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.
Selected Publications since 2000:
1. Krishanan H, Goldberg G.S." Contact normalization or escape from the matrix." In: Kandous, M. (Eds) Intercellular communication and Cancer. Heidelberg: Springer. In press.
2. Krishnan H, Retzbach EP, Ramirez MI, Liu T, Li H, Todd Miller W, Goldberg GS. "PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility." Exp Cell Res. 2015 May 7. pii: S0014-4827(15)00168-8. doi: 10.1016/j.yexcr.2015.04.019. [Epub ahead of print]
3. Ochoa-Alvarez JA, Krishnan H, Pastorino JG, Nevel E, Kephart D, Lee JJ, Retzbach EP, Shen Y, Fatahzadeh M, Baredes S, Kalyoussef E, Honma M, Adelson ME, Kaneko MK, Kato Y, Young MA, Deluca-Rapone L, Shienbaum AJ, Yin K, Jensen LD, Goldberg GS. "Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms." Oncotarget. 2015 Apr 20;6(11):9045-60.
4. Kolar K, Freitas-Andrade M, Bechberger JF, Krishnan H, Goldberg GS, Naus CC, Sin WC. "Podoplanin: a marker for reactive gliosis in gliomas and brain injury." J Neuropathol Exp Neurol. 2015 Jan;74(1):64-74. doi: 10.1097/NEN.0000000000000150.
5. Mayan MD, Gago-Fuentes R, Carpintero-Fernandez P, Fernandez-Puente P, Filgueira-Fernandez P, Goyanes N, Valiunas V, Brink PR, Goldberg GS, Blanco FJ. "Articular chondrocyte network mediated by gap junctions: role in metabolic cartilage homeostasis." Ann Rheum Dis. 2015 Jan;74(1):275-84. doi: 10.1136/annrheumdis-2013-204244. Epub 2013 Nov 13. Erratum in: Ann Rheum Dis. 2015 Apr;74(4):792.
6. Krishnan H, Ochoa-Alvarez JA, Shen Y, Nevel E, Lakshminarayanan M, Williams MC, Ramirez MI, Miller WT, Goldberg GS. "Serines in the intracellular tail of podoplanin (PDPN) regulate cell motility." J Biol Chem. 2013 Apr 26;288(17):12215-21. doi: 10.1074/jbc.C112.446823. Epub 2013 Mar 25.
7. Krishnan H, Miller WT, Goldberg GS. "SRC points the way to biomarkers and chemotherapeutic targets." Genes Cancer. 2012 May;3(5-6):426-35. doi: 10.1177/1947601912458583.
8. Ochoa-Alvarez JA, Krishnan H, Shen Y, Acharya NK, Han M, McNulty DE, Hasegawa H, Hyodo T, Senga T, Geng JG, Kosciuk M, Shin SS, Goydos JS, Temiakov D, Nagele RG, Goldberg GS. "Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration." PLoS One. 2012;7(7):e41845. doi: 10.1371/journal.pone.0041845. Epub 2012 Jul 23.
9. Scholl TO, Chen X, Goldberg GS, Khusial PR, Stein TP. "Maternal diet, C-reactive protein, and the outcome of pregnancy. "J Am Coll Nutr. 2011 Aug;30(4):233-40.
10. Khusial PR, Vadla B, Krishnan H, Ramlall TF, Shen Y, Ichikawa H, Geng JG, Goldberg GS. "Src activates Abl to augment Robo1 expression in order to promote tumor cell migration." Oncotarget. 2010 Jul;1(3):198-209.
11. Funasaka K, Ito S, Hasegawa H, Goldberg GS, Hirooka Y, Goto H, Hamaguchi M, Senga T. "Cas utilizes Nck2 to activate Cdc42 and regulate cell polarization during cell migration in response to wound healing." FEBS J. 2010 Sep;277(17):3502-13. doi: 10.1111/j.1742-4658.2010.07752.x. Epub 2010 Jul 19.
