Abstract
The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9-dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.
Highlights
The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stemlike cells sustain tumors and drive metastasis
SW480 and SW620 cell lines were derived from a primary colorectal adenocarcinoma and its lymph node metastasis, respectively[27]
We started by characterizing the expression of colorectal cancer stem cells (CR-CSCs) markers[3], finding that metastatic SW620 cells had higher levels of BMI1, CD133 and SOX9 than SW480 primary cells (Fig. 1A)
Summary
High levels of SOX9 correlate in CR-CSCs and metastatic cells. SW480 and SW620 cell lines were derived from a primary colorectal adenocarcinoma and its lymph node metastasis, respectively[27]. That low dose of rapamycin promoted a decrease of 66 and 90% in primary and secondary tumorspheres in SW620 control cells, whereas the decline was only of 32 and 18% respectively in shSOX9 cells (Fig. 6E) These observations confirm that SOX9 levels sensitize CR-CSCs to rapamycin treatment, an effect likely mediated by the impairment of the mTOR signaling pathway, rather than the decline in SOX9 levels themselves. In order to validate the antitumor activity of rapamycin in cells with different SOX9 expression in vivo, we injected SW620 and SW480 cells subcutaneously in nude mice and treated animals with 5 mg/Kg of rapamycin twice a week This treatment resulted in delayed tumor initiation and a significant decrease in tumor growth in SW620 cells (p < 0.01) compared to that observed with the vehicle control treatments (Fig. 7A–C). We reveal that SOX9 levels define the antitumor action of the mTOR inhibitor rapamycin in colorectal cells, providing preclinical evidence to justify further research into therapeutic strategies based on this agent, using SOX9 levels as a biomarker for patient stratification
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