Welcome to the

Williams Laboratory

Overview

Cell Signaling and Carcinogenesis

The Williams Laboratory is interested in understanding how alterations in the Wnt signaling pathway cause human disease. Wnt signaling is an evolutionarily conserved process that functions in the differentiation of most tissues within the body. Given its central role in growth and differentiation, it is not surprising that alterations in the pathway are among the most common events associated with human cancer. In addition, several other human diseases, including osteoporosis, cardiovascular disease, and diabetes, have been linked to altered regulation of this pathway. A specific focus of the lab’s work is characterizing the role of Wnt signaling in bone formation. Our interest is not only from the perspective of normal bone development, but also in trying to understand whether aberrant Wnt signaling plays a role in the predisposition of some common tumor types (for example, prostate, breast, lung, and renal tumors) to metastasize to and grow in bone. The long-term goal of this work is to provide insights useful in developing strategies to lessen the morbidity and mortality associated with skeletal metastasis.

Our Impact

We’re raising thousands to save millions.

We’re turning hope into action for the millions of people around the world affected by diseases like cancer and Parkinson’s. Find out how you can help us make a difference.

  • 171 studies published from Nov. 1, 2020 to Oct. 1, 2021
  • 68 studies in high-impact journals from Nov. 1, 2020-Oct. 1, 2021
  • 41 clinical trials launched

Bart Williams, Ph.D.

Director, Core Technologies and Services; Professor, Department of Cell Biology

Areas of Expertise

Wnt signaling, skeletal metastases, normal bone development, genetic models, skeletal diseases

Biography

Dr. Williams received his Ph.D. in biology from Massachusetts Institute of Technology in 1996 where he trained with Tyler Jacks. For three years, he was a postdoctoral fellow at the National Institutes of Health in the laboratory of Harold Varmus, former Director of NIH. Dr. Williams joined VAI as a Scientific Investigator in July 1999. He is now a professor and served as chair of the Department of Cell Biology.

Wnt Signaling in Normal Bone Development

Mutations in the Wnt receptor Lrp5 have been causally linked to alterations in human bone development. We have characterized a mouse strain deficient in Lrp5 and have shown that it recapitulates the low-bone-density phenotype seen in human patients who have a Lrp5 deficiency. We have further shown that mice carrying mutations in both Lrp5 and the related Lrp6 protein have even more-severe defects in bone density. To test whether Lrp5 deficiency causes changes in bone density due to aberrant signaling through β-catenin, we created mice carrying an osteoblast-specific deletion of β-catenin (OC-Cre;β-cateninflox/flox mice). We are addressing how other genetic alterations linked to Wnt/β-catenin signaling affect bone development and osteoblast function. We have generated mice with conditional alleles of Lrp6 and Lrp5 that can be inactivated via Cre-mediated recombination and demonstrated that both Lrp5 and Lrp6 function within osteoblasts to regulate normal bone development and homeostasis. We have also created mice that lack the ability to secrete Wnts from osteoblasts and shown that these mice also have extremely low bone mass, establishing that the mature osteoblast is an important source of Wnts for establishing and maintaining normal bone mass. We are also examining the effects on normal bone development and homeostasis of chemical inhibitors of the enzyme porcupine, which is required for the secretion and activity of all Wnts. Given that such inhibitors are currently in human clinical trials for treatment of several tumor types, their side effects related to the lowering bone mass be evaluated.

Project 1

Wnt signaling in mammary development and cancer

We also are addressing the relative roles of Lrp5 and Lrp6 in Wnt1-induced mammary carcinogenesis. A deficiency in Lrp5 dramatically inhibits the development of mammary tumors, and a germline deficiency for Lrp5 or Lrp6 results in delayed mammary development. Because Lrp5-deficient mice are viable and fertile, we have focused our initial efforts on these mice. We also have found that Lrp6 plays a key role in mammary development, and we are focusing on the mechanisms underlying this role. We are particularly interested in how these pathways may regulate the proliferation of normal mammary progenitor cells, as well as of tumor-initiating cells.

Project 2

Wnt signaling in prostate development and cancer

Two hallmarks of advanced prostate cancer are the development of skeletal osteoblastic metastasis and the ability of the tumor cells to become independent of androgen for survival. We have created mice with a prostate-specific deletion of the Apc gene. These mice develop fully penetrant prostate hyperplasia by four months of age, and these tumors progress to frank carcinomas by seven months. We have found that these tumors initially regress under androgen ablation but show signs of androgen-independent growth some months later.

Project 3

Genetically engineered mouse models of bone disease

We have also focused on developing mouse models of osteoarthritis and of fracture repair. In addition, we are interested in identifying novel genes that play key roles in skeletal development and maintenance of bone mass. For example, current work is focused on the role of galectin-3, a member of the lectin family, in this context.

2022

Liegel R, Michalski MN, Vaidya S, Bittermann E, Finnerty E, Menske C, Diegel CR, Zhong ZA, Williams BO, Stottmann R. 2022. Dkk1 inhibition normalizes limb phenotypes in a mouse model of Fzd2 associated omodysplasia Robinow syndromes. bioRXiv.

Ubels JL, Lin CM, Antonetti DA, Diaz-Coranguez M, Diegel CR, Williams BO. 2022. Structure and function of the retina of low-density lipoprotein receptor-related protein 5 (Lrp5)-deficient rats . Exp Eye Res.

2021

Zhong ZA, Michalski, MN, Stevens PD, Sall EA, Williams BO. 2021. Regulation of Wnt receptor activity: Implications for therapeutic development in colon cancerJ Biol Chem:100782.

