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SEMA3A-mediated crosstalk between prostate cancer cells and tumor-associated macrophages promotes androgen deprivation therapy resistance

Cellular & Molecular Immunology volume 18, pages 752–754 (2021)Cite this article

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Androgen deprivation therapy (ADT) is an important treatment strategy that can be used to delay the progression of prostate cancer. However, after an initial response, which varies significantly among patients, the disease eventually progresses despite the low levels of testosterone in the systemic circulation.1 The mechanism underlying the progression of prostate cancer to castration-resistant prostate cancer (CRPC) is not yet clear, and further investigation is needed.2 Tumor-associated macrophages (TAMs) are associated with resistance to ADT in prostate cancer.3,4 This study discovered that SEMA3A expression was upregulated in CRPC, which resulted in enhanced recruitment of monocytes and their polarization into the M2 subtype. Activated M2 TAMs could in turn promote cancer cell resistance to ADT. Mechanistically, SEMA3A could bind to the NRP1 receptor of TAMs, boosting the phosphorylation of downstream PI3K and AKT. Moreover, targeting SEMA3A and its receptor NRP1 proved to be a potent approach for CRPC treatment, offering a novel method for ameliorating ADT resistance in prostate cancer.

The above results showed that SEMA3A was coexpressed with TAMs and negatively correlated with prognosis. To further clarify the relationship between SEMA3A and TAMs, SEMA3A was knocked out utilizing Cas9 technology in the enzalutamide-resistant cell line C4-2B-enza. Then, THP1 cells and monocytes were stimulated with three (C4-2B, C4-2B-enza and C4-2B-enza/SEMA3A-KO) cell culture supernatants. A cell migration experiment was conducted to examine the ability of SEMA3A to recruit either THP1 cells or monocytes. As shown in Fig. 1E and Fig. S1B, C4-2B-enza cells promoted enhanced migration of THP1 cells and monocytes compared with C4-2B cells. However, when SEMA3A was knocked out, this enhanced migration was weakened. In addition, the results of qPCR experiments showed that the supernatant of the C4-2B-enza group could downregulate the expression of M1 markers in THP1 cells or monocytes and upregulate that of M2 markers in these cells compared to that of the C4-2B group. However, when SEMA3A was knocked out, this regulation was diminished (Fig. 1F, G). These results suggested that tumor cells could affect the migration and differentiation of THP1 cells or monocytes and that SEMA3A might participate in this process. A coculture model was constructed to investigate the effect of THP1 cells or monocytes on cancer cells. The proportion of apoptotic cells in cocultures with THP1 cells or monocytes and enzalutamide was significantly lower than that in control cultures (Fig. S1C). Thus, experimental data showed that SEMA3A secreted by prostate cancer cells could recruit monocytes and differentiate them toward the M2 subtype, which in turn promoted drug resistance in tumor cells.

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Acknowledgements

The National Natural Science Foundation of China (81472397 to S.R. and 81773154 to C.W.). The Top-level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03, C.W.). The Shanghai Natural Science Foundation (20ZR1449600, C.W.). The Leadership Program in Science and Technology of Beijing Municipal Science and Technology Commission (181100006318007, N.X.).

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Authors and Affiliations

  1. Department of Urology, Shanghai Changhai Hospital, Shanghai, China

    Fei Liu, Yue Yang, Lihe Dai & Shancheng Ren

  2. Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Fei Liu, Sujun Han & Nianzeng Xing

  3. State Key Laboratory of Kidney Diseases, Beijing, China

    Fei Liu

  4. Department of Urinary Surgery, Gongli Hospital, the Second Military Medical University, Shanghai, China

    Chao Wang

  5. Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiao tong University School of Medicine, Shanghai, China

    Hai Huang

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Liu, F., Wang, C., Huang, H. et al. SEMA3A-mediated crosstalk between prostate cancer cells and tumor-associated macrophages promotes androgen deprivation therapy resistance. Cell Mol Immunol 18, 752–754 (2021). https://doi.org/10.1038/s41423-021-00637-4

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