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Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer

Oncogene volume��43, pages 2325–2337 (2024)Cite this article

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Abstract

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.

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Fig. 1: PLXND1 is upregulated in NEPC and prostate cancer cells showing neural lineage plasticity.
Fig. 2: AR signaling negatively regulates the expression of PLXND1 in enzalutamide-resistant prostate cancer.
Fig. 3: Knockdown of PLXND1 represses the cell proliferation and improves enzalutamide treatment.
Fig. 4: Knockdown of PLXND1 decreases the neuroendocrine traits.
Fig. 5: Knockout of PLXND1 by CRISPR/Cas9 inhibits the NEPC cells in vitro, organoids viability, and tumor growth in vivo.
Fig. 6: HSP70 inhibition affects the protein stability of PLXND1.

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Data availability

The RNA sequence data in the present study have been deposited in Gene Expression Omnibus (GEO) with the accession number GSE267961. The data obtained in this study are available upon reasonable request from the corresponding authors.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health R37CA249108 (Liu), R01CA251253 (Liu), R21CA277171 (Liu), Department of Defense HT9425-23-1-0144 (Liu), HT9425-23-1-0325 (Liu), and a UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373). The maintenance and characterization of the LuCaP PDX models were supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183), and National Institutes of Health P01-CA163227.

Funding

This work was supported in part by grants from NIH/NCI R37CA249108 (Liu), R01CA251253 (Liu), R21CA277171 (Liu), Department of Defense HT9425-23-1-0144 (Liu), HT9425-23-1-0325 (Liu), and UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373).

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Authors and Affiliations

  1. Department of Urologic Surgery, University of California, Davis, CA, USA

    Bo Chen, Pengfei Xu, Joy C. Yang, Christopher Nip, Leyi Wang, Yuqiu Shen, Shu Ning, Yufeng Shang, Allen C. Gao & Chengfei Liu

  2. Department of Urology, West China Hospital, Sichuan University, Sichuan, China

    Bo Chen, Qiang Wei & Liangren Liu

  3. Graduate Group in Integrative Pathobiology, University of California, Davis, CA, USA

    Leyi Wang & Chengfei Liu

  4. Department of Urology, University of Washington, Washington, WA, USA

    Eva Corey

  5. University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Allen C. Gao & Chengfei Liu

  6. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA

    Jason E. Gestwicki

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Contributions

BC and CL conceived of the project and designed the experiments. BC, PX, JCY, SN, and CL developed the methodology. BC, PX, JCY, CN, YQS, and YFS performed the experiments and acquired the data. CN, LW, LL, QW, ACG, EC, JEG, and CL provided the technical and material support. BC and SN performed bioinformatics analysis. BC, PX, JCY, and CL interpreted and analyzed the data. BC and JCY wrote the manuscript. CN and CL edited the manuscript. CL supervised the study.

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Correspondence to Chengfei Liu.

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Chen, B., Xu, P., Yang, J.C. et al. Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer. Oncogene 43, 2325–2337 (2024). https://doi.org/10.1038/s41388-024-03081-6

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