Pseudopodia couple microenvironmental sensing to adaptive transcriptional reprogramming

Pseudopodia are actin-rich membrane extensions that allow cells to sense and respond to environmental cues, including hypoxia, inflammation, and chemotactic signals. Although these sensory structures are thought to transmit information from the cell periphery to the nucleus to regulate cell-state changes, including those involved in cancer progression, the underlying mechanisms remain poorly understood. To address this gap, we used a unique combination of intracellular spatial multiomics approaches to identify transcription factors and chromatin remodeling genes enriched within protrusions. Our findings reveal that these transcriptional regulators are selectively positioned for local translation in pseudopodia and subsequent transport to the nucleus, where they can drive rapid genetic reprogramming. These findings reveal a previously underappreciated function of pseudopodia as spatially organized genetic regulatory structures that enable cells, including cancer cells, to rapidly adapt to diverse microenvironmental stressors.