Using SCLC circulating tumour cell (CTC)-derived tumour explant (CDX) models, the authors here report the first functional evidence of the role of NOTCH-driven NE to Non-NE plasticity in SCLC, facilitating vasculogenic mimicry (VM).

Authors identify TIAM1, a selective activator of the small GTPase RAC1, as a gene product upregulated in neuroendocrine SCLC cells. They show that depletion of TIAM1 or RAC1 inhibition leads to SCLC cell apoptosis through cytoplasmic translocation of the orphan nuclear receptor Nur77 and proapoptotic BCL2 conformational change.

Authors using paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models reveal a mechanism of drug resistance in SCLC mediated by Notch and nitric oxide activation of soluble guanylate cyclase signalling.