RHOB influences lung adenocarcinoma metastasis and resistance in a host-sensitive manner

Lung adenocarcinoma (ADC) is the most common lung cancer subtype and presents a high mortality rate. Clinical recurrence is often associated with the emergence of metastasis and treatment resistance. The purpose of this study was to identify genes with high prometastatic activity which could potentially account for treatment resistance.Global transcriptomic profiling was performed by robust microarray analysis in highly metastatic subpopulations. Extensive in vitro and in vivo functional studies were achieved by overexpression and by silencing gene expression.We identified the small GTPase RHOB as a gene that promotes early and late stages of metastasis in ADC. Gene silencing of RHOB prevented metastatic activity in a systemic murine model of bone metastasis. These effects were highly dependent on tumor-host interactions. Clinical analysis revealed a marked association between high RHOB levels and poor survival. Consistently, high RHOB levels promote metastasis progression, taxane-chemoresistance, and contribute to the survival advantage to γ-irradiation. We postulate that RHOB belongs to a novel class of >genes of recurrence> that have a dual role in metastasis and treatment resistance.This work was supported by “UTE project FIMA” agreement The Cancer Research Thematic Network of the Health Institute Carlos III (RTICC RD06/0020/0066), Spanish Ministry of Science and Innovation & European Regional Development Fund (ERDF) “Una manera de hacer Europa”, PI042282, FIT-090100-2005-46, SAF-2009-11280, SAF-2012-40056 grants 67/2005 and 09/2009 from the Government of Navarra, and “La Caixa Foundation” awards to F.L. PI10/00166 to L.M. D.L-R was supported by the FIMA and FPU. I.A. was funded by the Basque Government. F.L. is an investigator from the I3 Program.Peer Reviewe