CtBP modulates Snail-mediated tumor invasion in Drosophila

Chenxi Wu,Chunhua Jiang,Xiaojin La,Wenzhe Li,Rui Zou,Yuanyuan Huang,Hong Chang,Mingyang Zhao,Zhuojie Li,Xiang Ding,Qian Xu,Gufa Lin,Lei Xue

doi:10.1038/s41420-021-00516-x

Abstract

Cancer is one of the most fatal diseases that threaten human health, whereas more than 90% mortality of cancer patients is caused by tumor metastasis, rather than the growth of primary tumors. Thus, how to effectively control or even reverse the migration of tumor cells is of great significance for cancer therapy. CtBP, a transcriptional cofactor displaying high expression in a variety of human cancers, has become one of the main targets for cancer prediction, diagnosis, and treatment. The roles of CtBP in promoting tumorigenesis have been well studied in vitro, mostly based on gain-of-function, while its physiological functions in tumor invasion and the underlying mechanism remain largely elusive. Snail (Sna) is a well-known transcription factor involved in epithelial-to-mesenchymal transition (EMT) and tumor invasion, yet the mechanism that regulates Sna activity has not been fully understood. Using Drosophila as a model organism, we found that depletion of CtBP or snail (sna) suppressed RasV12/lgl-/--triggered tumor growth and invasion, and disrupted cell polarity-induced invasive cell migration. In addition, loss of CtBP inhibits RasV12/Sna-induced tumor invasion and Sna-mediated invasive cell migration. Furthermore, both CtBP and Sna are physiologically required for developmental cell migration during thorax closure. Finally, Sna activates the JNK signaling and promotes JNK-dependent cell invasion. Given that CtBP physically interacts with Sna, our data suggest that CtBP and Sna may form a transcriptional complex that regulates JNK-dependent tumor invasion and cell migration in vivo.

Highlights

Tumor metastasis is a major contributor to the high mortality rate of cancer and accounts for more than 90% of cancer-related fatalities in patients with palpable clinical traits[1,2]
We found that Drosophila carboxy-terminal binding protein (CtBP) and Sna are physiologically required for RasV12/lgl-/- triggered tumor growth and invasion, and loss-of-cell polarityinduced invasive cell migration
Loss-of-CtBP suppresses RasV12/lgl-/- induced tumor growth and invasion In line with previous studies[38,39], clones of GFP-marked wild-type cells mediated by eyeless-Flp/MARCM system were observed in the larval eye–antennal imaginal disks and the brain optic lobes (Fig. 1a and Supplementary Fig. 1a), but were not seen in the adjacent ventral nerve cord (VNC) of the central nervous system (Fig. 1i)

Summary

Introduction

Tumor metastasis is a major contributor to the high mortality rate of cancer and accounts for more than 90% of cancer-related fatalities in patients with palpable clinical traits[1,2]. Metastasis is a process of cancer cells disseminating from a primary lesion via lymphatic and/or blood circulations to distal organs, which involves a variety of cellular mechanisms[3]. These include invading through basement membranes (BM), escaping immune surveillance, modulating tissue microenvironment, and. The homozygous mutation of mCtBP2 in mouse leads to developmental defects and embryonic death, while mCtBP1 homozygous deletion reduces their offsprings’ life span[18]. Whether endogenous CtBP is involved in cell invasion and EMT, or interacts with tumor-related signal pathways, as well as the potential molecular mechanisms, needs to be further explored

Methods

Results

Conclusion