Oncogenic Ras cooperates with knockdown of the tumor suppressor Lkb1 by RNAi to override organ size limits in Drosophila wing tissue.

• Type of Material: Article
• Authors: Briana Brown Rackley, Emory University; Evan Kiely, Emory University; Chang-Soo Seong, Emory University; Manali Rupji, Emory University; Melissa Gilbert-Ross, Emory University
• Language: English
• Date: 2020-03-03
• Publisher: DOAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2020 DOAJ.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.17912/micropub.biology.000223
• Title of Journal or Parent Work: MicroPublication Biology
• Volume: 2020
• Grant/Funding Information: This work was supported by National Institutes of Health grant 1R01CA201340 to MGR.; Research reported in this publication was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute of Emory University and NIH/NCI under award number, 2P30CA138292-04.
• Keywords: Oncology; Tumor suppressor; Hematology; Bioinformatics; Medical oncology; Biostatistics
• Research Categories: Biology, Cell; Biology, Bioinformatics; Biology, Biostatistics; Health Sciences, Oncology

Abstract

KRAS is the most frequently mutated oncogene in human cancer, particularly in cancers with a high mortality rate such as pancreatic, colorectal, and non-small cell lung cancer (NSCLC) (Ryan and Corcoran, 2018). While effective therapies directly targeting KRAS-mutant tumors have yet to be fully validated, recent clinical trials show positive progress for patients with the KRAS(G12C) mutation (Canon et al. 2019). Moreover, sequencing data has allowed for better understanding of how secondary mutations synergize with oncogenic KRAS to drive tumor progression. For example, activating mutations in KRAS frequently occur with loss-of-function mutations in the gene STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), resulting in decreased patient survival, de novo resistance to targeted treatments and immunotherapies, and increased likelihood of tumor recurrence (Cancer Genome Atlas Research Network 2014, Skoulidis et al. 2018, Caiola et al. 2018). Additionally, previous work from genetically engineered mouse models (GEMMs) suggests loss of Lkb1 is sufficient to promote the progression and metastasis of nascent Kras-driven lung adenocarcinoma (Ji et al. 2007). Therefore, we sought to determine whether knockdown of Lkb1 by RNAi could cooperate with activating mutations in Ras to drive tissue overgrowth in wing imaginal discs of the genetically tractable model organism Drosophila melanogaster.