Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

Han, H.; Wang, Y.; Curto, J. N.; Gurrapu, S.; Laudato, S.; Rumandla, A.; Chakraborty, G.; Wang, X.; Chen, H.; Jiang, Y.; Kumar, D.; Caggiano, E. G.; Zhang, B.; Ji, Y.; Maity, S. N.; Hu, M.; Bai, S.; Aparicio, A.; Logothetis, C. J.; Navin, N.; Navone, N. M.; Chen, Y.; Giancotti, F. G.

doi:10.1101/2021.04.14.439569

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bioRxiv · 10.1101/2021.04.14.439569

Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer

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Abstract

Unsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.

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Han, H., Wang, Y., Curto, J. N., Gurrapu, S., Laudato, S., Rumandla, A., Chakraborty, G., Wang, X., Chen, H., Jiang, Y., Kumar, D., Caggiano, E. G., Zhang, B., Ji, Y., Maity, S. N., Hu, M., Bai, S., Aparicio, A., Logothetis, C. J., Navin, N., Navone, N. M., Chen, Y., Giancotti, F. G.. 2021-04-15. Transcriptional Inactivation of TP53 and the BMP Pathway Mediates Therapy-induced Dedifferentiation and Metastasis in Prostate Cancer. https://doi.org/10.1101/2021.04.14.439569

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