Generation of ductal organoids from normal mammary luminal cells reveals invasive potential

Here we present an experimental model for human luminal progenitor cells that enables single, primary cells isolated from normal tissue to generate complex branched structures resembling the ductal morphology of low‐grade carcinoma of no special type. Thereby, we find that ductal structures are generated through invasive branching morphogenesis via matrix remodeling and identify reduced actomyosin contractility as a prerequisite for invasion. In addition, we show that knockout of E‐cadherin causes a dissolution of duct formation as observed in invasive lobular carcinoma, a subtype of invasive carcinomas where E‐cadherin function is frequently lost. Thus, our model shows that invasive capacity can be elicited from normal luminal cells in specific environments, which results in low‐grade no special type morphology. This assay offers a platform to investigate the dynamics of luminal cell invasion and unravel the impact of genetic and non‐genetic aberrations on invasive morphology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.