Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion

Yugang Wang, Udit Singhal, Yuanyuan Qiao, Tadas Kasputis, Jae Seung Chung, Huiru Zhao, Farah Chammaa, Jacob A. Belardo, Therese M. Roth, Hao Zhang, Alexander B. Zaslavsky, Ganesh S. Palapattu, Kenneth J. Pienta, Arul M. Chinnaiyan, Russell S. Taichman, Frank C. Cackowski, Todd M. Morgan

Research output: Contribution to journalArticle

Abstract

Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilection to the hindlimb (femur) compared to the forelimb (humerus). Comparative gene expression profiling was performed within the humerus and femur from non–tumor-bearing mice to evaluate differences in the microenvironments of these locations. This revealed the relative overexpression of the Wnt signaling inhibitors WIF1 and SOST in the humerus compared to the femur, with increased WNT5A expression in femur bone marrow, suggesting a coordinated upregulation of Wnt signals within the femur compared to the humerus. Conditioned medium (CM) from bone marrow stromal cells (HS-5 cells) was used to mimic the bone marrow microenvironment, which strongly promoted prostate cancer cell invasion (3.3-fold increase in PC3 cells, P < .05; 7-fold increase in LNCaP cells, P < .05). WNT5A shRNA knockdown within the CM-producing HS-5 cells significantly decreased PC3 (56%, P < .05) and LNCaP (60%, P < .05) cell invasion. Similarly, preincubation of CM with WIF1 significantly blocked LNCaP cell invasion (40%, P < .05). shRNA-mediated knockdown of the Wnt receptors FZD4 and FZD8 also strongly inhibited tumor cell invasion (60% inhibition shFZD4, P < .05; 63% shFZD8, P < .05). Furthermore, small molecule inhibition of JNK, which is an important component of the noncanonical Wnt signaling pathway, significantly inhibited CM-mediated tumor invasion. Overall, this study reveals a role for Wnt signaling as a driver of prostate cancer bone metastatic tropism and invasion.

Original languageEnglish (US)
Article number100747
JournalTranslational Oncology
Volume13
Issue number4
DOIs
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, Y., Singhal, U., Qiao, Y., Kasputis, T., Chung, J. S., Zhao, H., Chammaa, F., Belardo, J. A., Roth, T. M., Zhang, H., Zaslavsky, A. B., Palapattu, G. S., Pienta, K. J., Chinnaiyan, A. M., Taichman, R. S., Cackowski, F. C., & Morgan, T. M. (2020). Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion. Translational Oncology, 13(4), [100747]. https://doi.org/10.1016/j.tranon.2020.100747