Context-Dependent Tumorigenic Effect of Testis-Specific Mitochondrial Protein Tiny Tim 2 in Drosophila Somatic Epithelia.

Cristina Molnar,Cayetano Gonzalez,Anxela Louzao

doi:10.3390/cells9081842

Abstract

We have undertaken a study towards understanding the effect of ectopic expression of testis proteins in the soma in Drosophila. Here, we show that in the larval neuroepithelium, ectopic expression of the germline-specific component of the inner mitochondrial translocation complex tiny tim 2 (ttm2) brings about cell autonomous hyperplasia and extension of G2 phase. In the wing discs, cells expressing ectopic ttm2 upregulate Jun N-terminal kinase (JNK) signaling, present extended G2, become invasive, and elicit non-cell autonomous G2 extension and overgrowth of the wild-type neighboring tissue. Ectopic tomboy20, a germline-specific member of the outer mitochondrial translocation complex is also tumorigenic in wing discs. Our results demonstrate the tumorigenic potential of unscheduled expression of these two testis proteins in the soma. They also show that a unique tumorigenic event may trigger different tumor growth pathways depending on the tissular context.

Highlights

Cancer/Testis (CT) genes are a heterogeneous group of genes that under normal conditions are predominantly expressed in testis and trophoblast, but are atypically upregulated in cancers of various histological origins [1,2,3]
In the context of a long-term study using Drosophila towards understanding the effect of ectopic expression of testis proteins in the soma, we have found that Tiny tim 2 (Ttm2) and Tomboy20, have tumorigenic effects when expressed in somatic epithelia
These results strongly suggest that, as it does in many other tumor models, Jun N-terminal kinase (JNK) could play a key role in ttm2-dependent non-autonomous apoptosis and overgrowth in wing disc epithelia [39]

Summary

Introduction

Cancer/Testis (CT) genes are a heterogeneous group of genes that under normal conditions are predominantly expressed in testis and trophoblast, but are atypically upregulated in cancers of various histological origins [1,2,3]. Because the blood-testis barrier creates an immune privileged site [4] some of the proteins encoded by CT genes are antigenic and elicit humoral and cellular immune responses when expressed in somatic tumors. It was through the autoimmune response against such. Some CT proteins have become instrumental in oncology as candidates for immunotherapy [9,10,11,12], or as biomarkers to predict recurrence or to discern malignancy grades [13] Beyond these applications, the key standing question regarding CT genes is whether they are just coincidental markers of tumor progression or significant mediators of tumorigenesis.

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