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Professional Summary
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Dr. Georg F. Weber has made contributions to metastasis research by discovering the interaction between the molecules osteopontin and CD44 and by defining the physiologic role of metastasis genes as stress response genes. While he continues to address fundamental questions, he is researching new venues for diagnosis and therapy of cancer progression.
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Research Support
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Weber, Georg 02/02/2005 08/31/2006 Department of Defense A Molecular Connection Between Breast CancerProliferation & Metastasis Mediated by Akt Kinase Role:PI $219,397.36 Closed Federal
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Grant #R43 CA136011 Weber, Georg 03/01/2009 05/31/2010 National Cancer Institute Therapeutic Anti-Metastasis Antibodies Role:PI $50,000.00 Closed Federal
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Grant #W81XWH-10-1-0324 / PR094070 Weber, Georg 06/01/2010 04/30/2014 Department of the Army Medical Research Acquisition Activity Molecular Signatures of Cancer Metastasis Role:PI $706,500.00 Completed
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Grant #W81XWH-10-1-0465 Weber, Georg 09/15/2010 10/14/2013 Department of the Army Medical Research Acquisition Activity An Engineered Breast Cancer Vaccine Role:PI $577,995.00 Closed Federal
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Grant #R15CA224104 Baccei, Mark; Waltz, Susan; Weber, Georg 09/15/2018 08/31/2021 National Cancer Institute Metabolic Mechanisms in Cancer Progression Role:PI $479,534.00 Active
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Publications
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Peer Reviewed Publications
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Mirza M, Shaughnessy E, Hurley JK, Vanpatten KA, Pestano GA, He B, Weber GF (2008). Osteopontin-c is a highly selective marker for breast cancer. International Journal of Cancer, 122, 889-897.
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Whalen KA, Weber GF, Benjamin TL, Schaffhausen BS (2008). Polyomavirus middle T antigen induces the transcription of osteopontin, a gene important for migration of transformed cells. The Journal of Virology, 82, 4946-4954.
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Syed M, Fenoglio-Preiser C, Skau KA, Weber GF (2008). Acetylcholinesterase supports anchorage independence in colon cancer. Clinical and Experimental Metastasis, 25, 787-798.
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Sullivan J, Blair L, Alnajar A, Aziz T, Ng CY, Chipitsyna G, Gong Q, Witkiewicz A, Weber GF, Denhardt DT, Yeo CJ, Arafat HA. (2009). Expression of a prometastatic splice variant of osteopontin, OPNC, in human pancreatic ductal adenocarcinoma. Surgery, 146, 232-240.
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Weber GF (2010). Molecular genetics and metastasis. Encyclopedia of Life Sciences, DOI 10.1002/9780470015902.a0022447.
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Weber GF (2010). Toward a molecular classification of cancer. Biomarker Theme Issue of Toxicology, 278, 195-198.
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Weber GF, Lett GS, Haubein NC (2010). Osteopontin is a marker for cancer aggressiveness and patient survival. British Journal of Cancer, 103, 861-869.
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Tilli TM, Franco VF, Robbs BK, Wanderley JL, Silva F, Duarte de Mello K, Viola JPB, Weber GF, Gimba ERP (2011). Osteopontin-c splicing isoform contributes to ovarian cancer progression. Molecular Cancer Research, 9, 280-293.
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Shen H, Weber GF (2014). The osteopontin-c splice junction is important for anchorage-independent growth. Molecular Carcinogenesis, 53, 480-487.
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Shi Z, Mirza M, Wang B, Kennedy MA, Weber GF (2014). Osteopontin-a alters glucose homeostasis in anchorage-independent breast cancer cells. Cancer Letters, 344, 47-53.
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Weber GF (2011). The cancer biomarker Osteopontin: Combination with other markers. Cancer Genomics and Proteomics, 8, 263-288.
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Weber GF, Johnson BN, Yamamoto BK, Gudelsky GA (2014). Effects of stress and MDMA on hippocampal gene expression. BioMed Research International, 2014, 141396.DOI:10.1155/2014/141396
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Hartung F, Weber GF (2013). RNA blood levels of osteopontin splice variants are cancer markers. SpringerPlus, 2, 110.
