JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila.

Bojie Cong,Shizue Ohsawa,Takefumi Kondo,Tatsushi Igaki,Mai Nakamura,Yukari Sando

doi:10.1371/journal.pgen.1009893

Abstract

Identifying a common oncogenesis pathway among tumors with different oncogenic mutations is critical for developing anti-cancer strategies. Here, we performed transcriptome analyses on two different models of Drosophila malignant tumors caused by Ras activation with cell polarity defects (RasV12/scrib-/-) or by microRNA bantam overexpression with endocytic defects (bantam/rab5-/-), followed by an RNAi screen for genes commonly essential for tumor growth and malignancy. We identified that Juvenile hormone Inducible-21 (JhI-21), a Drosophila homolog of the L-amino acid transporter 1 (LAT1), is upregulated in these malignant tumors with different oncogenic mutations and knocking down of JhI-21 strongly blocked their growth and invasion. JhI-21 expression was induced by simultaneous activation of c-Jun N-terminal kinase (JNK) and Yorkie (Yki) in these tumors and thereby contributed to tumor growth and progression by activating the mTOR-S6 pathway. Pharmacological inhibition of LAT1 activity in Drosophila larvae significantly suppressed growth of RasV12/scrib-/- tumors. Intriguingly, LAT1 inhibitory drugs did not suppress growth of bantam/rab5-/- tumors and overexpression of bantam rendered RasV12/scrib-/- tumors unresponsive to LAT1 inhibitors. Further analyses with RNA sequencing of bantam-expressing clones followed by an RNAi screen suggested that bantam induces drug resistance against LAT1 inhibitors via downregulation of the TMEM135-like gene CG31157. Our observations unveil an evolutionarily conserved role of LAT1 induction in driving Drosophila tumor malignancy and provide a powerful genetic model for studying cancer progression and drug resistance.

Highlights

Cancer development is achieved by the accumulation of oncogenic mutations that promote cell proliferation, survival, invasion, and metastasis
We identified that Juvenile hormone Inducible-21 (JhI-21), a Drosophila homolog of the L-amino acid transporter 1 (LAT1), is upregulated in these malignant tumors with different oncogenic mutations and knocking down of JhI-21 strongly blocked their growth and invasion
Mutations that drive tumor growth and malignancy are different between tumors and identification of a common oncogenesis pathway among tumors with different oncogenic alterations is crucial for establishing effective anti-cancer strategies

Summary

Introduction

Cancer development is achieved by the accumulation of oncogenic mutations that promote cell proliferation, survival, invasion, and metastasis. Mutations that drive tumor growth and malignancy are different between tumors and identification of a common oncogenesis pathway among tumors with different oncogenic alterations is crucial for establishing effective anti-cancer strategies. LAT1 is a plasma membrane transporter for branched-chain amino acids (BCAAs) such as leucine and isoleucine[1], thereby promoting tumor growth by activating mTOR signaling[2]. CD98 promotes LAT1 protein stability and mediates the translocation of LAT1 to the cell membrane[3]. Genetic complexity and heterogenous nature of cancer have hindered progress in understanding the mechanism of the common genetic pathway of tumor growth and malignancy in mammalian systems

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Conclusion