Cancer and Bone

Fatal Attraction – Why Bone Cells Home to Bone

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Over the course of their lifetime, one out of eight women and men will develop breast or prostate cancer. These tumors display a high tendency to spread to bone, hibernate for several years, and rapidly destroy bone at later stages of bone metastases. Bone metastases due to breast and prostate cancer severely compromise the quality of life and indicate poor outcome. The mechanisms how and why these tumor cells metastasize to bone and the contribution of host factors from the bone microenvironment are still poorly understood.

Our group aims at identifying important bone and tumor factors that cause bone metastasis in breast and prostate cancer. The specific projects include host-derived Wnt5a, the prognostic value of the Wnt inhibitor Dickkopf-1, and the role of the osteocyte network. To accomplish these ambitious aims, our group employs modern cell culture systems, combines preclinical models of bone metastases with high-resolution imaging, and makes use of access to patient material for clinical validation.

We expect that a better knowledge of these principles facilitates individualized therapies in the future.

Principal Investigators

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Martina Rauner, PhD

Martina Rauner, PhD

«Cancer is tricky. Its complexity is overwhelming, yet, it needs to be better understood in order to diagnose it early and treat cancer patients more effectively»

Tilman Rachner, MD

Tilman Rachner, MD

«Be curious! Ask questions! Find out!»

Andy Göbel

Andy Göbel, PhD

„All questions in science are tricky puzzles, you might not see the whole truth until you have found the last piece.“

Lorenz Hofbauer

Lorenz Hofbauer, MD

«It takes a motivated team to move ahead.»

Peyman Hadji, Krankenhaus Nordwest, Frankfurt
Sabine Kasimir-Bauer, Universitätsklinikum Essen
Christian Schem, Universitätsklinikum Schleswig-Holstein, Kiel
Pauline Wimberger & PD Jan Kuhlmann, Universitätsklinikum Dresden
Laurie McCauley, University of Michigan, Ann Arbor, USA
Ben Wielockx, Universitätsklinikum Dresden

Krug J, Plumeyer C, Davydok A, Dragoun Kolibová S, Fischer N, Le-Phuoc XT, Rauner M, Sihota P, Schweizer M, Busse B, Fiedler IAK, Jähn-Rickert K. Bone-seeking tumor cells alter bone material quality parameters on the nanoscale in mice. Biomater Adv. 2024 Oct 18;167:214060.

Göbel A, Pählig S, Motz A, Breining D, Traikov S, Hofbauer LC, Rachner TD. Overcoming statin resistance in prostate cancer cells by targeting the 3-hydroxy-3-methylglutaryl-CoA-reductase. Biochem Biophys Res Commun. 2024 May 28;710:149841.

Chang CY, Pearce G, Betaneli V, Kapustsenka T, Hosseini K, Fischer-Friedrich E, Corbeil D, Karbanová J, Taubenberger A, Dahncke B, Rauner M, Furesi G, Perner S, Rost F, Jessberger R. The F-actin bundler SWAP-70 promotes tumor metastasis. Life Sci Alliance. 2024 May 17;7(8):e202302307.

Göbel A, Rachner TD, Hoffmann O, Klotz DM, Kasimir-Bauer S, Kimmig R, Hofbauer LC, Bittner AK. High serum levels of leucine-rich α-2 glycoprotein 1 (LRG-1) are associated with poor survival in patients with early breast cancer. Arch Gynecol Obstet. 2024 Jun;309(6):2789-2798.

Link-Rachner CS, Göbel A, Jaschke NP, Rachner TD. Endocrine health in survivors of adult-onset cancer. Lancet Diabetes Endocrinol. 2024 May;12(5):350-364.

Jaschke NP, Breining D, Hofmann M, Pählig S, Baschant U, Oertel R, Traikov S, Grinenko T, Saettini F, Biondi A, Stylianou M, Bringmann H, Zhang C, Yoshida TM, Weidner H, Poller WC, Swirski FK, Göbel A, Hofbauer LC, Rauner M, Scheiermann C, Wang A, Rachner TD. Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response. Immunity. 2024 Feb 13;57(2):364-378.e9.

Jaschke NP, Rachner TD. Cancer cachexia as a blueprint for treating obesity. Trends Endocrinol Metab. 2023 May 10:S1043-2760(23)00087-5.

Link-Rachner CS, Rachner TD. Long-term bone health in childhood cancer survivors: underappreciated and undertreated? Lancet Diabetes Endocrinol. 2023:2-3.

Jaschke NP, Pählig S, Sinha A, Adolph TE, Colunga ML, Hofmann M, Wang A, Thiele S, Schwärzler J, Kleymann A, Gentzel M, Tilg H, Wielockx B, Hofbauer LC, Rauner M, Göbel A, Rachner TD. Dickkopf1 fuels inflammatory cytokine responses. Commun Biol. 2022;5:1391.

