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Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition

Oncogene volume 41, pages 757–769 (2022)Cite this article

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Abstract

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted bone morphogenetic protein 4 (BMP4). Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion, and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (Isobaric Tags for Relative and Absolute Quantitation) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced OSBs was confirmed by immunohistochemistry of MDA PCa-118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC-neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while the addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC-overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.

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Fig. 1: EC-OSB conditioned medium increases the migration, invasion, and anchorage-independent growth of PCa cells.
Fig. 2: iTRAQ analysis identifies Tenascin C in EC-OSB conditioned medium.
Fig. 3: Tenascin C is expressed in tumor-induced osteoblasts in human bone metastasis specimens and Tenascin C-neutralizing antibody reduces EC-OSB-CM-mediated migratory activity in PCa cells.
Fig. 4: BMP4 stimulates Tenascin C expression in 2H11 cells through Smad1-Notch/Hey1 pathway.
Fig. 5: Knockdown of Tenascin C decreases the migration, invasion, and anchorage-independent growth of PC3-mm2 cells in vitro and the metastasis of PC3-mm2 cells to the bone in vivo.
Fig. 6: Tenascin C increases the migration and anchorage-independent growth of C4-2b cells in vitro and metastasis to lymph nodes in vivo.
Fig. 7: Tenascin C promotes prostate cancer cell migration through the α5β1-YAP1 pathway.

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Funding

This work was supported by grants from the NIH R01CA174798 (to S-HL, L-YY-L), NIH 5P50CA140388 (to CJL, S-HL), NIH P30CA16672 Core grant to MD Anderson Cancer Center, and Cancer Prevention Research Institute of Texas grants RP150179 and RP190252 (to S-HL and L-YY-L).

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Authors and Affiliations

  1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Yu-Chen Lee, Song-Chang Lin, Guoyu Yu & Sue-Hwa Lin

  2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Ming Zhu, Jian H. Song, Christopher J. Logothetis, Theocharis Panaretakis, Guocan Wang & Sue-Hwa Lin

  3. Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, NY, USA

    Keith Rivera & Darryl J. Pappin

  4. Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Li-Yuan Yu-Lee

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Contributions

L-YY-L and S-HL: conceived the idea, planned the experiments, and wrote the manuscript. Y-CL, S-CL, GY, MZ, JHS, KR, and DJP: carried out the experiments. Y-CL, S-CL, GY, L-YY-L, and S-HL: performed data analysis and interpretation. TP, GW, CJL, L-YY-L, and S-HL: provided scientific inputs for the development of the project.

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Correspondence to Sue-Hwa Lin.

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CJL reports receiving commercial research grants from Janssen, ORIC Pharmaceuticals, Novartis, Aragon Pharmaceuticals, and honoraria from Merck, Sharp & Dohme, Bayer, Amgen. The other authors declare no competing interests.

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Lee, YC., Lin, SC., Yu, G. et al. Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition. Oncogene 41, 757–769 (2022). https://doi.org/10.1038/s41388-021-02131-7

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