/project 3

L. Hofbauer, Dresden

Role of prostate cancer-derived Wnt5a on the bone microenvironment

Prostate cancer has a high propensity to home to bone and commonly forms osteosclerotic lesions. In the first funding period, we identified Wnt5a to be specifically expressed in primary samples of osteotropic prostate cancer cells and found that overexpression of Wnt5a induced apoptosis and inhibited proliferation in vitro and correspondingly inhibited subcutaneous and intratibial tumor growth and subsequent bone destruction. Congruently, a high tumor expression of Wnt5a was associated with a longer survival in a cohort of 397 prostate cancer patients. Based on these results and its known regulation of bone remodeling and immune reactions, we hypothesize that Wnt5a affects key steps of skeletal metastases and represents a therapeutic target in the treatment of prostate cancer and related bone metastases.

To test our hypotheses we will address the following specific aims:
(I) To determine the paracrine effects of bone marrow cell-derived Wnt5a on prostate cancer cell biology. Underlying mechanisms will be determined using RNAi and specific inhibitors. Conditional knock-out mice that lack Wnt5a will be used to determine migration and skeletal metastasis of murine prostate cancer cells.
(II) To examine the paracrine effects of tumor-derived Wnt5a on bone cells in vitro and ex vivo using calvaria cultures. The potential of tumor-derived Wnt5a to form a pre-metastatic niche and to promote bone metastases will be investigated in mouse models using multimodal bone imaging. Further, correlations of Wnt5a with the presence and type of bone metastases will be validated using our established tissue microarray (TMA).
(III) To assess the modulation of immune cell migration and function by tumor-derived Wnt5a in vitro and in vivo. These studies will help to clarify the contribution of Wnt5a in prostate cancer and bone metastasis and to define its suitability as a novel biomarker and potential drug target.

Using a Wnt signaling PCR array, we identified Wnt5a as an interesting candidate in prostate cancer. While overexpressing Wnt5a induces apoptosis in hormone positive and negative prostate cancer cell lines, knocking-down Wnt5a suppresses apoptosis. Correspondingly, Wnt5a overexpression reduces prostate cancer cell proliferation, while suppressing Wnt5a expression increases tumor cell proliferation. Currently, we are evaluating the anti-tumor potential of Wnt5a in a preclinical mouse model and are assessing the correlation of Wnt5a with the rate of apoptosis and proliferation in a human prostate cancer tissue microarray with more than 400 patient samples. These studies will identify the potential of Wnt5a to suppress prostate cancer growth and skeletal metastasis.

Prof. Dr. med. Lorenz Hofbauer heads the Division of Endocrinology and Bone Diseases at Dresden University Clinics and the certified (DVO) osteoporosis center that offers state-of-the art care for patients with bone disorders, including active participation in phase 3 clinical studies that involved denosumab and sclerostin antibodies. In addition, he is the director of the UniversityCenter for Healthy Ageing and heads the molecular and translational bone laboratory. He was recruited from the University of Marburg where he has been a DFG Heisenberg senior fellow as a W3 Professor of Medicine.

Project-related list of publications
Thiele S, Rachner TD, Rauner M, Hofbauer LC. WNT5A and Its Receptors in the Bone-Cancer Dialogue. J Bone Miner Res. 2016;31:1488-96. 

Rachner TD, Jakob F, Hofbauer LC. Bone metastases: New aspects of pathogenesis and systemic therapy. Internist (Berl). 2016;57:666-74.
Dotterweich J, Tower RJ, Brandl A, Müller M, Hofbauer LC, Beilhack A, Ebert R, Glüer CC, Tiwari S, Schütze N, Jakob F. The KISS1 receptor as an in vivo microenvironment imaging biomarker of multiple myeloma bone disease. PLoS One. 2016;11:e0155087.
Dhawan A, von Bonin M, Bray LJ, Freudenberg U, Pishali Bejestani E, Werner C, Hofbauer LC, Wobus M, Bornhäuser M. Functional interference in the bone marrow microenvironment by disseminated breast cancer cells. Stem Cells. 2016;34:2224-35.
Göbel A, Thiele S, Browne AJ, Rauner M, Zinna VM, Hofbauer LC, Rachner TD. Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells. Cancer Lett. 2016;375:162-71.
Browne AJ, Göbel A, Thiele S, Hofbauer LC, Rauner M, Rachner TD.p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells. Cell Death Dis. 2016;7: e2119.
Göbel A, Browne AJ, Thiele S, Rauner M, Hofbauer LC, Rachner TD. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. Breast Cancer Res Treat. 2015;154:623-31.
Rachner TD, Göbel A, Browne A, Hötzel J, Rauner M, Hofbauer LC. P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer. Biochym Biophys Res Commun. 2015;466:728-32.
Rachner TD, Jakob F, Hofbauer LC. Cancer-targeted therapies and radiopharmaceuticals. Bonekey Rep. 2015;4:707. Review.
Todenhöfer T, Stenzl A, Hofbauer LC, Rachner TD. Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;2015:838202. 
Thiele S, Göbel A, Rachner TD, Fuessel S, Froehner M, Muders MH, Baretton GB, Bernhardt R, Jakob F, Glüer CC, Bornhäuser M, Rauner M, Hofbauer LC. WNT5A has anti-prostate cancer effects in vitro and reduces tumor growth in the skeleton in vivo. J Bone Miner Res. 2015;3:488-97.

Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol 2014;2:500-12.

