Department of Cancer Biology
Great Departments / Cancer Medicine
|Associate Professor||YAMAGUCHI Tomoya
tyamaguchi (at mark) kumamoto-u.ac.jp
|Assistant Professor||YAMAMOTO Masatoshi
myamamoto (at mark) kumamoto-u.ac.jp
We previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a target for transcriptional activation via the lineage-survival oncogene TTF-1 in lung adenocarcinoma (Cancer Cell, 2012). ROR1 is necessary to sustain the EGFR survival signaling in both kinase-dependent and -independent manners. ROR1 also sustains a favorable balance between pro-survival PI3K-AKT and pro-apoptotic ASK1-p38 signaling pathway in lung adenocarcinoma cells (Cancer Sci, 2016). We also identified MYBPH as a transcriptional target of TTF-1 and its ROCK-inhibiting and consequently invasion and metastasis-inhibiting roles (EMBO J, 2012). We therefore proposed that TTF-1 is an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression (Cancer Cell, 2013). Recently, we found that ROR1 facilitates the interaction of CAVIN1 and CAV1 at the plasma membrane in a kinase activity-independent manner, which in turn sustains caveolae formation and pro-survival signaling towards AKT through multiple RTKs such as EGFR, MET and IGF-IR, via its scaffold function for CAVIN1 and CAV1 in lung adenocarcinoma (Nat Commun, 2016; Fig. 1). These results suggest that the scaffold function of ROR1 is an attractive target for overcoming EGFR-TKI (Gefitinib) resistance due to bypass signaling in lung cancer. We also found that ROR1 as a caveolae-regulation molecule is involved in cell membrane organization and dynamics in cancer.
The goal of our laboratory is to understand the molecular pathogenesis of human solid tumor, hard-to-cure cancers, especially lung cancer, and then to translate our findings in order to develop novel strategies for better diagnosis, treatment and prevention.