Chassé MH, Johnson BK, Boguslawski EA, Sorensen KM, Rosien JE, Kang MH, Reynolds CP, Heo L, Madaj ZB, Beddows I, Foxa GE, Kitchen-Goosen SM, Williams BO, Triche TJ Jr, Grohar PJ. 2021. Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor. EMBO Mol Med 13(2):e12640.

Michalski MN, Diegel CR, Zhong ZA, Suino-Powell K, Blazer L, Adams J, VAI Vivarium and Transgenics Core, Beddows I, Melcher K, Sidhu SS, Angers S, Williams BO. 2021. Generation of a new Frizzled 2 flox mouse to clarify its role in development. bioRxiv.

Stevens PD, Williams BO. 2021. LGR4: Not just for Wnt anymore? Cancer Res 81(17):4397–4398.

Foxa GE, Liu Y, Turner LM, Robling AG, Yang T, Williams BO. 2021. Generation and characterization of mouse models for skeletal disease. Methods Mol Biol 2221:165–191.

2020

Diegel CR, Hann S, Ayturk UM, Hu JCW, Lim K, Droscha CJ, Madaj ZB, Foxa GE, Izaguirre I, VAI Vivarium and Transgenics Core, Paracha N, Pidhaynyy B, Dowd TL, Robling AG, Warman ML, Williams BO. 2020. An osteocalcin-deficient mouse strain without endocrine abnormalitiesPLOS Genet.

Maupin KA, Dick D, Lee J, Williams BO. 2020. Loss of Lgals3 protects against gonadectomy-induced cortical bone loss in miceCalcif Tiss Intl.

Lim KE, Bullock WA, Horan DJ, Williams BO, Warman ML, Robling AG. 2020. Co-deletion of Lrp5 and Lrp6 in the skeleton severely diminishes bone gain from sclerostin antibody administration. Bone 143:115708.

Ubels JL, Diegel CR, Foxa GE, Ethen NJ, Lensing JN, Madaj ZB, VAI Vivarium and Transgenics Core, Williams BO. 2020. Low-density lipoprotein-related protein 5 (LRP5)-deficient rats have reduced bone mass and abnormal development of the retinal vasculature. The CRISPR Journal 3(4):284–298.

Jeong W, Kim S, Lee U, Zhong ZA, Savitskiy M, Kwon H, Him J, Lee T, Cho JW, Williams BO, Katanaev VL, Jho EH. 2020. Lrp6 senses the level of nutrients and regulates Hippo signaling. EMBO Rep 21(9):e50103.

Diegel CR, Hann S, Ayturk UM, Hu JCW, Lim K, Droscha CJ, Madaj ZB, Foxa GE, Izaguirre I, VAI Vivarium and Transgenics Core, Robling AG, Warman ML, Williams BO. 2020. Independent validation of experimental results requires timely and unrestricted access to animal models and reagents. PLOS Genetics 16(6):e1008940.

Kushwaha P, Kim S, Foxa GE, Michalski MN, Williams BO, Tomlinson RE, Riddle RC. 2020. Frizzled-4 is required for normal bone acquisition despite compensation by Frizzled-8. J Cell Physiol. 235(10):6673–6683.

Williams BO, Johnson ML. 2020. Wnt signaling and bone cell activity. In: Principles of Bone Biology. Elsevier.

2019

Bergsma A, Ganguly SS, Wiegand ME, Dick D, Williams BO, Miranti CK. 2019. Regulation of cytoskeleton and adhesion in osteoclasts by tetraspanin CD82. Bone Rep.  10:100196.

Mirabelli CK, Nusse R, Tuveson DA, Williams BO. 2019. Perspectives on the role of Wnt biology in cancer. Sci Signal 1:eaay4494.

2018

Bergsma A, Ganguly SS, Dick D, Williams BO, Miranti CK. 2018. Global deletion of tetraspanin CD82 attenuates bone growth and enhances bone marrow adipogenesisBone 113:105–113.

Lu D, Li J, Liu H, Foxa GE, Weaver K, Li J, Williams BO, Yang T. 2018. LRP1 suppresses bone resorption in mice by inhibiting the RANKL-stimulated NFκB and p38 pathways during osteoclastogenesisJ Bone Miner Res.

Maupin K, Weaver K, Bergsma A, Christie C, Zhong Z, Yang T, Williams BO. 2018. Enhanced cortical bone expansion in Lgals3-deficient mice during agingBone Res 6(7).

Li J, Lu D, Dou H, Liu H, Weaver K, Wang W, Li JD, Yeh E, Williams BO, Zheng L, Yang T. 2018. Demsumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathwayNat Commun 9(1):143.

Madan B, McDonald MJ, Foxa GE, Diegel CR, Williams BO*, Virshup DM*. 2018. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res 25(6):17.
*Co-corresponding authors

Ganguly SS, Daft PG, Cao J, Meng X, Zhong ZA, Vander Ark A, Meadows A, Madaj Z, Williams BO, Li X. 2018. Loss of myeloid-specific TGF-B signaling decreases CTHRC1 to downregulate bFGF and the development of H1993-induced osteolytic bone lesions. Cancers 10(12):463.

Michalski MN, Williams BO. 2018. A quest for clarity in bone erosion: The role of sequestosome 1 in Paget’s disease of bone. J Biol Chem 293(24):9542–9543.

Nayak G, Odaka Y, Prasad V, Solano AF, Yeo EJ, Vemuraju S, Molkentin JD, Trump A, Williams BO, Rao S, Lang RA. 2018. Developmental vascular regression is regulated by a Wnt/B-catenin, MYC, P21 (CDKN1A) pathway that controls cell proliferation and cell death. Development 145(12):dev154898.

