Seminars

In pancreatic cancer (PDAC), epithelial–mesenchymal plasticity (EMP) drives metastasis and drug resistance, yet how it is controlled remains undefined. Dissecting it causally requires perturbing many genes while tracking rare state transitions at single-cell resolution over weeks. Pairing optical pooled screening with Perturb-seq, we mapped 800+ regulators and identified coherent pathways that resolve into distinct functional classes of plasticity control, including bidirectional regulators converging on H3K9me3 reprogramming.

Transcription factors (TFs) regulate gene expression via intrinsically disordered regions (IDRs), but the lack of defined binding pockets makes TFs difficult to target. To unlock IDR-targeted therapeutics, we present an optical pooled screening platform to systematically map TF-IDR interactions within native nuclear environments. We show these interactions are rare and highly selective. By characterizing CREB3–TAZ2 as a proof of concept, we elucidate its biophysical drivers, establishing a framework to drug historically undruggable TFs.