Katherine N. Weilbaecher, M.D.

Internal Medicine
Molecular Oncology
Cell Biology and Physiology

Molecular Cell Biology Program
Molecular Genetics and Genomics Program

Research Abstract:

The skeleton is the organ most commonly affected by metastatic cancer in humans. Mechanisms by which skeletal metastases are established are unclear; however, osteoclast activation plays a critical role in the pathogenesis of bone metastases. Our laboratory focuses on the molecular mechanisms through which tumor cells metastasize to bone. The projects in our laboratory include: The role of beta 3 integrin in skeletal metastases. The beta 3 integrin subunit (b3) has been implicated in the development of metastases because of its critical role in osteoclastic bone resorption (avb3), and its role in platelets in tumor cell homing (aIIbb3). We have established an in vivo model of bone metastasis using the osteolytic and osteoblastic tumor cell lines. To examine the role of the b3 integrins in skeletal metastases we utilize mice with a disruption of the beta 3 integrin subunit gene (b3-/-); The role of Tax oncogene in skeletal metastases. HTLV I associated Adult T cell leukemia (ATLL) is distinctive for its high rate of osteolytic skeletal metastases and hypercalcemia. Expression of HTLV-1 Tax oncogene, under the regulation of the granzyme B promoter, results in tumors. We find that these mice also develop lytic bone lesions, a clinical feature of ATLL. Our laboratory studies the molecular mechanisms of Tax oncogene induced bone disease; and, The role of CXCR4 in bone metastasis. SDF-1 and its receptor CXCR-4 have been shown to be one mechanism by which blood cell precursors home to the bone. We hypothesize that the SDF-1/CXCR-4 interaction plays a role in tumor cell homing to bone as well. We are evaluating if the disruption of the CXCR-4/SDF-1 interaction can prevent bone metastasis in a murine model.

Dr. Weilbaecher is also a practicing breast cancer oncologist at the Siteman Cancer Center and her translational research focuses on defining the molecular pathogenesis of bone metastases and the role of the bone microenvironment in supporting tumor growth and metastasis to bone. Her lab has developed useful pre-clinical models of breast cancer, melanoma and multiple myeloma bone metastases and she has translated her preclinical research findings that targeting osteoclast and platelet function can prevent bone metastases into the clinics. She has developed 4 clinical trials that directly stemed from her research.

Selected Publications:

Su X, Floyd D, Hughes A, Xiang J, Schneider J, Uluckan O, Heller E, Deng H, Zou W, Craft C, Wu K, Hirbe A, Grabowska D, Eagleton M, Townsley S, Collins L, Piwnica-Worms D, Steinberg T, Novack D, Conley P, Hurchla M, Rogers M, Weilbaecher K. The ADP receptor P2Y12 regulates osteoclast function and pathologic bone remodeling. J Clinical Investigation. 2012. Oct 1;122(10):3579-92.

Heller E, Hurchla MA, Xiang J, Chen S, Schneider J, Joeng KS, Vidal M, Goldberg L, Deng H, Hornick MC, Prior J, Piwnica-Worms DR, Long F, Cagan R, Weilbaecher K. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Research 2011. PMID:22186138

Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nature Reviews Cancer 2011 Jun;11(6):411-25. PMID: 21593787.

Rauch DA, Hurchla MA, Harding JC, Deng H, Shea LK, Eagleton MC, Niewiesk S, Lairmore MD, Piwnica-Worms D, Rosol TJ, Weber JD, Ratner L, Weilbaecher KN. The ARF tumor suppressor regulates bone remodeling and osteosarcoma development in mice. PLoS One 2010 Dec 30;5(12):e15755. PMID: 21209895

Schneider JG, Amend SR, Weilbaecher KN. Integrins and bone metastasis: integrating tumor cell and stromal cell interactions. Bone 2011 Jan;48(1):54-65. PMID: 20850578

Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, Zhai J, Kuo S, Shannon W, Diemer K, Herrmann V, Dietz J, Ali A, Ellis M, Weiss P, Eberlein T, Ma C, Fracasso PM, Zoberi I, Taylor M, Gillanders W, Pluard T, Mortimer J, Weilbaecher K. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncology 2010 May; 11(5):421-8. PMID: 20362507

Hirbe AC, Morgan EA, Weilbaecher KN. The CXCR4/SDF-1 chemokine axis: a potential therapeutic target for bone metastases? Curr Pharm Des. 2010 16(11):1284-90. PMID: 20166978

Morgan EA, Schneider JG, Baroni TE, Ulukan O, Heller E, Hurchla MA, Deng H, Floyd D, Berdy A, Prior JL, Piwnica-Worms D, Teitelbaum SL, Ross FP, Weilbaecher KN. Dissection of platelet and myeloid cell defects by conditional targeting of the beta3-integrin subunit. FASEB Journal. 2010 Apr;2 4(4):1117-27. PMID: 19933310

Ulukan O, Becker SN, Deng H, Zou W, Prior JL, Piwnica-Worms D, Frazier WA, Weilbaecher KN. CD47 regulates bone mass and tumor metastasis to bone. Cancer Research. 2009 Apr 1; 69(7):3196-204. PMID: 19276363

Xu Z, Hurchla MA, Deng H, Ulukan O, Bu F, Berdy A, Eagleton MC, Heller EA, Floyd DH, Dirksen WP, Shu S, Tanaka Y, Fernandez SA, Rosol TJ, Weilbaecher KN. Interferon-gamma targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases. J Biol Chem. 2009 Feb 13; 284(7):4658-66. PMID: 19059914

Last Updated: 5/7/2014 4:23:27 PM

Cancer to bone: a fatal attraction. Can we modulate the host stroma to treat cancer? (Weilbaecher,Guise, and McCauley. Nat Rev Cancer. 2011 Jun;11(6):411-25.)
Back To Top

Follow us: