JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila
Open Access
- 15 November 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 17 (11), e1009893
- https://doi.org/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. Cancers develop through the accumulation of multiple oncogenic mutations. Such mutations are different among tumors of different origins and thus identification of a common oncogenesis pathway among different tumors is crucial for developing effective anti-cancer strategies. Here, using fruit fly Drosophila as a model organism, we searched for a common oncogenesis pathway between two malignant tumor models with different oncogenic alterations, namely oncogenic Ras activation with cell polarity defects (RasV12/scrib-/-) and oncogenic microRNA bantam overexpression with endocytic defects (bantam/rab5-/-). Transcriptome analyses followed by an RNAi screen identified Juvenile hormone Inducible-21 (JhI-21), a Drosophila homolog of the L-amino acid transporter 1 (LAT1), as essential for growth and malignancy of these tumor models. Similar to mammalian cancers, JhI-21 was upregulated in these tumors and promoted tumor growth and progression by activating the mTOR-S6 pathway. Administration of LAT1 inhibitors to flies significantly suppressed growth of RasV12/scrib-/-, but not bantam/rab5-/- tumors. Our analyses revealed that bantam induces drug resistance against LAT1 inhibitors via downregulation of the TMEM135-like gene CG31157. Our observations establish a powerful genetic model for studying cancer progression and drug resistance in Drosophila.Funding Information
- Grant-in-Aid for Scientific Research (20H00515)
- Japan Agency for Medical Research and Development (21gm5010001)
- Grant-in-Aid for Scientific Research on Innovative Areas (20H05320)
- Grant-in-Aid for Transformative Research Areas A (20H05945)
- Grant-in-Aid for Transformative Research Areas A (21H05284)
- JST Moonshot R&D (JPMJMS2022)
- Naito Foundation
- Naito Foundation
- Takeda Science Foundation
- Takeda Science Foundation
- Toray Science Foundation
- MSD Life Science Foundation
- JSPS Research Fellowships
This publication has 42 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- mTOR Signaling in Growth Control and DiseaseCell, 2012
- The Hippo Signaling Pathway in Development and CancerDevelopmental Cell, 2010
- Organogenesis and tumorigenesis: Insight from the JAK/STAT pathway in the Drosophila eyeDevelopmental Dynamics, 2010
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Drosophila expresses a CD98 transporter with an evolutionarily conserved structure and amino acid-transport propertiesBiochemical Journal, 2009
- The functional contrariety of JNKMolecular Carcinogenesis, 2007
- JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in DrosophilaThe EMBO Journal, 2006
- The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAPCell, 2005
- Evolution of TNF Signaling Mechanisms: JNK-Dependent Apoptosis Triggered by Eiger, the Drosophila Homolog of the TNF SuperfamilyCurrent Biology, 2002