BRMS1-Mediated Suppression of Metastases in p53 Mutant Lung Adenocarcinoma

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In LUAD p53 mutations occur more commonly (45%) than KRAS, EGFR, or ELM4/ALK genomic alterations, combined. Previously we have shown that BRMS1-mediated suppression of cell migration and invasion is associated with loss of p53. An unbiased analysis of the TCGA database reveals low BRMS1 expression is associated with a poor progression-free survival in p53mut LUAD, not p53WT, and in LUAD with a solid histologic subtype. Gene expression arrays confirm that BRMS1KD correlates with multiple p53 regulated genes involved in migration and invasion. Our lab is currently examining how BRMS1 transcriptionally regulates metastasis-related p53-target genes in p53mut LUAD. Using RNA-seq and ChIP-seq we have shown that BRMS1 transcriptionally upregulates and/or downregulates selected pro- and anti-metastatic genes, respectively typically regulated by p53WT. We have previously shown that inhibition of BRMS1 degradation using the CK2 inhibitor CX4945 results in significantly less cell migration and invasion in p53mut compared to p53WT LUAD cells. To better characterize mechanisms of action and functional assessments in vivo we have generated the first Brms1-/- GEMM in oncogenic Kras+/LSL-G12D/ p53fl/fl with different Brms1 profiles (Brms1-/-, +/+, +/-) (KPB mice). The goals of this project are to understand the transcriptional mechanisms of BRMS1-mediated suppression of metastases in p53mut LUAD. Using patient-derived samples (human tumors and PDOs) we plan to discern the contribution of BRMS1 to the development of metastases and assess the therapeutic significance of targeting BRMS1 in p53mut LUAD with different histologic subtypes. We collaborate with the Marty W. Mayo Laboratory, the Jorge Reis-Filho Laboratory, and the Prasad S. Adusumilli Laboratory.

BMSR1 Models

A. CK2a’-induced BRMS1 degradation promotes metastasis of NSCLC in vivo. A, induction of CK2a’ promotes distant metastasis of NSCLC. H157 stable cell lines were orthotopically injected into the left lung of mice. Mouse bioluminescent CT images show the growth of tumor and metastatic sites in three representative mice in each group (1–3, control; 4–6, BRMS1WT without doxycycline; 7–9, BRMS1WT with doxycycline (Doxy.); 10–12, BRMS1S30A with doxycycline). The scale indicates the signal intensity cell quantification. B. activation of CK2a’ induces metastasis of tumors with BRMS1 wild-type. The graph represents fold changes of metastasis burden over control group 43 days postinjection. (Cancer Res 2016)