Liu H, Li J, Lu D, Li J, He Y, Williams BO, Yang T. 2018. Ginkgolic acid, a sumoylation inhibitor, promotes adipocyte commitment but suppresses adipocyte terminal differentiation of mouse bone marrow stromal cells. Sci Rep 8(1):2545.

Zhong ZA, Ethen NJ, Williams BO. 2018. Using genetically engineered mouse models to study Wnt signaling in bone development and disease. In: Regulation of Signal Transduction in Human Cell Research, Springer, 119-25.

2017

Valkenburg KC, DeMarzo AM, Williams BO. 2017. Deletion of tumor suppressors adenomatous polyposis coli and Smad4 in murine luminal epithelial cells causes invasive prostate cancer and loss of androgen receptor expressionOncotarget 8(46):80265–80277.

DeBruine ZJ, Ke J, Harikumar KG, Gu X, Borowsky P, Williams BO, Miller LJ, Xu HE, Melcher K. 2017. Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerizationGenes Dev 31(9):916–926.

Li J, Lu D, Liu H, Williams BO, Overbeek PA, Lee B, Zheng L, Yang T. 2017. Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signalingHum Mol Genet 26(15):2949–2960.

Janda CY, Dang LT, You C, Chang J, de Lau W, Zhong ZA, Yan KS, Marecic O, Siepe D, Li X, Moody JD, Williams BO, Clevers H, Kuo CJ, Piehler J, Baker D, Garcia KC. 2017. Surrogate Wnt ligands that phenocopy canonical Wnt/B-catenin signalingNature 545(7653):234–237.

Walls GV, Stevenson M, Lines KE, Newey PJ, Reed AAC, Bowl MR, Jeyabalan J, Harding B, Bradley KJ, Manek S, Chen J, Wang P, Williams BO, Teh BT, Thakker RV. 2017. Mice deleted for Cell division cycle 73 (Cdc73) gene develop parathyroid and uterine tumors: model for the hyperparathyroidism-jaw tumour syndromeOncogene.36(28):4025–4036.

Droscha CJ, Diegel CR, Ethen NJ, Burgers TA, McDonald MJ, Maupin KA, Naidu AS, Wang PF, Teh BT, Williams BO. 2017. Osteoblast-specific deletion of Hrpt2/Cdc73 results in high bone mass and increased bone turnoverBone 98:68–78.

Pridgeon MG, Grohar PJ, Steensma MR, Williams BO. 2017. Wnt signaling in Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumorsCurr Osteoporos Rep 15(4):239–246.

Yang T, Williams BOLow-density lipoprotein receptor-related proteins in skeletal development and diseasePhysiol Rev 97(3):1211–1228.

Williams BO. 2017. LRP5: From bedside to bench to boneBone 102:26–30.

Williams BO, Warman ML. 2017. CRISPR/Cas9 technologiesJ Bone Miner Res 32(5):883–888.

2016

Zhong ZA, Ethen NJ, Williams BO. 2016. Use of primary calvarial osteoblasts to evaluate the function of Wnt signaling in osteogenesisMethods Mol Biol 1481:199–125.

Williams BO. 2016. Genetically engineered mouse models to evaluate the role of Wnt secretion in bone development and homeostasisAm J Med Genet Semin Med Genet 172C(1):24–26.

Chin AM, Tsai YH, Finkbeiner SR, Nagy NS, Walker EM, Ethen NJ, Williams BO, Battle MA, Spence JR. 2016. A dynamic Wnt/B-catenin signaling environment leads to the Wnt-independent and Wnt-dependent proliferation of embryonic intestinal progenitor cellsStem Cell Reports 7(5):826–839.

Burgers TA, Vivanco JF, Zahatnansky J, Moren AJ, Mason JJ, Williams BO. 2016. Mice with a heterozygous Lrp6 deletion have impaired fracture healingBone Res 4:16025.

Schumacher CA, Joiner DM, Less KD, Drewry MO, Williams BO. 2016. Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6Bone Res 4:15042.

Meng X, Vander Ark A, Lee P, Hostetter G, Bhowmick NA, Matrisian LM, Williams BO, Miranti CK, Li X. 2016. Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasisOncogene 35(18):2370–2378.   

Weivoda MM, Ruan M, Hachfeld CM, Pederson L, Howe A, Davey R, Zajac J, Kobayashi Y, Williams BO, Westendorf JJ, Khosla S, Oursler MJ. 2016. Wnt signaling inhibits osteoclast differentiation by activating canonical and non-canonical cAMP/PKA pathwaysJ Bone Miner Res 31(1):65–75.

Rudnicki MA, Williams BO. 2016. Wnt signaling in bone and muscleBone 80:60–66.

2015

Oursler MJ, Westendorf JJ, Weivoda MM, Ruan M, Hachfeld CM, Howe A, Davey R, Zajac J, Williams BO, Khosla S. 2015. Response to Wnt signaling pathwaysJ Bone Miner Res 30(11):2135–2136.

Chen J, Huang D, Rubera I, Futami K, Wang PF, Zickert P, Khoo SK, Dykema KJ, Zhao P, Petillo D, Cao B, Zhang Z, Si S, Schoen SR, Yang XJ, Zhou M, Xiao GQ, Wu G, Nordenskjold M, Tauc M, Williams BO, Furge KA, Teh BT. 2015. Disruption of tubular Flcn expression as a mouse model for renal tumor inductionKidney Int 88(5):1057–1069.

