Differentiation as a tool to treat rhabdomyosarcoma tumors

Rhabdomyosarcoma (RMS) is a soft tissue cancer that occurs predominantly in children and adolescents. RMS tumor cells resemble skeletal muscle cells. However, unlike normal skeletal muscle cells which undergo terminal differentiation, RMS tumor cells do not differentiate. The ability to remain undifferentiated could underlie the tumor-specific properties such as proliferation and metastasis in RMS. In this study, we identify the Wnt-pathway as a target signaling cascade that can promote RMS tumor cell differentiation. The Wnt-pathway is poorly active in RMS tumors due to elevated expression of the corepressor Transducin-like Enhancer of Split 3 (TLE3). Loss of TLE3 function resulted in Wnt-pathway activation, reduced proliferation, decreased migration and enhanced differentiation in RMS cells. We also uncover that TLE3 interacts with and recruits the histone methyltransferase KMT1A, causing repression of target genes and inhibition of differentiation in RMS. A combination treatment using the Wnt-pathway activating small molecule BIO and the KMT1A inhibiting drug chaetocin led to reduced tumor volume, decreased proliferation, increased differentiation and longer survival in RMS tumor-bearing mice. Thus, TLE3, the Wnt-pathway and KMT1A are excellent drug targets which can be exploited for treating RMS tumors.

Kalita B, Sahu S* , Bharadwaj A * , Singh J, Panneerselvam L, Martinez-Cebrian G, Agarwal M, and Mathew, SJ. (2024). The Wnt-pathway corepressor TLE3 interacts with the histone methyltransferase KMT1A to inhibit differentiation in Rhabdomyosarcoma. Oncogene. doi: https://doi.org/10.1038/s41388-023-02911-3

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Model depicting how activation of the Wnt-pathway by TLE3 knockout or using the small molecule BIO, and inhibition of the histone methyltransferase KMT1A can promote differentiation to target rhabdomyosarcoma tumors.