in melanoma. Long non-coding RNAs (lncRNAs), transcripts longer than 500 nucleotides with no or poor coding potential, regulate all epigenetic and post-transcriptional processes, and their aberrant expression is linked to cancer progression and therapy resistance. How such low-abundance transcripts exert broad effects remains unclear. Here, we propose that osmotic stress induces lncRNA dysregulation in drug-tolerant subpopulations, promotes molecular crowding and liquid-liquid phase separation. Consistent with this, we show that osmotic stress-induced reprogramming associates with a distinct lncRNA signature enriched in repetitive, RBP-binding transcripts. Finally, we identify DDERMMAL, a melanocytic lineage-enriched lncRNA deregulated by osmotic stress and linked to poor prognosis. DDERMMAL interacts with the DNA damage response machinery and may act as a molecular switch between genetic and non-genetic resistance, highlighting its potential as a biomarker for therapy responses.