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Wang B, Shi Z, Weber GF, Kennedy MA (2013). Introduction of a new critical p value correction method for statistical significance analysis of metabonomics data. Analytical and Bioanalytical Chemistry, 405, 8419-8429.
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Ramchandani D, Weber GF (2013). An osteopontin promoter polymorphism is associated with aggressiveness in breast cancer. Oncology Reports, 30, 1860-1868.
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Weber GF (2013). Gene therapy--why can it fail?. Medical Hypotheses, 80, 613-616.
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Weber GF, Lett GS, Haubein NC (2011). Categorical meta-analysis of Osteopontin as a clinical cancer marker. Oncology Reports, 25, 433-441.
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Zhang R, Pan X, Huang Z, Weber GF, Zhang G (2011). Osteopontin enhances the expression and activity of MMP-2 via the SDF-1/CXCR4 axis in hepatocellular carcinoma cell lines. PloS One, 6, e23831.
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Weber GF (2008). Molecular mechanisms of metastasis. Cancer Letters, 270, 181-190.
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Milanowski P, Carter TJ, Weber GF (2013). Enzyme catalysis and the outcome of biochemical reactions. Journal of Proteomics and Bioinformatics, 6, 132-141.
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Weber GF (2013). Dynamic knowledge - a century of evolution. Sociology Mind, 3, 268-277.
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Weber GF, Warren J, Shoma H, Chen T, Halim A, Chakravarty G (2012). Biomarkers - A pot of gold or a can of worms? Meeting report from the 2nd world congress on biomarkers in clinical research, 2011, Baltimore, USA. Cancer Biology & Therapy, 13, 831-835.
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Shi Z, Wang B, Kennedy MA, Weber GF (2014). Metabolic skewing during anchorage independence. Induction by osteopontin-c. PlosOne, 9, e105675.
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Mesa C Jr, Mirza M, Mitsutake N, Sartor M, Medvedovic M, Tomlinson C, Knauf JA, Weber GF, Fagin JA (2006). Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Research, 66, 6521-6529.
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Weber GF (2012). Why does cancer therapy lack effective anti-metastasis drugs?. Cancer Letters, 328, 207-211.
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Zduniak K, Ziolkowski P, Ahlin C, Agrawal A, Agrawal S, Blomqvist C, Fjällskog ML, Weber GF (2015). Nuclear Osteopontin-c is a marker for breast cancer prognosis. British Journal of Cancer, 112, 729-738.
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He B, Mirza M, Weber GF (2006). An osteopontin splice variant induces anchorage independence in human breast cancer cells. Oncogene, 25, 2192-2202.
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Weber GF (2015). Somnambulism and allergy. Clinical and Experimental Neuroimmunology, 6, 321.
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Weber GF (2015). Molecular analysis of a recurrent sarcoma identifies a mutation in FAF1. Sarcoma, 839182, doi:10.1155/2015/839182.
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Weber GF (2004). The absence of CD44 ameliorates Faslpr/lpr disease. Autoimmunity, 37, 1-8.
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Ramchandani D, Weber GF (2015). Interactions between OPN and VEGF in health and disease. Implications for cancer. BBA Reviews on Cancer, 1855, 202-222.
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He B, Weber GF (2004). Synergistic activation of the CMV promoter by NF-kB P50 and Cyclic GMP-Dependent Kinase. Biochemical and Biophysical Research Communications, 321, 13-20.
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Ramchandani D, Weber GF (2015). Interactions between OPN and VEGF in health and disease. Implications for the skeletal system. Bone, 81, 7-15.
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Craig-Mylius C, Weber GF, Coburn JL, Glickstein LG (2005). Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response. Journal of Leukocyte Biology, 77, 710-718.
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Weber GF (2009). Drug targets in cancer metastasis. American Association For Cancer Research 100th Annual Meeting Education Book, 137-140.
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Weber GF (2016). (In Press).Metabolism in cancer metastasis. International Journal of Cancer.