Zhong ZA, Zahatnansky J, Snider J, Van Wieren E, Diegel CR, Williams BO. 2015. Wntless spatially regulates bone development through β-catenin-dependent and independent mechanismsDev Dyn 244(10):1347–1355.

Cheng SL, Ramachandran B, Behrmann A, Shao JS, Mead M, Smith C, Krchma K, Arrendondo YB, Kovacs A, Kapoor K, Brill LM, Perera R, Williams BO, Towler DA. 2015. Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR–/– mice by restraining noncanonical Wnt signalsCirc Res 117(2):142–156.

Collins CJ, Vivanco JF, Sokn SA, Williams BO, Burgers TA, Ploeg HL. 2015. Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femurJ Biomech 48(2):310–317.

Peacock JD, Dykema KJ, Toriello HV, Mooney MR, Scholten DJ 2nd, Winn ME, Borgman A, Duesbery NS, Hiemenga JA, Liu C, Campbell S, Nickoloff BP, Williams BO, Steensma MR. 2015. Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterationsAm J Med Genet A 167(7):1429–1435.

Qin L, Yin YT, Zheng FJ, Peng LX, Yang CF, Bao YN, Liang YY, Li XJ, Xiang YQ, Sun R, Li AH, Zou RH, Pei XQ, Huang BJ, Kang TB, Liao DF, Zeng YX, Williams BO, Qian CN. 2015. WNT5A promotes stemness characteristics in nasopharyngeal carcinoma cells leading to metastasis and tumorigenesisOncotarget 6(12):10239–10252.

Valkenburg KC, Hostetter G, Williams BO. 2015. Concurrent hepsin overexpression and adenomatous polyposis coli deletion causes invasive prostate carcinoma in miceProstate 75(14):1579–1585.

Zhong ZA, Peck A, Li S, VanOss J, Snider J, Droscha CJ, Chang TA, Williams BO. 2015. 99mTC-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization during bone healing in miceBone Res 3:15013.

2014

Valkenburg KC, Yu X, De Marzo AM, Spiering TJ, Matusik RJ, Williams BO. 2014. Activation of Wnt/b-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasiaProstate 74(15):1506–1520.

Zhong Z, Ethen NJ, Williams BO. 2014. WNT signaling in bone development and homeostasisWiley Interdiscip Red Dev Biol 3(6):489–500.

Li C, Williams BO, Cao X, Wan M. 2014. LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodelingBone Res 2:14006.

Yang J, Mowry LE, Nejak-Bowen KN, Okabe H, Diegel CR, Lang RA, Williams BO, Monga SP. 2014. b-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60(3):964–976.

Scholten DJ 2nd, Timmer CM, Peacock JD, Pelle DW, Williams BO, Steensma MR. 2014. Down regulation of Wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cellsPLoS One 9(10):e111431.

Cui Y, Niziolek PJ, MacDonald BT, Alenina N, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Powell DR, Bader M, Williams BO, Warman ML, Robling AG. 2014. Reply to Lrp5 regulation of bone mass and gut serotonin synthesisNat Med 20(11):1229–1230.

Hoffmann FM, Burgers T, Mason JJ, Williams BO, Sietsema DL, Jones CB. 2014. Biomechanical evaluation of fracture fixation constructs using a variable-angle locked periprosthetic femur plate systemInjury 45(7):1035–1041.

Joiner DM, Less KD, Van Wieren EM, Hess D, Williams BO. 2014. Accelerated and increased joint damage in young mice with global inactivation of mitogen-inducible gene 6 (Mig-6) after ligament and meniscus injuryArthritis Res Ther 16(2):R81.

Kabiri Z, Greicius G, Madan B, Biechele S, Zhong Z, Zaribafzadeh H, Aliyed J, Wu Y, Bunte RM, Williams BO, Rossant J, Virshup DM. 2014. Stroma provides an intestinal stem cell niche in the absence of epithelial WntsDevelopment 141(11):2206–2215.

Lim WH, Liu B, Cheng D, Williams BO, Mah SJ, Helms JA. 2014. Wnt signaling regulates homeostasis of the periodontal ligamentJ Periodontal Res 49(6):751–759.

Lim WH, Liu B, Cheng D, Hunter DJ, Zhong Z, Ramos DM, Williams BO, Sharpe PT, Bardet C, Mah SJ, Helms JA. 2014. Wnt signaling regulates pulp volume and dentin thicknessJ Bone Miner Res 29(4):892–901.

Staal B, Williams BO, Beier F, Vande Woude GF, Zhang YW. 2014. Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chrondrocyte proliferationProc Natl Acad Sci U S A 111(7):2590–2595.

Williams BO. 2014. Insights into the mechanisms of sclerostin action in regulating bone mass accrualJ Bone Min Res 29(1):24–28.

2013

Burgers TA, Williams BO. 2013. Regulation of Wnt/β-catenin signaling within and from osteocytesBone 54(2):244–249.

Burgers TA, Hoffmann MF, Collins CJ, Zahatnansky J, Alvarado MA, Morris MR, Sietsma DL, Mason JJ, Jones CB, Ploeg HL, Williams BO. 2013. Mice lacking Pten in osteoblasts have improved intramembranous and late endochondral fracture healingPLoS One 8(5):e63857.

Hu B, Chen Y, Usmani SZ, Ye S, Qiang W, Papanikolaou X, Heuck CJ, Yaccoby S, Williams BO, Van Rhee F, Barlogie B, Epstein J, Qiang YW. 2013. Characterization of the molecular mechanism of the bone-anabolic activity of carfilzomib in multiple myelomaPLoS One 8(9):e74191.

