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

• Main Authors: Anjali Bajpai, Taushif Ahmad Quazi, Hong-Wen Tang, Nishat Manzar, Virender Singh, Ashwani Thakur, Bushra Ateeq, Norbert Perrimon, Pradip Sinha
• Format: Article
• Language: English
• Published: The Company of Biologists 2020-07-01
• Series: Disease Models & Mechanisms
• Subjects: drosophila; peptide therapeutic; yki; intestinal stem cells; integrin signaling
• Online Access: http://dmm.biologists.org/content/13/7/dmm044420

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.