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Unruh D, Ünlu B, Lewis CS, Qi X, Chu Z, Sturm R, Keil R, Ahmad SA, Sovershaev T, Adam M, Van Dreden P, Woodhams BJ, Ramchandani D, Weber GF, Rak JW, Wolberg AS, Mackman N, Versteeg HH, Bogdanov VY (2016). (In Press).Antibody-based targeting of alternatively spliced Tissue Factor: a new approach to impede the primary growth and aggressiveness of pancreatic ductal adenocarcinoma. Oncotarget.
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Alsarkhi, L. K., & Weber, G. F. (2018). Anti?osteopontin autoantibodies in various types of cancer. Oncology Reports, 40(6), 3879-3889.DOI:10.3892/or.2018.6768
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Walaszek, K., Lower, E. E., Ziolkowski, P., & Weber, G. F. (2018). Breast cancer risk in premalignant lesions: osteopontin splice variants indicate prognosis. British Journal of Cancer, 119(10), 1259-1266.DOI:10.1038/s41416-018-0228-1
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Weber, Georg F (2018). The Phylogeny of Osteopontin-Analysis of the Protein Sequence. International Journal of Molecular Sciences, 19(9). DOI:10.3390/ijms19092557
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Hartung, F., Wang, Y., Aronow, B., & Weber, G. F. (2017). A core program of gene expression characterizes cancer metastases. Oncotarget, 8(60), 102161-102175.DOI:10.18632/oncotarget.22240
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Briones-Orta, M. A., Avendaño-Vázquez, S. E., Ivette Aparicio-Bautista, D., Coombes, J. D., Weber, G. F., & Syn, W. (2017). Prediction of transcription factor bindings sites affected by SNPs located at the osteopontin promoter. Data in Brief, 14, 538-542.DOI:10.1016/j.dib.2017.07.057
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Briones-Orta, M. A., Avendaño-Vázquez, S. E., Aparicio-Bautista, D. I., Coombes, J. D., Weber, G. F., & Syn, W. (2017). Osteopontin splice variants and polymorphisms in cancer progression and prognosis. Biochimica Et Biophysica Acta. Reviews on Cancer, 1868(1), 93-108.A.DOI:10.1016/j.bbcan.2017.02.005
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Weber, Georg F (2016). Time and Circumstances: Cancer Cell Metabolism at Various Stages of Disease Progression. Frontiers in Oncology, 6, 257.DOI:10.3389/fonc.2016.00257
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Ramchandani, D., Unruh, D., Lewis, C. S., Bogdanov, V. Y., & Weber, G. F. (2016). Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions. Laboratory Investigation; A Journal of Technical Methods and Pathology, 96(12), 1234-1245.DOI:10.1038/labinvest.2016.103
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Zduniak, K., Agrawal, A., Agrawal, S., Hossain, M. M., Ziolkowski, P., & Weber, G. F. (2016). Osteopontin splice variants are differential predictors of breast cancer treatment responses. BMC Cancer, 16, 441.DOI:10.1186/s12885-016-2484-x
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Unruh, D., Ünlü, B., Lewis, C. S., Qi, X., Chu, Z., Sturm, R., Keil, R., Ahmad, S. A., Sovershaev, T., Adam, M., Van Dreden, P., Woodhams, B. J., Ramchandani, D., Weber, G. F., Rak, J. W., Wolberg, A. S., Mackman, N., Versteeg, H. H., & Bogdanov, V. Y. (2016). Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma. Oncotarget, 7(18), 25264-75.DOI:10.18632/oncotarget.7955
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Weber, Georg F (2016). Metabolism in cancer metastasis. International Journal of Cancer, 138(9), 2061-6.DOI:10.1002/ijc.29839
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Ramchandani, D., & Weber, G. F. (2015). Interactions between osteopontin and vascular endothelial growth factor: Implications for skeletal disorders. Bone, 81, 7-15.DOI:10.1016/j.bone.2015.05.047
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Ramchandani, D., & Weber, G. F. (2015). Interactions between osteopontin and vascular endothelial growth factor: Implications for cancer. Biochimica Et Biophysica Acta, 1855(2), 202-22.DOI:10.1016/j.bbcan.2015.02.003
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Zduniak, K., Ziolkowski, P., Ahlin, C., Agrawal, A., Agrawal, S., Blomqvist, C., Fjällskog, M., & Weber, G. F. (2015). Nuclear osteopontin-c is a prognostic breast cancer marker. British Journal of Cancer, 112(4), 729-38.DOI:10.1038/bjc.2014.664
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Weber, Georg F (2015). Molecular Analysis of a Recurrent Sarcoma Identifies a Mutation in FAF1. Sarcoma, 2015, 839182.DOI:10.1155/2015/839182
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Shi, Z., Wang, B., Chihanga, T., Kennedy, M. A., & Weber, G. F. (2014). Energy metabolism during anchorage-independence. Induction by osteopontin-c. PloS One, 9(8), e105675.DOI:10.1371/journal.pone.0105675
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Weber, Georg F (2013). Why does cancer therapy lack effective anti-metastasis drugs?. Cancer Letters, 328(2), 207-11.DOI:10.1016/j.canlet.2012.09.025
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Weber, Georg F The cancer biomarker osteopontin: combination with other markers. Cancer Genomics & Proteomics, 8(6), 263-88.
