Extracellular RNA signatures of mutant KRAS(G12C) lung adenocarcinoma cells

Abstract

Extracellular RNAs (exRNAs) are actively secreted from cells in membrane-bound extracellular vesicles (EVs). Diverse classes of RNAs are secreted as exRNAs, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and transposable element RNAs (TE RNAs). However, the full composition and clinical utility of exRNAs secreted in response to oncogenic signaling are unknown. Here we use both affinity- and nanofiltration-based EV isolation approaches to show that mutant KRAS(G12C) signaling results in the secretion of specific lncRNAs, TE RNAs, and mRNAs, some of which are prognostic for lung adenocarcinoma (LUAD) patient survival. We found that inhibition of KRAS(G12C) signaling broadly reprograms the noncoding transcriptome, as evidenced by a substantial increase in TE RNA secretion. KRAS(G12C) inhibition also increased the abundance of secreted lncRNAs and retained intron-containing transcripts, while decreasing the mRNA content of EVs. Oncogenic KRAS(G12C) signaling was required for the secretion of mRNAs from a set of 20 genes that are significantly associated with unfavorable clinical outcomes in LUAD. Our study suggests that both coding and noncoding RNAs that are secreted in EVs may serve as KRAS(G12C)-specific signatures for diagnosing lung cancer.

Transposable element RNA dysregulation in mutant KRAS(G12C) 3D lung cancer spheroids

“…Future studies may provide new insights into the potential roles of noncoding/TE RNAs in mechanisms of KRAS(G12C) inhibitor resistance. Furthermore, TE RNAs that are secreted from cancer cells upon KRAS inhibition may serve as extracellular RNA biomarkers 2,3,5,18,19 of response and/or resistance to KRAS inhibitor therapies 20 .…”