A model of oral peptide therapeutics for adult Intestinal Stem Cell tumors

Citation:

Bajpai A, Ahmad QT, Tang H-W, Manzar N, Singh V, Thakur A, et al. A model of oral peptide therapeutics for adult Intestinal Stem Cell tumors. Dis Model Mech. 2020;
2020_DMM_Bajpai.pdf6.34 MB

Date Published:

2020 Jun 15

Abstract:

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/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) protein, specifically its TONDU domain, competitively inhibits YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that either overexpression of the TONDU peptide or its oral uptake leads to suppression of Yorkie (Yki)-driven intestinal stem cell (ISC) tumors in the adult midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with ChIP analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish as a reliable platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.

Last updated on 07/12/2020