Joiner DM, Less KD, Van Wieren EM, Hess D, Williams BO. 2013. Heterozygosity for an inactivating mutation in low-density lipoprotein-related receptor 6 (Lrp6) increases osteoarthritis severity in mice after ligament and meniscus injuryOsteoarthritis Cartilage 21(10):1576–1585.

Joiner DM, Ke J, Zhong Z, Xu HE, Williams BO. 2013. LRP5 and LRP6 in development and diseaseTrends Endocrin Metab 24(1):31–39.

Ke J, Xu HE, Williams BO. 2013. Lipid modification in Wnt structure and functionCurr Opin Lipidol 24(2):129–133.

Ke J, Harikumar KG, Jurecky C, Chen C, Gu X, Wang L, Parker N, Cheng Z, Xu W, Williams BO, Melcher K, Miller LJ, Xu HE. 2013. Structure and function of Norrin in assembly and activation of a Frizzled 4–Lrp5/6 complexGenes Dev 27(21):2305–2319.

Loftus JC, Dhruv H, Tuncali S, Kloss J, Yang Z, Schumacher CA, Cao B, Williams BO, Eschbacher JM, Ross JTD, Tran NL. 2013. TROY (TNFRSF19) promotes glioblastoma cell survival signaling and therapeutic resistanceMol Cancer Res 11(8): 865–874.

Maupin KA, Droscha CJ, Williams BO. 2013. A comprehensive overview of skeletal phenotypes associated with alterations in Wnt/β-catenin signaling in humans and miceBone Res 1(1):27–71.

Riddle RC, Diegel CR, Leslie KM, Van Koevering KK, Faugere MC, Clemens TL, Williams BO. 2013. Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisitionPLoS One 8(5):e63323.

Steensma MR, Tyler WK, Shaber AG, Goldring SR, Ross FP, Williams BO, Healey JH, Purdue PE. 2013. Targeting the giant cell tumor stromal cell: functional characterization and a novel therapeutic strategyPLoS One 8(7):e69101.

Valkenburg KC, Steensma MR, Williams BO, Zhong Z. 2013. Skeletal metastasis: treatments, mouse models, and the Wnt signalingChin J Cancer 32(7):380–396.

2012

Fortin SP, Ennis MJ, Schumacher CA, Zylstra-Diegel CR, Williams BO, Ross JTD, Winkles JA, Loftus JC, Symons MH, Tran NL. 2012. Cdc42 and the guanine nucleotide exchange factors Ect2 and Trio mediate Fn14-Rac1-induced migration and invasion of glioblastoma cellsMol Cancer Res 10(7):958–968.

Ke J, Zhang C, Harikumar KG, Zylstra-Diegel CR, Wang L, Mowry LE, Miller LJ, Williams BO, Xu HE. 2012. Modulation of β-catenin signaling by glucagon receptor activationPLoS One 7(3):e33676.

Li Y, Ferris A, Lewis BC, Orsulic S, Williams BO, Holland EC, Hughes SH. 2012. The RCAS/TVA somatic gene transfer method in modeling human cancer. In Genetically Engineered Mice for Cancer Research, J.E. Green and T. Ried, eds. Berlin: Springer Verlag, pp. 83–112.

Regard JB, Zhong Z, Williams BO, Yingzi Y. 2012. Wnt signaling in bone development and disease: making stronger bones with WntsCold Spring Harb Perspect Biol4(12):a007997.

Zhong Z, Williams BO. 2012. Integration of cellular adhesion and Wnt signaling: interactions between N-cadherin and LRP5 and their role in regulating bone massJ Bone Miner Res27(9):1849–1851.

Zhong Z, Williams BO, Steensma MR. 2012. The activation of β-catenin by Gαs contributes to the etiology of phenotypes seen in fibrous dysplasia and McCune-Albright syndromeIBMS BoneKEy 9:113.

Zhong Z, Baker JJ, Zylstra-Diegel CR, Williams BO. 2012. Lrp5 and Lrp6 play compensatory roles in mouse intestinal developmentJ Cell Biochem 113(1):31–38.

Zhong Z, Zylstra-Diegel CR, Schumacher CA, Baker JJ, Carpenter AC, Rao S, Yao W, Guan M, Helms JA, Lane NE, Lang RA, Williams BO. 2012. Wntless functions in mature osteoblasts to regulate bone massProc Natl Acad Sci U S A 109(33): E2197–E2204.

2011

Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, Zhong Z, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Liu Q, Mseeh F, Powell DR, Yang QM, Zambrowicz B, Gerrits H, Gossen JA, He X, Bader M, Williams BO, Warman ML, Robling AG. 2011. Lrp5 functions in bone to regulate bone massNat Med17(6):684–691.

Joeng KS, Schumacher C, Zylstra-Diegel CR, Long F, Williams BO. 2011. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryoDev Biol 359(2):222–229.

Qian CN, Williams BO. 2011. The induction of high endothelial venule remodeling by primary tumors does not correlate to the metastatic capability of tumor cellsJ Blood Lymph 1(1):e102.

Stefater JA 3rd, Lewkowich I, Rao S, Mariggi G, Carpenter AC, Burr AR, Fan J, Ajima R, Molkentin JD, Williams BO, Wills-Karp M, Pollard JW, Yamaguchi T, Ferrara N, Gerhardt H, Lang RA. 2011. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cellsNature 474(7352):511–515.

Valkenburg KC, Williams BO. 2011. Mouse models of prostate cancerProstate Cancer 2011: 22 pp.

