Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

Panesso-Gomez, S.; Cole, A. J.; Wield, A.; Anyaeche, V. I.; Shah, J.; Jiang, Q.; Ebai, T.; Sharrow, A.; Tseng, G.; Yoon, E.; Brown, D. D.; Clark, A. M.; Larsen, S. D.; Eder, I.; Gau, D.; Roy, P.; Dahl, K. N.; Tran, L.; Jiang, H.; McAuliffe, P. F.; Lee, A.; Buckanovich, R.

doi:10.1101/2024.11.15.623825

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bioRxiv · 10.1101/2024.11.15.623825

Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

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Abstract

Chemoresistance is a major driver of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single cell culture to identify, retrieve, and RNA-Seq profile primary quiescent ovarian cancer cells (qOvCa). We found that many qOvCa differentially expressed genes are transcriptional targets of the Myocardin Related Transcription Factor/Serum Response Factor (MRTF/SRF) pathway. We also found that genetic disruption of MRTF-SRF interaction, or an MRTF/SRF inhibitor (CCG257081) impact qOvCa gene expression and induce a quiescent state in cancer cells. Suggesting a broad role for this pathway in quiescence, CCG257081 treatment induced quiescence in breast, lung, colon, pancreatic and ovarian cancer cells. Furthermore, CCG081 (i) maintained a quiescent state in patient derived breast cancer organoids and, (ii) induced tumor growth arrest in ovarian cancer xenografts. Together, these data suggest that MRTF/SRF pathway is a critical regulator of quiescence in cancer and a possible therapeutic target. SignificanceQuiescence is a critical driver of chemoresistance. The MRFT-SRF pathway regulates cancer cell quiescence and inhibiting the MRTF-SRF pathway can prevent the outgrowth of quiescent cancer cells and improve cancer outcomes.

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Panesso-Gomez, S., Cole, A. J., Wield, A., Anyaeche, V. I., Shah, J., Jiang, Q., Ebai, T., Sharrow, A., Tseng, G., Yoon, E., Brown, D. D., Clark, A. M., Larsen, S. D., Eder, I., Gau, D., Roy, P., Dahl, K. N., Tran, L., Jiang, H., McAuliffe, P. F., Lee, A., Buckanovich, R.. 2024-11-17. Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.. https://doi.org/10.1101/2024.11.15.623825

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