Panoply™ Human YES1 Over-expressing Stable Cell Line

Identifying novel gene mutations is crucial for effective personalized treatment of non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is also essential for successful individualized therapy. YES1 is a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family of kinases (SFKs), and its molecular alterations can be found in a significant proportion of lung cancer patients. Here, researchers confirmed that YES1 is crucial for the development and progression of NSCLC. Moreover, in preclinical in vivo models, YES1 overexpression induced tumor metastasis. Knocking out the YES1 gene using CRISPR/Cas9 technology significantly inhibited tumor growth and metastasis. The effects of YES1 are primarily mediated through the mTOR (mammalian target of rapamycin) signaling pathway. Interestingly, cell lines and patient-derived xenograft models carrying YES1 gene amplification showed high sensitivity to the SFK inhibitor dasatinib, suggesting that YES1 status could serve as a predictive biomarker for dasatinib efficacy. In addition, high levels of YES1 protein expression are an independent predictor of poor prognosis in lung cancer patients.

To evaluate the pro-tumorigenic effect of YES1, researchers induced stable overexpression of YES1 in lung cancer cell lines of different histological subtypes (adenocarcinoma: H1792, H2009, A549; squamous cell carcinoma: Calu-1, SW900). In cells with basal YES1 gene amplification and high protein expression (high YES1 cell lines), YES1 overexpression significantly enhanced cell proliferation (Figure 1A, left panel). In contrast, no effect on cell proliferation was observed in cells without basal YES1 gene amplification (low YES1 cell lines) (Figure 1B, left panel). Next, the researchers evaluated the effects of YES1 overexpression in vivo. Subcutaneous models showed that, except for one cell line (Calu-1, which showed a negative correlation), tumors formed by all YES1-overexpressing cells were larger than those in the control group, regardless of the basal YES1 status (Figure 1A and 1B, middle panels). Although no difference in tumor proliferation was observed, apoptosis was significantly reduced in YES1-overexpressing tumors as detected by cleaved-caspase 3 staining (Figure 1A and 1B, right panels).

In YES1-overexpressing Calu-1 cells, significant metastatic lesions were found in the lungs (Figure 1C). In fact, no metastatic lesions were found in the control group. In A549 cells, lung metastasis occurred in both the control and YES1-overexpressing cells. Notably, a significant increase in liver metastasis was observed in YES1-overexpressing cells (Figure 1D). No metastatic lesions were found in tumor-bearing mice injected with H2009, H1792, and SW900 cell lines. To further investigate the pro-metastatic activity of YES1 in lung cancer cells, the researchers evaluated another intracardiac injection and bone metastasis model. Intracardiac injection of A549-TM-YES1 cells resulted in increased total tumor burden (Figure 1E). Notably, bone metastasis was only present in mice injected with YES1-overexpressing A549 cells (Figure 1F). These research findings indicate that YES1 can promote the spread of tumor cells and suggest that YES1 expression may play an important role in regulating the metastatic potential of non-small cell lung cancer.

Figure 1. YES1 overexpression induces tumor growth and metastatic spreading. (Garmendia I, et al., 2019)