Jaschke NP, Funk AM, Jonas S, Riffel RM, Sinha A, Wang A, Pählig S, Hofmann M, Altmann H, Von Bonin S, Koch T, Spieth P, Tausche K, Akgün K, Rauner M, Kronstein-Wiedemann R, Odendahl M, Tonn T, Göbel A, Hofbauer LC, Rachner TD. Circulating Dickkopf1 Parallels Metabolic Adaptations and Predicts Disease Trajectories in Patients With COVID-19. J Clin Endocrinol Metab. 2022;107:3370-3377.

Klotz DM, Kuhlmann JD, Link T, Goeckenjan M, Hofbauer LC, Göbel A, Rachner TD, Wimberger P. Clinical impact of soluble Neuropilin-1 in ovarian cancer patients and its association with its circulating ligands of the HGF/c-MET axis. Front Oncol. 2022;12:974885.

Furesi G, de Jesus Domingues AM, Alexopoulou D, Dahl A, Hackl M, Schmidt JR, Kalkhof S, Kurth T, Taipaleenmäki H, Conrad S, Hofbauer C, Rauner M, Hofbauer LC. Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice. Int J Mol Sci. 2022;23:1285.

Dutta S, Polavaram NS, Islam R, Bhattacharya S, Bodas S, Mayr T, Roy S, Albala SAY, Toma MI, Darehshouri A, Borkowetz A, Conrad S, Fuessel S, Wirth M, Baretton GB, Hofbauer LC, Ghosh P, Pienta KJ, Klinkebiel DL, Batra SK, Muders MH, Datta K. Neuropilin-2 regulates androgen-receptor transcriptional activity in advanced prostate cancer. Oncogene. 2022;41:3747-3760.

Göbel A, Riffel RM, Hofbauer LC, Rachner TD. The mevalonate pathway in breast cancer biology. Cancer Lett. 2022;542:215761.

Riffel RM, Göbel A, Rachner TD. Bone Metastases: From Mechanisms to Treatment. Semin Oncol Nurs. 2022:151277.

Hemmatian H, Conrad S, Furesi G, Mletzko K, Krug J, Faila AV, Kuhlmann JD, Rauner M, Busse B, Jähn-Rickert K. Reorganization of the osteocyte lacuno-canalicular network characteristics in tumor sites of an immunocompetent murinemodel of osteotropic cancers. Bone. 2021;152:116074.

Rachner TD, Coleman R, Hadji P, Hofbauer LC. Individualized Bone-Protective Management in Long-Term Cancer Survivors With Bone Metastases. J Bone Miner Res. 2021;36:1906-1913.

Klotz DM, Link T, Goeckenjan M, Wimberger P, Poetsch AR, Jaschke N, Hofbauer LC, Göbel A, Rachner TD, Kuhlmann JD. Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients. Clin Chem Lab Med. 2021 Oct 25;60:109-117.

Hofbauer LC, Bozec A, Rauner M, Jakob F, Perner S, Pantel K. Novel approaches to target the microenvironment of bone metastasis. Nat Rev Clin Oncol. 2021;18:488-505.

Schagdarsurengin U, Luo C, Slanina H, Sheridan D, Füssel S, Böğürcü-Seidel N, Gattenloehner S, Baretton GB, Hofbauer LC, Wagenlehner F, Dansranjav T. Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature. Clin Epigenetics. 2021;13:211

Rachner TD, Kasimir-Bauer S, Goebel A, Erdmann K, Hoffmann O, Rauner M, Hofbauer LC, Kimmig R, Bittner AK. Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer. J Cancer Res Clin Oncol. 2021;147:2233-2238.

Gaculenko A, Gregoric G, Popp V, Seyler L, Ringer M, Kachler K, Wu Z, Kisel W, Hofbauer C, Hofbauer LC, Uder M, Schett G, Bäuerle T, Bozec A. Systemic PPARγ Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents. J Bone Miner Res. 2021;36:2440-2452.

Polavaram NS, Dutta S, Islam R, Bag AK, Roy S, Poitz D, Karnes J, Hofbauer LC, Kohli M, Costello BA, Jimenez R, Batra SK, Teply BA, Muders MH, Datta K. Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases. Bone Res. 2021 May 14;9:24.

Göbel A, Dell’Endice S, Jaschke N, Pählig S, Shahid A, Hofbauer LC, Rachner TD. The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone. Int J Mol Sci. 2021 11;22:5078.

Jaschke N, Wang A, Hofbauer LC, Rauner M, Rachner TD. Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations. Ageing Res Rev. 2021;67:101301

Jaschke N, Pählig S, Pan YX, Hofbauer LC, Göbel A, Rachner TD. From Pharmacology to Physiology: Endocrine Functions of μ-Opioid Receptor Networks. Trends Endocrinol Metab. 2021 May;32:306-319.

Kisel W, Conrad S, Borkowetz A, Furesi G, Füssel S, Sommer U, Rauner M, Thomas C, Baretton GB, Schaser KD, Hofbauer C, Hofbauer LC. High stroma-derived WNT5A is an indicator for low-risk prostate cancer. FEBS Open Bio. 2021 11:1186-1194.

Waqas K, Lima Ferreira J, Tsourdi E, Body JJ, Hadji P, Zillikens MC. Updated guidance on the management of cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer. J Bone Oncol. 2021 18;28:100355.

