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Abstract The prognosis of colorectal cancer (CRC) patients with distant metastasis remains poor, requiring elucidation of molecular mechanisms and identification of therapeutic targets. While cancer stem cells have been implicated in metastasis, recurrence, and drug resistance, our understanding of the regulatory mechanisms governing the stemness of CRC stem cells remains largely incomplete. In this study, we utilized an innovative autochthonous metastatic mouse model of CRCs generated by the introduction of sporadic mutations in Ctnnb1, Kras, Trp53, and Smad4 genes (CKPS mice) and CRC cell lines derived from the mice (CKPS cells). Our investigation revealed that the cAMP/PKA/CREB and TGFβ/SMAD4 pathways play a positive and negative role, respectively, in the sphere-forming and metastasis-initiating ability of CRC cells. Treatment with the CREB inhibitor 666-15 or the genetic knockout of CREB significantly reduced the spheroid-forming and metastasis-initiating potentials of CKPS cells. Intriguingly, we observed that the irinotecan treatment induced CREB phosphorylation in liver metastases, and co-treatment of 666-15 greatly potentiated the inhibitory effect of irinotecan on liver metastasis. Furthermore, we found that the transition from 2D to 3D spheroid culture of CKPS cells led to the induction of RhoC expression. Notably, RhoC knockout in CKPS cells effectively suppressed spheroid formation in vitro and inhibited metastasis formation in an intrasplenic injection liver metastasis assay. Potential therapeutic implications of these findings will be discussed. Citation Format: Teruaki Fujishita, Makoto M. Taketo, Masahiro Aoki. Exploring signaling pathways essential for stemness and metastasis of colorectal cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5449.
Fujishita et al. (Fri,) studied this question.