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

Lee, Yu-Chen, Lin, Song-Chang, Yu, Guoyu, Zhu, Ming, Song, Jian, Rivera, Keith, Pappin, Darryl, Logothetis, Christopher, Panaretakis, Theocharis, Wang, Guocan, Yu-Lee, Li-Yuan, Lin, Sue-Hwa (November 2021) Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition. BioRxiv. (Unpublished)

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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 (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted 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 (iTRAQ) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced osteoblasts was confirmed by immunohistochemistry of MDA-PCa118b 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 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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > metastasis diseases & disorders > cancer > cancer types > prostate cancer
CSHL Authors:	Pappin, Darryl J. Rivera, Keith
Communities:	CSHL labs > Pappin lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	8 November 2021
Date Deposited:	26 May 2022 14:40
Last Modified:	26 May 2022 14:40
URI:	https://repository.cshl.edu/id/eprint/40633

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