A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors.

Anjali Bajpai, Taushif Ahmad Quazi, Hong-Wen Tang, Nishat Manzar, Virender Singh, Ashwani Thakur, Bushra Ateeq, Norbert Perrimon, Pradip Sinha

Disease models & mechanisms 2020 Jul 23

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Peptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper. © 2020. Published by The Company of Biologists Ltd.

Citation

Anjali Bajpai, Taushif Ahmad Quazi, Hong-Wen Tang, Nishat Manzar, Virender Singh, Ashwani Thakur, Bushra Ateeq, Norbert Perrimon, Pradip Sinha. A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors. Disease models & mechanisms. 2020 Jul 23;13(7)