Faculty and Research Interests
Gary S. Goldberg, PhD
Science Center B307
West Virginia University, WV
PhD (Genetics and Developmental Biology) , 1990
University of Georgia , GA
BS (Biology and Genetics) , 1983
Cells must communicate with each other to coordinate the development and survival of an animal. This communication can be mediated by diffusible factors that pass between cells, or by direct contact through cell junctions. We are interested in how intercellular communication affects cell growth and differentiation, with an emphasis on how cell communication can control tumor cell growth, invasion, and metastasis.
Intercellular junctions mediate signals that allow normal cells to inhibit the transformed growth of neighboring tumor cells. This process is called “contact normalization”. Tumor cells need to escape contact normalization in order to become malignant or metastatic. We are defining how cell junctions, including connexins, integrins, and cadherins, as well as receptor mediated signaling and signal transduction events control or override contact normalization. This has enabled us to identify tumor biomarkers and chemotherapeutic targets, and to develop agents that effectively block cancer cell growth without harming other cells in the body. For example, as shown in Figure 1, we have identified reagents that specifically inhibit pathways required for nonanchored tumor cell growth, migration, and survival.
Figure 1: Contact normalization and neutralization of tumor cell growth. The Src kinase phosphorylates Cas, which associates with Cx43 and Crk to block gap junctional communication and promote nonanchored cell growth and migration. However, cancer cell growth can be controlled by adjacent nontransformed cells. We have found specific growth factor receptors, adaptor proteins, and other signaling molecules, including miRNAs, that promote (red) or inhibit (blue) this process. These molecules can be used as biomarkers to detect cancer, as well as targets to neutralize malignant and metastatic cancer cells. For example, we have identified kinase blockers, siRNA molecules, antisera, and competitive receptor ligands (green) that can synergistically suppress coordinated pathways that are required for tumor cell survival and invasion.
1. Silva, T.A., Smuczek, B., Valadão, I.C., Dzik, L.M., Iglesia, R.P., Cruz, M.C., Zelanis, A., de Siqueira, A.S., Serrano, S.M.T., Goldberg, G.S., Jaeger, R.G., Freitas, V.M. (2016) AHNAK enables mammary produce extracellular produce extracellular vesicles that increase neighboring fibroblast cell motility. Oncotarget. 7:49998-50016.
2. Krishnan, H., Retzbach, E.P., Ramirez, M.I., Liu, T., Li, H., Miller, W.T., Goldberg, G.S. (2015) PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility. Experimental Cell Research. 335: 115-122.
3. Ochoa-Alvarez, J.A., Krishnan, H., Pastorino, J.G., Nevel, E.M., Kephart, D., Lee, J.J., Retzbach, E.P., Shen, Y., Fatahzadeh, M., Baredes, S., Kalyoussef, E., Honma, M., Adelson, M.E., Kaneko, M.K., Kato, Y, Young, M.A., Deluca-Rapone, L., Shienbaum, A.J., Yin, K., Jensen, L.D., and Goldberg, G.S. (2015) Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms. Oncotarget, 6: 9045-90604. (highlighted in issue cover art)
4. Kolar, K., Freitas-Andrade, M., Bechberger, J.F., Krishnan, H., Goldberg, G.S., Naus, C.C., and Sin, W.C. (2015) Podoplanin: a marker of reactive gliosis in gliomas and brain injury. Journal of Neuropathology and Experimental Neurology, 74: 64-74. (Highlighted in issue cover art).
5. Mayan, M.D., Gago-Fuentes, R., Carpintero-Fernandez, P., Fernandez-Puente, P., Filgueira-Fernandez, P., Goyanes, N., Valiunas, V., Brink, P.R., Goldberg, G.S., and Blanco, F.J. (2015) Articular chondrocyte network mediated by gap junctions: Role in metabolic cartilage homeostasis. Annals of the Rheumatic Diseases, 74: 275-84.
6. Krishnan, H., Ochoa-Alvarez, J.A., Shen, Y., Nevel, E., Lakshminarayanan, M., Williams, M.C., Ramirez, M.I., Miller, W.T., and Goldberg, G.S. (2013) Serines in the intracellular tail of podoplanin (PDPN) regulate cell motility. Journal of Biological Chemistry, 288, 12215-12221. (published as “report” - reserved for “topics of exceptional novelty, significance and broad interest …. within the top 5 percent of all articles published in the journal”)
7. Krishnan, H., Miller, W.T., and Goldberg, G.S. (i2012) Src points the way to biomarkers and chemotherapeutic targets. Genes and Cancer 3, 426-435.
Ochoa-Alvarez, J.A., Krishnan, H., Shen, Y., Acharya, N.K., Han, M., McNulty, D.E., Hasegawa, H., Hyodo, T., Senga, T., Geng, J.-G., Kosciuk, M., Shin, S.S., Goydos, J.S., Temiakov, D., Nagele, R.G., and Goldberg, G.S. (2012) Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration. PLoS One 7:e41845.
8. Alvarez, J.A.O., George, C., Krishnan, H., Wu, X., and Goldberg, G.S. (2011) Contact Normalization: mechanisms and pathways to biomarkers and chemotherapeutic targets. In: Adams, J. (Eds.) Extracellular and Intracellular Signaling. pp. 105-115. Cambridge: Royal Society of Chemistry.