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Tilli, T. M., Franco, V. F., Robbs, B. K., Wanderley, J. L. M., da Silva, F. R. d. A., de Mello, K. D., Viola, J. P. B., Weber, G. F., & Gimba, E. R. (2011). Osteopontin-c splicing isoform contributes to ovarian cancer progression. Molecular Cancer Research : MCR, 9(3), 280-93.DOI:10.1158/1541-7786.MCR-10-0463
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Weber, Georg F (2010). Toward a molecular classification of cancer. Toxicology, 278(2), 195-8.DOI:10.1016/j.tox.2009.10.016
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Weber, G. F., Lett, G. S., & Haubein, N. C. (2010). Osteopontin is a marker for cancer aggressiveness and patient survival. British Journal of Cancer, 103(6), 861-9.DOI:10.1038/sj.bjc.6605834
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Sullivan, J., Blair, L., Alnajar, A., Aziz, T., Ng, C. Y., Chipitsyna, G., Gong, Q., Witkiewicz, A., Weber, G. F., Denhardt, D. T., Yeo, C. J., & Arafat, H. A. (2009). Expression of a prometastatic splice variant of osteopontin, OPNC, in human pancreatic ductal adenocarcinoma. Surgery, 146(2), 232-40.DOI:10.1016/j.surg.2009.03.036
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Whalen, K. A., Weber, G. F., Benjamin, T. L., & Schaffhausen, B. S. (2008). Polyomavirus middle T antigen induces the transcription of osteopontin, a gene important for the migration of transformed cells. Journal of Virology, 82(10), 4946-54.DOI:10.1128/JVI.02650-07
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Mirza, M., Shaughnessy, E., Hurley, J. K., Vanpatten, K. A., Pestano, G. A., He, B., & Weber, G. F. (2008). Osteopontin-c is a selective marker of breast cancer. International Journal of Cancer, 122(4), 889-97.DOI:10.1002/ijc.23204
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Syed, M., Fenoglio-Preiser, C., Skau, K. A., & Weber, G. F. (2008). Acetylcholinesterase supports anchorage independence in colon cancer. Clinical & Experimental Metastasis, 25(7), 787-98.DOI:10.1007/s10585-008-9192-0
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Published Books
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Georg F. Weber (2005). Cancer Therapy: Molecular Targets in Tumor-Host Interactions. Wymondham: Horizon Press.
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Georg F. Weber (2007). Molecular Mechanisms of Malignancy in Cancer. Dordrecht: Springer.
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Georg F. Weber (2015). Molecular Therapies of Cancer. Switzerland: Springer.