12. Shen Y, Chen CS, Ichikawa H, Goldberg GS. "SRC induces podoplanin expression to promote cell migration." J Biol Chem. 2010 Mar 26;285(13):9649-56. doi: 10.1074/jbc.M109.047696. Epub 2010 Feb
13. Li X, Shen Y, Ichikawa H, Antes T, Goldberg GS. "Regulation of miRNA expression by Src and contact normalization: effects on nonanchored cell growth and migration." Oncogene. 2009 Dec 3;28(48):4272-83. doi: 10.1038/onc.2009.278. Epub 2009 Sep 21.
14. Li X, Jia Z, Shen Y, Ichikawa H, Jarvik J, Nagele RG, Goldberg GS. "Coordinate suppression of Sdpr and Fhl1 expression in tumors of the breast, kidney, and prostate." Cancer Sci. 2008 Jul;99(7):1326-33. doi: 10.1111/j.1349-7006.2008.00816.x. Epub 2008 Apr 15.
15. Shen Y, Khusial PR, Li X, Ichikawa H, Moreno AP, Goldberg GS. "SRC utilizes Cas to block gap junctional communication mediated by connexin43." J Biol Chem. 2007 Jun 29;282(26):18914-21. Epub 2007 May 7.
16. Patwardhan P, Shen Y, Goldberg GS, Miller WT. "Individual Cas phosphorylation sites are dispensable for processive phosphorylation by Src and anchorage-independent cell growth." J Biol Chem. 2006 Jul 28;281(30):20689-97. Epub 2006 May 17.
17. Shen Y, Jia Z, Nagele RG, Ichikawa H, Goldberg GS. "SRC uses Cas to suppress Fhl1 in order to promote nonanchored growth and migration of tumor cells." Cancer Res. 2006 Feb 1;66(3):1543-52.
18. Goldberg GS, Kunimoto T, Alexander DB, Suenaga K, Ishidate F, Miyamoto K, Ushijima T, Teng CT, Yokota J, Ohta T, Tsuda H. "Full length and delta lactoferrin display differential cell localization dynamics, but do not act as tumor markers or significantly affect the expression of other genes." Med Chem. 2005 Jan;1(1):57-64.
19. Valiunas V, Bechberger JF, Naus CC, Brink PR, Goldberg GS. "Nontransformed cells can normalize gap junctional communication with transformed cells." Biochem Biophys Res Commun. 2005 Jul 22;333(1):174-9.
20. Alexander DB, Ichikawa H, Bechberger JF, Valiunas V, Ohki M, Naus CC, Kunimoto T, Tsuda H, Miller WT, Goldberg GS. "Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and SRC activity." Cancer Res. 2004 Feb 15;64(4):1347-58.
21. Goldberg GS, Alexander DB, Pellicena P, Zhang ZY, Tsuda H, Miller WT." Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells." J Biol Chem. 2003 Nov 21;278(47):46533-40. Epub 2003 Sep 11.
22. Goldberg GS, Moreno AP, Lampe PD. "Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP." J Biol Chem. 2002 Sep 27;277(39):36725-30. Epub 2002 Jul 15.
23. Goldberg GS, Jin Z, Ichikawa H, Naito A, Ohki M, El-Deiry WS, Tsuda H. "Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis-inducing ligand in anoikis." Cancer Res. 2001 Feb 15;61(4):1334-7.
24. Goldberg GS, Bechberger JF, Tajima Y, Merritt M, Omori Y, Gawinowicz MA, Narayanan R, Tan Y, Sanai Y, Yamasaki H, Naus CC, Tsuda H, Nicholson BJ. "Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells." Cancer Res. 2000 Nov 1;60(21):6018-26.
25. Goldberg GS, Lampe PD, Nicholson BJ. "Selective transfer of endogenous metabolites through gap junctions composed of different connexins." Nat Cell Biol. 1999 Nov;1(7):457-9. No abstract available.
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.
The Foundation of UMDNJ has established a fund where 100% of donated money will go directly to this research program with no administrative or other deductions. To support the "Goldberg Cancer Research Program" with your charitable contribution, contact Gary Goldberg at (856) 566-6718 or at firstname.lastname@example.org.