Wan M, Li J, Herbst K, Zhang J, Yu B, Wu X, Qiu T, Lei W, Lindvall C, Williams BO, Ma H, Zhang F, Cao X. 2011. LRP6 mediates cAMP generation by G protein–coupled receptors through regulating the membrane targeting of GαsSci Signal 4(164):ra15.

2010

Coulibaly MO, Sietsema DL, Burgers TA, Mason J, Williams BO, Jones CB. 2010. Recent advances in the use of serological bone formation markers to monitor callus development and fracture healingCrit Rev Eukaryot Gene Expr 20(2):105–127.

Diegel CR, Cho KR, El-Naggar AK, Williams BO, Lindvall C. 2010. Mammalian target of rapamycin-dependent acinar cell neoplasia after inactivation of Apc and Pten in the mouse salivary gland: implications for human acinic cell carcinomaCancer Res 70(22):9143–9152.

Mason JJ, Williams BO. 2010. SOST and DKK: antagonists of LRP family signaling as targets for treating bone diseaseJ Osteoporos 2010:460120.

2009

Badders NM, Goel S, Clark RJ, Klos KS, Kim S, Bafico A, Lindvall C, Williams BO, Alexander CM. 2009. The Wnt receptor, Lrp5, is expressed by mouse mammary stem cells and is required to maintain the basal lineagePLoS One 4(8):e6594.

Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. 2009. mTOR mediates Wnt-induced epidermal stem cell exhaustion and agingCell Stem Cell5(3):279–289.

Lindvall C, Zylstra CR, Evans N, West RA, Dykema K, Furge KA, Williams BO. 2009. The Wnt co-receptor Lrp6 is required for normal mouse mammary gland developmentPLoS One 4(6):e5813.

Qian CN, Furge KA, Knol J, Huang D, Chen J, Dykema KJ, Kort EJ, Massie A, Khoo SK, Vanden Beldt K, Resau JH, Anema J, Kahnoski RJ, Morreau H, Camparo P, Comperat E, Sibony M, Denoux Y, Molinie V, Vieillefond A, Eng C, Williams BO, Teh BT. 2009. Activation of the PI3K/AKT pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal modelsCancer Res 69(21):8256–8264.

Williams BO, Insogna KL. 2009. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in boneJ Bone Miner Res 24(2):171–178.

2008

Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J, Li Y, Khoo SK, Huang D, Qian CN, Zhao P, Dykema K, Zhang R, Cao B, Yang XJ, Furge K, Williams BO, Teh BT. 2008. Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasiaPLoS One 3(10):e3581.

Qian Z, Chen L, Fernald AA, Williams BO, Le Beau MM. 2008. A critical role for Apc in hematopoietic stem and progenitor cell survivalJ Exp Med 205(9):2163–2175.

Robinson DR, Zylstra CR, Williams BO. 2008. Wnt signaling and prostate cancerCurr Drug Targets 9(7):571–580.

Shekhar MPV, Gerard B, Pauley RJ, Williams BO, Tait L. 2008. Rad6B is a positive regulator of β-catenin stabilizationCancer Res 68(6):1741–1750.

VanKoevering KK, Williams BO. 2008. Transgenic mouse strains for conditional gene deletion during skeletal development. IBMS BoneKEy 5(5):151–170.

Wang P, Bowl MR, Bender S, Peng J, Farber L, Chen J, Ali A, Zhang Z, Alberts AS, Thakker RV, Shilatifard A, Williams BO, Teh BT. 2008. Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult miceMol Cell Biol 28(9):2930–2940.

Wolf J, Palmby TR, Gavard J, Williams BO. 2008. Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6FEBS Letters582(2): 255–261.

Zylstra CR, Wan C, VanKoevering KK, Sanders AK, Lindvall C, Clemens TL, Williams BO.  2008.  Gene targeting approaches in mice: assessing the roles of LRP5 and LRP6 in osteoblastsJ Musculoskelet Neuronal Interact 8(4):291–293.

2007

Bruxvoort KJ, Charbonneau HM, Giambernardi TA, Goolsby JC, Qian CN, Zylstra CR, Robinson DR, Roy-Burman P, Shaw AK, Buckner-Berghuis BD, Sigler RE, Resau JH, Sullivan R, Bushman W, Williams BO. 2007. Inactivation of Apc in the mouse prostate causes prostate carcinomaCancer Res 67(6):2490–2496.

Hinoi T, Akyol A, Theisen BK, Ferguson DO, Greenson JK, Williams BO, Cho KR, Fearon ER. 2007. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivationCancer Res 67(20):9721–9730.

Lindvall C, Bu W, Williams BO, Li Y. 2007. Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev 3(2):157–168.

Liu X, Bruxvoort KJ, Zylstra CR, Liu J, Cichowski R, Faugere MC, Bouxsein ML, Wan C, Williams BO, Clemens TL. 2007. Lifelong accumulation of bone in mice lacking Pten in osteoblastsProc Natl Acad Sci 104(7):2259–2264.

Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DE, Katabuchi H, Williams BO, Fearon ER, Cho KR. 2007. Mouse model of human ovarian endometroid adenocarcinoma based on somatic defects in the Wnt β-catenin and PI3K/Pten signaling pathwaysCancer Cell 11(4):321–333.

Young JJ, Bromberg-White JL, Zylstra CR, Church JT, Boguslawski E, Resau JH, Williams BO, Duesbery NS. 2007. LRP5 and LRP6 are not required for protective antigen–mediated internalization or lethality of anthrax lethal toxinPLoS Pathog 3(3):e27.

2006

Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL. 2006. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growthCell 126(5):955–968.

Lindvall C, Evans NC, Zylstra CR, Li Y, Alexander CM, Williams BO. 2006. The Wnt signaling receptor LRP5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesisJ Biol Chem 281(46):35081–35087.