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Positions and Work Experience
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2004 to Present College of Pharmacy, University of Cincinnati. Cincinnati,OH
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2000 -2004 Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine. Boston, MA
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1999 -2004 Tufts-New England Medical Center. Boston, MA
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1996 -2000 Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School. Boston, MA
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1993 -1996 Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School. Boston, MA
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2006 to Present Graduate Program in Cell and Cancer Biology University of Cincinnati, OH
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2004 to Present Cancer Center University of Cincinnati
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2020 to Present Professor College of Pharmacy University of Cincinnati
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Research and Practice Interests
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Molecular Mechanisms of Metastasis
Malignant tumors are characterized by excessive growth, immortalization, and metastatic spread, whereas benign tumors are subject to growth dysregulation and immortalization without expressing gene products that mediate invasion (Weber 2007; Weber 2010a). Gain-of-function mutations of oncogenes or loss-of-function mutations of tumor suppressor genes underlie excessive cell division. Activation of senescence suppressor genes or inactivation of senescence genes underlies immortalization. While molecular studies have made their relation to the uncontrolled expansion of tumor cells obvious, it has not been clear why these defects also induce the ability to metastasize.
Cancers are increasingly classified on the molecular level (Weber 2010b). Based on the phenotypes of knockout mice for various confirmed metastasis genes, we have identified the genetic basis of metastasis formation as aberrant expression or splicing of a unique set of developmentally non-essential genes (stress response genes) that physiologically mediate the homing of immune system cells. Metastasis genes encode homing receptors, their ligands, and extracellular matrix-degrading proteinases, which jointly cause invasion. The specific interaction of homing receptors on the tumor cell surface and their cognate cytokine ligands mediates migration and invasion. The organ preference of metastasis formation is determined by the particular identity of the homing receptors expressed on the tumor cell surface and their ligands (Weber/Ashkar 2000a,b; Ashkar et al. 2000; Weber 2008).
Our laboratory has studied the cytokine osteopontin (Weber 2002), which acts as a metastasis gene in multiple malignancies and is therefore a progression marker (Weber et al. 2010a; Weber et al. 2011; Weber 2011). Based on the molecular mechanisms of osteopontin induction and function in cancer metastasis, we have established the following paradigms:
Osteopontin and variant CD44 interact. We have identified a CD44 splice variant as a receptor for osteopontin (Weber et al. 1996; Weber et al. 1997) and as a metastasis gene (Weber et al. 2002a). We have characterized osteopontin functions, exerted through CD44 and integrin receptors, that mediate cell invasion and protection from apoptosis (Weber et al. 1999; Weber et al. 2002b; Zhang et al. 2011).
Multiple osteopontin splice variants are expressed in invasive, but not in non-invasive, human tumor cells. Osteopontin-c is a sensitive marker for breast and pancreas cancers. It is present in close to 80% of breast cancers and correlates with tumor grade in multiple cancers (Mirza et al. 2007; Sullivan et al. 2009; Tilli et al. 2011). The shortest splice variant, osteopontin-c, supports anchorage-independence, whereas an osteopontin domain that is missing from this splice variant is important for aggregation of the protein (He et al. 2006).
Metastasis genes support anchorage-independence in an autocrine fashion. Most non-hematopoietic cells depend on contact with the substratum for survival. Enhanced energy production is a prerequisite for cancer dissemination. Osteopontin-c supports anchorage-independence through inducing oxidoreductase genes that are associated with the mitochondrial energy metabolism and with the hexose monophosphate shunt (He et al. 2006).
Oncogenes induce distinct pathways to growth and invasiveness. The constitutive activation of the oncogene product Akt kinase in breast cancer cells is a mediator and checkpoint for cell cycle progression as well as induction of the metastasis gene osteopontin (Zhang et al. 2003). Similar relationships apply to the induction of osteopontin by the model oncogene polyoma middle T (Whalen et al. 2008). Distinct signals downstream of RET-PTC or B-RAF in thyroid cancer also account for differences in invasiveness (Mesa et al. 2006).
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Keywords
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cancer, metastasis, cytokines, biomarkers
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Contact Information
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Address type:Academic Location Name:UC College of Pharmacy 231 Albert Sabin Way, MSB Cincinnati 36 45267 Phone:513-558-0947 Email:Georg.Weber@uc.edu
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Address type:Research Location Name:Weber's Lab 231 Albert Sabin Way 3503 MSB Cincinnati 36 45229 273 Phone:513-558-8369 Email:http://pharmacy.uc.edu/weber
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IRB Protocol
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CR01_2021-0043 Continuing Review for Study Osteopontin variants in breast lesions Approval:02/23/2022 Principal Investigator Weber, Georg Pharmacy Weber Lab
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