Abstract / Summary
Transcriptional heterogeneity drives malignant progression, yet how it emerges within tumors remains unclear. By combining genetic perturbation and lineage tracing with parallel single-cell multiomics, we tracked the consequences of ARID1A loss within individual clonal lineages. ARID1A deficiency increased transcriptional variability both within and across clones, recurrently giving rise to diverse transcriptional profiles that did not converge on a common, coordinated pattern. This variability was accompanied by broadened chromatin accessibility at normally silenced loci and depended on residual SMARCA4 activity. Clones in which this variability was prominent showed no growth advantage under standard conditions but were preferentially recovered under specific environmental stresses and during lung colonization, a context dependence consistent with bet-hedging. Our findings suggest that loss of an epigenetic regulator can promote tumor evolution by relaxing transcriptional constraints and widening the range of phenotypes accessible to a clonal lineage, rather than by imposing a single fixed phenotype.