CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

Musicant, A. M.; Parag-Sharma, K.; Gong, W.; Sengupta, M.; Chatterjee, A.; Henry, E. C.; Tsai, Y.-H.; Hayward, M.; Sheth, S.; Betancourt, R.; Hackman, T.; Padilla, R. J.; Parker, J. S.; Giudice, J.; Flaveny, C. A.; Hayes, D. N.; Amelio, A. L.

doi:10.1101/2020.06.03.129668

bioRxiv · 10.1101/2020.06.03.129668

CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition

Musicant, A. M.·Parag-Sharma, K.·Gong, W.·Sengupta, M.·Chatterjee, A.·Henry, E. C.·Tsai, Y.-H.·Hayward, M.·Sheth, S.·Betancourt, R.·Hackman, T.·Padilla, R. J.·Parker, J. S.·Giudice, J.·Flaveny, C. A.·Hayes, D. N.·Amelio, A. L.

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Abstract

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by the transcriptional co-activator fusion CRTC1-MAML2. The mechanisms by which the chimeric CRTC1-MAML2 oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that CRTC1-MAML2 induces transcriptional activation of the non-canonical PGC-1 splice variant PGC-14, which regulates PPAR{gamma}-dependent IGF-1 expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. CRTC1-MAML2 positive tumors are dominated by IGF-1 pathway activation and small molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1R inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPAR{gamma}inhibition with inverse agonists. These results yield insights into the aberrant co-regulatory functions of CRTC1-MAML2 and identify a specific vulnerability that can be exploited for precision therapy.

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Musicant, A. M., Parag-Sharma, K., Gong, W., Sengupta, M., Chatterjee, A., Henry, E. C., Tsai, Y.-H., Hayward, M., Sheth, S., Betancourt, R., Hackman, T., Padilla, R. J., Parker, J. S., Giudice, J., Flaveny, C. A., Hayes, D. N., Amelio, A. L.. 2020-06-03. CRTC1-MAML2 Establishes a PGC1α-IGF1 Circuit that Confers Vulnerability to PPARγ Inhibition. https://doi.org/10.1101/2020.06.03.129668

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