9. Khusial, P.R., Vadla, B., Krishnan, H., Ramlall, T.F., Shen, Y., Ichikawa, H., Geng, J.-G., and Goldberg, G.S. (2010) Src activates Abl to augment Robo1 expression in order to promote tumor cell migration. Oncotarget 4, 198-209. (highlighted in news section and issue cover illustration)
10. Shen, Y., Chen, C.-S., Ichikawa, H., and Goldberg, G.S. (2010) Src induces Pdpn expression to promote cell migration. Journal of Biological Chemistry 285, 9649-9656..
11. Li, X., Shen, Y., Ichikawa, H., Antes, T., and Goldberg, G.S. (2009) Regulation of miRNA expression by Src and contact normalization: effects on nonanchored cell growth and migration. Oncogene 28, 4272–4283.
12. Li, X., Jia, Z., Shen, Y., Ichikawa, H., Jarvik, J., Nagele, R.J., and Goldberg, G.S. (2008) Coordinate suppression of Sdpr and Fhl1 expression in tumors of the breast, kidney, and prostate. Cancer Science 99, 1326-1333.
13. Shen, Y., Khusial, P.R., Li, X., Ichikawa, H., Moreno, A.P., and Goldberg, G.S. (2007) Src utilizes Cas to block gap junctional communication mediated by connexin43. Journal of Biological Chemistry 282, 18914-18921.
14. Shen, Y., Jia Z., Nagele R.G., Ichikawa H., and Goldberg G.S. (2006) Src utilizes Cas to suppress Fhl1 in order to promote nonanchored growth and migration of tumor cells. Cancer Research 66, 1543-1552.
15. Valiunas, V., Bechberger, J.F., Naus, C.C.G., Brink, P.R., and Goldberg, G.S. (2005) Nontransformed cells can normalize gap junctional communication with transformed cells. Biochemical and Biophysical Research Communications 333, 174-179.
16. Alexander, D.B., Ichikawa, H., Bechberger, J.F., Valiunas, V., Ohki, M., Naus, C.C.G., Kunimoto, T., Tsuda, H., Miller, W.T., and Goldberg, G.S. (2004) Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and Src activity. Cancer Research 64, 1347-1358.
17. Goldberg, G.S., Alexander, D.B., Pellicena, P., Zhang, Z.-Y., Tsuda, H., and Miller, W.T. (2003) Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells. Journal of Biological Chemistry 278, 46533-46540. (highlighted in issue cover illustration)
18. Goldberg, G.S., Moreno, A.P., and Lampe, P.D. (2002) Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. Journal of Biological Chemistry 277, 36725-36730.
19. Goldberg, G.S., Jin, Z., Ichikawa, H., Naito, A., Ohki, M., El-Deiry, W.S., and Tsuda, H. (2001) Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis ligand in anoikis. Cancer Research 61, 1334-1337.
20. Goldberg, G.S., Bechberger, J.F., Tajima, Y., Merritt, M., Omori, Y., Gawinowicz, M.A., Narayanan, R., Tan, Y., Sanai, Y., Yamasaki, H., Naus, C.C.G., Tsuda, H., and Nicholson, B.J. (2000) Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. Cancer Research 60, 6018-6026.
21. Goldberg, G.S., Lampe, P.D., and Nicholson, B.J. (1999) Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nature Cell Biology 1, 457-459.
- 22. Goldberg, G.S., Lampe, P.D., and Nicholson, B.J. (1999) Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nature Cell Biology 1, 457-459.
Contribute to Cancer Research Project
A major problem with most current cancer treatments lies in their toxic effects on other cells in the body. Thus, chemotherapy often makes patients sick. Indeed, in some cases, it is not known if a patient actually dies from cancer rather than the treatment they undergo to combat it. However, nature has evolved a way to fight cancer without harming other cells in the body. This method is called, “contact normalization”.
Contact normalization describes the ability of nontransformed cells to normalize the growth of neighboring cancer cells. This is a very wide spread and powerful phenomenon. Tumor cells need to overcome this form of growth inhibition before they can become malignant or metastatic.
We have performed comprehensive analysis to identify genes that are affected during contact normalization. We found that expression of specific genes are activated in transformed cells, but suppressed in nontransformed cells. We also found that expression of these genes is inhibited in transformed cells that are undergoing contact normalization.
Several of these genes are, to the best of our knowledge, not yet described in the literature or any domain. It should be noted that our procedures enabled us to identify these genes as prime candidates for biomarkers and chemotherapy targets from a list comprising over 39 thousand mRNA transcripts (potentially representing every gene in the cell). At least one of these genes encodes an integral membrane protein with an extracellular domain. Therefore, this protein maybe readilyusedto targetcancer cells in patients. In fact, we haveidentifiedcompounds that can bind to thisreceptor and block tumor cell migration.
Thus, these genes can be used in a few ways: (1) as accurate biomarkers to detect cancer; (2) as prognostic indicators to determine the invasive and metastatic potential of cancer cells; and (3) as chemotherapeutic targets to specifically block malignant cancer cell invasion and neutralize their metastatic growth potential by application of nontoxic compounds. It should be stressed that these protocols are highly specific for malignant and metastatic cancer cells; they should not significantly interfere with other noncancerous cells in the adult body.