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LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer


The cover for issue 10 of Oncotarget features Figure 6, "Model of the role of LATS1/2 kinases in the pre–self-renewal (pre-SR) stage during sphere formation by CSCs," by Nozaki, et al.

Here, we found that LATS1/2, the core Hippo pathway-kinases, were highly expressed in the oral squamous cell carcinoma line SAS, which exhibits high capacity of CSCs, and that depletion of these kinases prevented SAS cells from forming spheres under serum-free conditions.

Detailed examination of the expression and activation of LATS kinases and related proteins over a time course of sphere formation revealed that LATS1/2 were more highly expressed and markedly activated before initiation of self-renewal.

"Cancer stem cells, also called tumor-initiating cells, drive tumorigenesis and tumor heterogeneity through their abilities to self-renew and generate tumorigenic progeny."

Figure 6: Model of the role of LATS1/2 kinases in the pre–self-renewal (pre-SR) stage during sphere formation by CSCs. The process of sphere formation of CSCs consists of four stages: early, pre-SR, initiation of self-renewal (in-SR), and mature sphere formation. LATS1/2 are required for self-renewal via regulation of TAZ and SNAIL. The solid and dashed lines show imaginary lines, not actual values, of independent expression and/or activity levels of the indicated proteins. Black arrows show the direction of the signaling cascade found in this study.

For instance, TAZ confers self-renewal capacity, a CSC property, on breast, brain, and oral cancer cells, probably by inducing the EMT.

Similarly, YAP confers some CSC properties, such as sphere formation and chemoresistance, on hepatocellular carcinoma, esophageal cancer, osteosarcoma, and basal-like breast cancer cells by coordinating the expression of interleukin 6 and stemness marker proteins such as SOX2, SOX9, and CD90.

Nevertheless, the biological roles of LATS1/2, as well as the mechanisms by which they enable cancer cells to acquire and maintain CSC properties, are incompletely understood.

In this study, using SAS cells as a model of CSCs in OSCC, we showed that LATS1/2 are essential for self-renewal of CSCs, and in particular for the initiation of sphere formation.

"Collectively, our results provide a new insight into the molecular mechanisms by which CSCs execute self-renewal and non-CSCs acquire the property of stemness."

Full text - https://doi.org/10.18632/oncotarget.26583

Correspondence to - Norikazu Yabuta - nyabuta@biken.osaka-u.ac.jp

Keywords - Hippo pathway, LATS, SNAIL, oral cancer, cancer stem cells (CSCs)

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