Park KS, Jeon SH, Kim SE, Bahk YY, Holmen SL, Williams BO, Chung KC, Surh YJ, Choi KY. 2006. APC inhibits ERK pathway activation and cellular proliferation induced by RasJ Cell Sci119(5):819–827.

Wang PF, Kong D, VanBrocklin MW, Peng J, Zhang C, Potter SJ, Gao X, Teh BT, Zhang N, Williams BO, Holmen SL. 2006. Simplified method for the construction of gene targeting vectors for conditional gene inactivation in mice. Transgenics 4:215–228.

Zhang C, Kong D, Tan MH, Pappas DL Jr, Wang PF, Chen J, Farber L, Zhang N, Koo HM, Weinreich M, Williams BO, Teh BT. 2006. Parafibromin inhibits cancer cell growth and causes G1 phase arrestBiochem Biophys Res Commun 350(1):17–24.

2005

Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. 2005. Prostaglandin E2 promotes colon cancer cell growth through a GS-axin-β-catenin signaling axisScience 310(5753):1504–1510.

Holmen SL, Williams BO. 2005. Essential role for Ras signaling in glioblastoma maintenanceCancer Res 65(18) 8250–8255.

Holmen SL, Zylstra CR, Mukherjee A, Sigler R, Faugere MC, Bouxsein M, Deng L, Clemens T, Williams BO. 2005. Essential role of ß-catenin in postnatal bone acquisitionJ Biol Chem 280(22):21162–21168.

Holmen SL, Robertson SA, Zylstra CR, Williams BO. 2005. Wnt-independent activation of ß-catenin mediated by a Dkk-1-Frizzled 5 fusion proteinBiochem Biophys Res Commun 328(2):533–539.

Qian CN, Knol J, Igarashi P, Lin F, Zylstra U, Teh BT, Williams BO. 2005. Cystic renal neoplasia following conditional inactivation of Apc in mouse renal tubular epitheliumJ Biol Chem280(5):3938–3945.

Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML. 2005. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling.  Mol Cell Biol 25(12):4946–4955.

Robertson SA, Schoumans J, Looyenga BD, Yuhas JA, Zylstra CR, Koeman JM, Swiatek PJ, Teh BT, Williams BO. 2005. Spectral karyotyping of sarcomas and fibroblasts derived from Ink4a/Arf-deficient mice reveals chromosomal instability in vitroInt J Oncol 26(3):629–634.

Wang PF, Kong D, VanBrocklin MW, Peng J, Zhang C, Potter SJ, Gao X, Teh BT, Zhang N, Williams BO, Holmen SL. 2005. Simplified method for the construction of gene targeting vectors for conditional gene inactivation in mice. Transgenics 4:215–218.

2004

Bromberg-White JL, Webb CP, Patacsil VS, Miranti CK, Williams BO, Holmen SL. 2004. Delivery of short hairpin RNA sequences by using a replication-competent avian retroviral vectorJ Virol 78(9):4914–4916.

Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO. 2004. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6J Bone Miner Res 19(12): 2033–2040.

Spike BT, Dirlam A, Dibling BC, Marvin J, Williams BO, Jacks T, Macleod KF. 2004. The Rb tumor suppressor is required for stress erythropoiesisEMBO J 23(21): 4319–4329.

2002

Holmen SL, Salic A, Zylstra CR, Kirschner MW, Williams BO. 2002. A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate beta -catenin-dependent signaling. J Biol Chem 277(38):34727–34735.

Takahashi M, Yang XJ, Lavery TT, Furge KA, Williams BO, Tretiakova M, Montag A, Vogelzang NJ, Re GG, Garvin AJ, Soderhall S, Kagawa S, Hazel-Martin D, Nordenskjold A, Teh BT. 2002. Gene expression profiling of favorable histology Wilms tumors and its correlation with clinical featuresCancer Res 62(22): 6598–6605.

Yang H, Williams BO, Hinds PW, Shih TS, Jacks T, Bronson RT, Livingston DM. 2002. Tumor suppression by a severely truncated species of retinoblastoma proteinMol Cell Biol 22(9):3103–3110. 

2001

Lipinski MM, Macleod KF, Williams BO, Mullaney TL, Crowley D, Jacks T. 2001. Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous systemEMBO J 20(13):3402–3413.

2000

Dunn KJ, Williams BO, Li Y, Pavan WJ. 2000. Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse developmentProc Natl Acad Sci U S A 97(18):10050–10055.

Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams BO, Theodorou E, Jacks T. 2000. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalizationGenes Dev 14(23):3037–3050.

Williams BO, Barish GD, Klymkowsky MW, Varmus HE. 2000. A comparative evaluation of beta-catenin and plakoglobin signaling activityOncogene 19(50): 5720–5728.

1999

Klymkowsky MW, Williams BO, Barish GD, Varmus HE, Vourgourakis YE. 1999. Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signalingMol Biol Cell 10(10):3151–3169.

Zorn AM, Barish GD, Williams BO, Lavender P, Klymkowsky MW, Varmus HE. 1999. Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-cateninMol Cell 4(4):487–498.

1998

Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E, Jacks T. 1998. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)miceNat Genet 18(4):360–364. 

1996

Herrera RE, Sah VP, Williams BO, Makela TP, Weinberg RA, Jacks T. 1996. Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblastsMol Cell Biol 16(5):2402–2407.

Lee MH, Williams BO, Mulligan G, Mukai S, Bronson RT, Dyson N, Harlow E, Jacks T. 1996. Targeted disruption of p107: functional overlap between p107 and RbGenes Dev 10(13):1621–1632.

