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

doi:10.1016/j.tranon.2020.100747

Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion

Transl Oncol. 2020 Apr;13(4):100747. doi: 10.1016/j.tranon.2020.100747. Epub 2020 Mar 25.

Authors

Yugang Wang¹, Udit Singhal¹, Yuanyuan Qiao², Tadas Kasputis¹, Jae-Seung Chung³, Huiru Zhao⁴, Farah Chammaa⁵, Jacob A Belardo⁵, Therese M Roth¹, Hao Zhang¹, Alexander B Zaslavsky⁶, Ganesh S Palapattu⁶, Kenneth J Pienta⁷, Arul M Chinnaiyan⁸, Russell S Taichman⁹, Frank C Cackowski¹⁰, Todd M Morgan¹¹

Affiliations

¹ Department of Urology, University of Michigan, Ann Arbor, MI 48109.
² Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
³ Department of Urology, University of Michigan, Ann Arbor, MI 48109; Department of Urology, Inje University, Haeundae Paik Hospital, Busan, Republic of Korea.
⁴ Department of Urology, University of Michigan, Ann Arbor, MI 48109; Medical Genetic Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, People's Republic of China.
⁵ College of Literature, Science, and Arts, University of Michigan, Ann Arbor, MI 48104.
⁶ Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109.
⁷ Departments of Urology and Medical Oncology, Johns Hopkins University School of Medicine and James Buchanan Brady Urological Institute, Baltimore, MD 21287.
⁸ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, Department of Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109.
⁹ Department of Periodontics, University of Alabama at Birmingham School of Dentistry, Birmingham, AL 35233.
¹⁰ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109.
¹¹ Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109. Electronic address: tomorgan@med.umich.edu.

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.

Abstract

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