Morphological Screening of Mesenchymal Mammary Tumor Organoids to Identify Drugs That Reverse Epithelial-mesenchymal Transition

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jul 13

PMID 34253738

Citations 23

Authors

Na Zhao

Reid T Powell

Xueying Yuan

Goeun Bae

Kevin P Roarty

Fabio Stossi

Martina Strempfl

Michael J Toneff

Hannah L Johnson

Sendurai A Mani

Philip Jones

Clifford C Stephan

Jeffrey M Rosen

Affiliations

Soon will be listed here.

Abstract

The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended "spikes" in 3D matrices. Upon a miR-200 induced mesenchymal-epithelial transition (MET), the organoids switch to a smoother round morphology. Based on these observations, we developed a morphological screening method with accompanying analytical pipelines that leverage deep neural networks and nearest neighborhood classification to screen for EMT-reversing drugs. Through screening of a targeted epigenetic drug library, we identified multiple class I HDAC inhibitors and Bromodomain inhibitors that reverse EMT. These data support the use of morphological screening of mesenchymal mammary tumor organoids as a platform to identify drugs that reverse EMT.

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