1995

Sah VP, Attardi LD, Mulligan GJ, Williams BO, Bronson RT, Jacks T. 1995. A subset of p53-deficient embryos exhibit exencephalyNat Genet 10(2):175–180.

Tischler AS, Shih TS, Williams BO, Jacks T. 1995. Characterization of pheochromocytomas in a mouse strain with a targeted disruptive mutation of the neurofibromatosis gene Nf1.  Endocr Pathol 6(4):323–335.

Haas AL, Baboshina O, Williams BO, Schwartz LM. 1995. Exponential increases in ubiquitin conjugate pools accompany the developmentally programmed cell death of insect skeletal muscle. J Biol Chem 270(16):9407–9412

1994

Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, Weinberg RA. 1994. Tumor spectrum analysis in p53-mutant miceCurr Biol 4(1):1–7.

Morgenbesser SD, Williams BO, Jacks T, DePinho RA. 1994. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lensNature 371(6492):72–74.

Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB, Cho KR. 1994.  p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoproteinProc Natl Acad Sci U S A 91(12):5320–5324.

Williams BO, Morgenbesser SD, DePinho RA, Jacks T. 1994. Tumorigenic and developmental effects of combined germ-line mutations in Rb and p53Cold Spring Harb Symp Quant Biol 59: 449–457.

Williams BO, Remington L, Albert DM, Mukai S, Bronson RT, Jacks T. 1994. Cooperative tumorigenic effects of germline mutations in Rb and p53Nat Genet 7(4):480–484.

Williams BO, Schmitt EM, Remington L, Bronson RT, Albert DM, Weinberg RM, Jacks T. 1994. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequencesEMBO J 13(18):4251–4259.

1993

Chen J, Gorman JR, Stewart V, Williams BO, Jacks T, Alt FW. 1993. Generation of normal lymphocyte populations by Rb-deficient embryonic stem cellsCurr Biol 3(7):405–413.

Zettergren LD, Cutlan R, Williams BO. 1991. Embryonic dorsal region compartments in B lymphopoiesis: Rana pipiensGallus gallus, and Mus musculusDev Comp Immunol 15:105S.

Sonya Craig, Ph.D.

Scientific Grant Writer

Cassandra Diegel, B.S.

Lab Manager

Megan Michalski, D.D.S., Ph.D.

Postdoctoral Fellow

Wnt signaling in craniofacial bone development

Michelle Minard, B.S.

Senior Administrative Assistant II

Emily Sall

Laboratory Aide

Payton Stevens, Ph.D.

Postdoctoral Fellow

Wnt/Frizzled receptor signaling during pancreatic cancer progression

Alex Zhong, Ph.D

Research Scientist

LAB ALUMNI

Jake Baker

Undergraduate Intern

Stephanie Berry

Undergraduate Intern

Michael Bessey

Undergraduate Intern

Katia Bruxvoort

Undergraduate Intern/Assistant Research Technician

Travis Burgers, Ph.D.

Postdoctoral Fellow

Holli Charbonneau

Undergraduate Intern/Assistant Research Technician

Cheryl Christie

Student Intern

Daniel Dick

Student Intern

Casey Droscha, Ph.D.

Van Andel Institute Graduate School Graduate Student

Patrick Eden

Senior Research Technician

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Undergraduate Intern

Nicole Ethen, B.S.

Assistant Research Technician

Nicole Evans

Undergraduate Intern/Assistant Research Technician

Amanda Field

Undergraduate Intern

Arianna Folkema

Undergraduate Intern

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Research Technician

Steve Geelhood

Undergraduate Intern

Troy Giambernardi, Ph.D

Postdoctoral Fellow

Rida Haider

Van Andel Institute Graduate School Graduate Student

Katie Hollis, M.S.

Van Andel Institute Graduate Student

Sheri Holmen, Ph.D.

Postdoctoral Fellow

Jennifer Holtrop

Undergraduate Intern

Hudson Hotaling

Undergraduate Intern

Isaac Izaguirre

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Danese Joiner-Fox, Ph.D

Postdoctoral Fellow

Clifford Jones, M.D.

Adjunct Faculty

Madison Kelly

Research Technician

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Undergraduate Intern

Jason Koning

Undergraduate Intern

Angela Lake

Assistant Research Technician

Johan Lee

Student Intern

Jon Lensing

Undergraduate Intern

Charlotta Lindvall, M.D., Ph.D.

Postdoctoral Fellow

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Research Technician

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Senior Research Technician

Agni Naidu, B.S., B.A., Ph.D.

Van Andel Institute Graduate School Graduate Student

Rebecca Nguyen

Undergraduate Intern

Melissa Oosterhouse

Undergraduate Intern

Adam Racette

Student Intern

Nolan Redtzke

Student Intern

Scott Robertson

Undergraduate Intern/Assistant Research Technician

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Ammar Salhadar

Undergraduate Intern/Assistant Research Technician

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Undergraduate Intern/Assistant Research Technician

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Cassie Schumacher

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Tyler Spiering

Undergraduate Intern

Ken Valkenburg, Ph.D.

Graduate student—Van Andel Institute Graduate School

Andy Vander Moren, MSE

Graduate Student—Grand Valley State University

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Visiting Scientist

Kyle Van Koevering

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Emily Van Wieren

Undergraduate Intern/Assistant Research Technician

Kate VanderWoude

Student Intern

Allison Weese

Assistant Research Technician

John Westerveld

Student Intern

Juraj Zahatnansky

Senior Research Technician

Alex Zhong, Ph.D.

Postdoctoral Fellow