Publications

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.

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.

Weber GF (2008). Molecular mechanisms of metastasis. Cancer Letters, 270, 181-190.

Syed M, Fenoglio-Preiser C, Skau KA, Weber GF (2008). Acetylcholinesterase supports anchorage independence in colon cancer. Clinical and Experimental Metastasis, 25, 787-798.

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.

Georg F. Weber (2005). Cancer Therapy: Molecular Targets in Tumor-Host Interactions. Wymondham: Horizon Press.

Georg F. Weber (2007). Molecular Mechanisms of Malignancy in Cancer. Dordrecht: Springer.

Weber GF (2009). Drug targets in cancer metastasis. In American Association for Cancer Research(Eds.), 100th Annual Meeting Education Book. (pp. 137-140). Philadelphia:

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). 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.

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, including breast cancer. 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).

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 (Mirza et al. 2007; Sullivan et al. 2009). 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. The induction of integrins on the surface of cancer cells can render them independent of microenvironmental cues and override cell cycle arrest after deadhesion (Syed et al. 2008). 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). Remarkably, full-length osteopontin may protect from an excessive production of hydrogen peroxide by these oxidoreductases, because it down-regulates the intracellular H₂O₂ levels, thus preventing cell death (Weber et al. 1999).

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).

The expression of metastasis genes is induced by cellular stress response programs and is regulated by multi-subunit transcription factor complexes. We have analyzed the molecular mechanisms that activate the stress-inducible transcription factor NF-kB, which contributes to the induction of various metastasis genes. A large number of gene promoters and enhancers contain recognition sites for this transcription factor. While the release of the DNA-binding subunits into the nucleus is insufficient to differentially regulate transactivation from cognate sites, their phosphorylation by an upstream kinase, such as PKG, can lead to the formation of transcription factor complexes and differential transactivation from a subset of NF-kB sites (Weber et al. 1995; He/Weber 2003; He/Weber 2004).

In the context of our molecular analyses of carcinogenesis, we have investigated the cellular effects (Weber et al. 1991; Weber/Nair 1992) and the metabolism of conventional anti-cancer drugs (LeBlanc et al. 1992; Weber/Waxman 1993a; Weber/Waxman 1993b; Chang et al. 1993). We have also studied ways to selectively target metastasis with anti-cancer agents (Weber 2001; Weber 2005; Weber 2009).