Klusa D, Lohaus F, Furesi G, Rauner M, Benešová M, Krause M, Kurth I, Peitzsch C. Metastatic Spread in Prostate Cancer Patients Influencing Radiotherapy Response. Front Oncol. 2021 4;10:627379.

Furesi G, Rauner M, Hofbauer LC. Emerging Players in Prostate Cancer-Bone Niche Communication. Trends Cancer. 2021;7:112-121.

Rachner TD, Göbel A, Jaschke NP, Hofbauer LC. Challenges in Preventing Bone Loss Induced by Aromatase Inhibitors. J Clin Endocrinol Metab. 2020 1;105:dgaa463.

Göbel A, Zinna VM, Dell’Endice S, Jaschke N, Kuhlmann JD, Wimberger P, Rachner TD. Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer. BMC Cancer. 2020 Jul 29;20:703

Jaschke N, Hofbauer LC, Göbel A, Rachner TD. Evolving functions of Dickkopf-1 in cancer and immunity. Cancer Lett. 2020 Jul 10;482:1-7

Rachner TD, Göbel A, Hoffmann O, Erdmann K, Kasimir-Bauer S, Breining D, et al. High serum levels of periostin are associated with a poor survival in breast cancer. Breast Cancer Res Treat. 2020;180:515–24.

Göbel A, Rauner M, Hofbauer LC, Rachner TD. Cholesterol and beyond – The role of the mevalonate pathway in cancer biology. Biochim Biophys Acta – Rev Cancer. 2020;1873:188351.

Jaschke N, Kleymann A, Hofbauer LC, Göbel A, Rachner TD. Dorsomorphin: A novel inhibitor of Dickkopf-1 in breast cancer. Biochem Biophys Res Commun. 2020;524:360–5.

Borkowetz A, Froehner M, Rauner M, Conrad S, Erdmann K, Mayr T, Datta K, Hofbauer LC, Baretton GB, Wirth M, Fuessel S, Toma M, Muders MH. Neuropilin‐2 is an independent prognostic factor for shorter cancer‐specific survival in patients with acinar adenocarcinoma of the prostate. International Journal of Cancer. 2019. 146(9):2619-262.

Bordoni V, Reina G, Orecchioni M, Furesi G, Thiele S, Gardin C, Zavan B, Cuniberti G, Bianco A, Rauner M, Delogu LG. Stimulation of bone formation by monocyte-activator functionalized graphene oxide in vivo. Nanoscale. 2019;11:19408-19421.

Rachner TD, Kasimir-Bauer S, Göbel A, Erdmann K, Hoffmann O, Browne A, Wimberger P, Rauner M, Hofbauer LC, Kimmig R, Bittner AK. Prognostic value of RANKL/OPG serum levels and disseminated tumor cells in nonmetastatic breast cancer. Clin Cancer Res. 2019; 25:1369-1378.

Kresinsky A, Schnöder TM, Jacobsen ID, Rauner M, Hofbauer LC, Ast V, König R, Hoffmann B, Svensson CM, Figge MT, Hilger I, Heidel FH, Böhmer FD, Müller JP. Lack of CD45 in FLT3-ITD mice results in a myeloproliferative phenotype, cortical porosity, and ectopic bone formation. Oncogene. 2019; 38:4773-4787.

Göbel A, Breining D, Rauner M, Hofbauer LC, Rachner TD. Induction of 3-hydroxy-3-methylglutaryl-CoA reductase mediates statin resistance in breast cancer cells. Cell Death Dis. 2019;10:91.

Thiele S, Zimmer A, Göbel A, Rachner TD, Rother S, Fuessel S, Froehner M, Wirth MP, Muders MH, Baretton GB, Jakob F, Rauner M, Hofbauer LC. Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget. 2018; 9:27293-304.

Browne AJ, Kubasch ML, Göbel A, Hadji P, Chen D, Rauner M, Stölzel F, Hofbauer LC, Rachner TD. Concurrent antitumor and bone-protective effects of everolimus in osteotropic breast cancer. Breast Cancer Res. 2017; 19, 1–15.

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.

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. MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells. Cell Death Dis. 2016; 7, 1–11.

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.

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; 30:471-80.

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; 14:649.

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

Research Question

What makes bone so attractive for tumor cells? If we understand the biological principles, we will be able to deliver more tailored strategies to prevent or treat bone metastases.

Approach

Our group employs advanced cell culture systems, combines preclinical breast and prostate cancer models of bone metastases with high-resolution imaging, and benefits from access to human tumor material for clinical validation

Projects

  • Dissecting the role of Dickkopf-1 as a mediator of inflammation in the metastatic bone microenvironment
  • Tumor-osteocyte interactions in the bone metastatic process
  • Role of hypoxia in malignant bone disease
  • Deciphering the mechanisms of the 3-hydroxy-3-methylglutaryl-CoA reductase mediated statin resistance in breast cancer
  • Analysis of extracellular vesicles and their miRNAs in prostate cancer

Funding

Our research is funded by the DFG priority programme µBONE, DKFZ and Deutsche Krebshilfe.

Explained

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