Rachner TD, Thiele S, Göbel A, Browne A, Fuessel S, Erdmann K, Wirth MP, Fröhner M, Todenhöfer T, Muders MH, Kieslinger M, Rauner M, Hofbauer LC. High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer. 2014 Sep 2;14:649.

Rachner TD, Göbel A, Thiele S, Rauner M, Benad-Mehner P, Hadji P, Bauer T, Muders MH, Baretton GB, Jakob F, Ebert R, Bornhäuser M, Schem C, Hofbauer LC. Dickkopf-1 is regulated by the mevalonate pathway in breast cancer. Breast Cancer Research 2014;16:20.

Erdmann K, Kaulke K, Thomae C, Huebner D, Sergon M, Froehner M, Wirth MP, Fuessel S. Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs. BMC Cancer 2014;14:82.

Rachner TD, Göbel A, Junker M, Hötzel J, Benad-Mehner P, Hadji P, Hofbauer LC. Regulation of VEGF by mevalonate pathway inhibition in breast cancer. J Bone Oncol 2013;2:110-115.

Rachner TD, Platzbecker U, Felsenberg D, Hofbauer LC. Osteonecrosis of the jaw after osteoporosis therapy with denosumab following long-term bisphosphonate therapy. Mayo Clin Proc 2013;88:418-9.

Shroff R, Beringer O, Rao K, Hofbauer LC, Schulz A. Denosumab for post-transplantation hypercalcemia in osteopetrosis. N Engl J Med 2012;367:1766-1767.

Fasslrinner F, Wobus M, Duryagina R, Müller K, Stopp S, Wehner R, Rauner M, Hofbauer LC, Schmitz M, Bornhäuser M. Differential effects of mixed lymphocyte reaction supernatant on human mesenchymal stromal cells. Exp Hematol 2012;40:934-944.

Hamann C, Lützner J, Wieczorek K, Hofbauer LC. Pulmonary metastases due to a giant-cell tumor of bone. J Clin Endocrinol Metab 2012;97:3408-3409.

Wobus M, Benath G, Ferrer RA, Wehner R, Schmitz M, Hofbauer LC, Rauner M, Ehninger G, Bornhäuser M, Platzbecker U. Impact of lenalidomide on the functional properties of human mesenchymal stromal cells. Exp Hematol 2012;40:867-876.

Rachner TD, Hadji P, Hofbauer LC. Novel therapies in benign and malignant bone diseases. Pharmacol Ther 2012;134:338-344.

Ebert R, Zeck S, Meissner-Weigl J, Klotz B, Rachner TD, Benad P, Klein-Hitpass L, Rudert M, Hofbauer LC, Jakob F. Krüppel-like factors KLF2 and 6 and Ki-67 are direct targets of zoledronic acid in MCF-7 cells. Bone 2012;50:723-732.

Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G, Distler JH, Albers J, Schulze J, Schinke T, Bornhäuser M, Platzbecker U, Hofbauer LC. WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res 2012;27:575-585.

Thiele S, Rauner M, Goettsch C, Rachner TD, Benad P, Fuessel S, Erdmann K, Hamann C, Baretton GB, Wirth MP, Jakob F, Hofbauer LC. Expression profile of WNT molecules in prostate cancer and its regulation by aminobisphosphonates. J Cell Biochem 2011,112:1593-600.

Benad P, Rauner M, Rachner TD, Hofbauer LC. The anti-progestin RU-486 inhibits viability of MCF-7 breast cancer cells by suppressing WNT1. Cancer Lett 2011;312:101-108.

Bauer W, Rauner M, Haase M, Kujawski S, Arabanian LS, Habermann I, Hofbauer L, Ehninger G, Kiani A. Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2. Haematologica 2011;96:1580-8.

Hofbauer LC, Rachner TD, Hamann C. From bone to breast and back - the bone cytokine RANKL and breast cancer. Breast Cancer Res 2011;13:107.

Singh SK, Baumgart S, Singh G, König AO, Reutlinger K, Hofbauer LC, Barth P, Gress TM, Lomberk G, Urrutia R, Fernandez-Zapico ME, Ellenrieder V. Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid. J Biol Chem 2011;286:28761-71.

Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377:1276-87. Review.

Rachner TD, Singh SK, Schoppet M, Benad P, Bornhäuser M, Ellenrieder V, Ebert R, Jakob F, Hofbauer LC. Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. Cancer Lett 2010;287:109-116.

Lutter AH, Hempel U, Wolf-Brandstetter C, Garbe AI, Goettsch C, Hofbauer LC, Jessberger R, Dieter P. A novel resorption assay for osteoclast functionality based on an osteoblast-derived native extracellular matrix. J Cell Biochem 2010;109:1025-1032.

Hofbauer LC, Zeitz U, Schoppet M, Skalicky M, Schüler C, Stolina M, Kostenuik PJ, Erben RG. Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL. Arthritis Rheum 2009;60:1427-1437.

Rachner TD, Benad P, Rauner M, Goettsch C, Singh SK, Schoppet M, Hofbauer LC. Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis. J Cell Biochem 2009;108:106-116.

Rachner TD, Schoppet M, Niebergall U, Hofbauer LC. 17β-Estradiol inhibits osteoprotegerin production by the estrogen receptor-α-positive human breast cancer cell line MCF-7. Biochem Biophys Res Commun 2008;368:736-741.
Technische Universitt Dresden    Christian-Albrechts-Universitt zu Kiel    Julius-Maximilians-Universitt Wrzburg
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