VCU Philips Institute of Oral and Craniofacial Molecular Biology

Image of Andrew Yeudall, B.D.S., Ph.D.

Andrew Yeudall, B.D.S., Ph.D.

  • Interim Director, Philips Institute of Oral and Craniofacial Molecular Biology
  • Member Scientist, VCU Philips Institute

Office Location: Perkinson Building, Room 4152
P.O. Box 980566
Phone: (804) 828-6415
Fax: (804) 828-0150
E-mail: wayeudall@vcu.edu

Research Interests

Our laboratory studies mechanisms through which squamous cell carcinomas of the head and neck (HNSCC) develop and progress to form invasive and metastatic cancers (Fig. 1).

Fig. 1. Schematic representation of HNSCC tumor progression. Squamous epithelium exposed to carcinogenic insult progresses through increasingly severe dysplastic stages, forming an invasive primary tumor. The tumor cells, together with other components in the microenvironment, stimulate development of a blood supply for the tumor, as well as enhancing tumor cell growth and migration into regional vessels, from whence the tumor cells are carried to sites of secondary growth.

Using a cell culture model, we found enhanced expression of the chemokine CXCL5 (ENA-78), in cells derived from metastatic HNSCC (Miyazaki et al., 2006a). Chemokines are small secreted polypeptides that play key roles as modulators of immune cell function. However, it is increasingly being recognized that some of these molecules may be important for malignant progression in a range of human cancers (Yeudall & Miyazaki, 2007). Our studies have implicated both CXCL5 and CXCL8 (IL-8) in growth and motility of oral cancer cells (Miyazaki et al., 2006b; Christofakis et al., 2008). Strikingly, using RNA interference directed against CXCL5, we were able to completely block tumor formation in vivo, in both flank xenografts and orthotopic transplantation experiments. Our data point to a central role for CXCL5 and related chemokines in regulating the biology of oral cancer cells. Current work in the lab is directed towards inhibiting chemokine function in oral cancer, as well as elucidating the biochemical pathways that regulate chemokine expression and which are, in turn, regulated by chemokines. The long term goal is to develop therapeutics that will interfere with chemokine-dependent functions in oral cancer. To do this, we have established collaborative links with the laboratory of Dr. Hu Yang in the VCU Department of Biomedical Engineering.

Fig. 2. The majority of mutations in the P53 gene occur in the DNA binding region. Many result in amino acid substitutions that give rise to aberrant, oncogenic proteins.

Another key focus of our work has been the contribution of mutant p53 to carcinogenesis. The wild-type p53 protein is a potent suppressor of tumor growth. However, gene mutations frequently result in production of an aberrant protein that can transform cells to a malignant state (Fig. 2). In previous work, we cloned and characterized aberrant p53 proteins from HNSCC cells (Yeudall et al., 1997; Cardinali et al., 1997; Wrighton et al., 2004). Of particular interest, expression of a p53 protein containing a histidine to leucine amino acid substitution at codon 179 (p53-H179L) was able to transform immortal cells to a fully malignant and metastatic phenotype (Fig. 3), with tumors showing a high degree of vascularization. These data provide support for the "gain-of-function" hypothesis of mutant p53 action, which suggests that certain mutations in p53 result not only in loss of the wild-type tumor suppressor functions but, additionally, endow the aberrant protein with oncogenic properties. Examples include p53 proteins that harbor amino acid substitutions at residues 175, 179, 245, 248, 273 and 281 (Fig. 2). However, the biochemical mechanisms that underpin p53 gain-of-function remain relatively unexplored.

Much of the current focus of our studies is aimed at understanding how gain-of-function p53 proteins deregulate cell growth and motility in oral cancer, as well as in lung, breast and other cancers. In this regard, we are fortunate to have a strong interaction with the laboratory of Dr. Sumitra Deb, a renowned expert in this field. Together, we are deciphering the molecular pathways that are subverted when cancer cells begin to express aberrant oncogenic forms of p53, with a view to identifying novel targets for therapeutic intervention.

Fig. 3. p53-H179L fosters development of a tumorigenic and metastatic phenotype. A. Mediastinal metastasis of p53-H179L-expressing cells from a flank region xenograft. H&E (upper), anti-p53 immunostain (lower). B. Immortal fibroblasts were transfected with an empty vector(left) or p53-H179L (right) and cultured in soft agar for 14 days. Cells expressing the aberrant p53 formed large colonies, whereas controls failed to grow.

In previous work, we also found high levels of expression of the protein EPS8, a downstream mediator of growth factor receptor tyrosine kinase signaling, in squamous carcinoma cells (Miyazaki et al., 2006a). EPS8 has been widely reported by others to play a critical role in signal transduction to the actin cytoskeleton and, hence, is important in regulating cell motility, a key property of cancer cells. Recently, we found that EPS8 enhances cell growth, in addition to motility and invasion, and is sufficient to convert non-tumorigenic oral epithelial cells to a fully malignant phenotype in vivo, with invasion of tumor cells into the underlying structures (Wang et al., 2009). We also found that elevated expression of EPS8 leads to enhanced expression and activity of the matrix metalloproteinase, MMP-9 (gelatinase B), which may provide some explanation for the invasive phenotype. In our ongoing research, we are elucidating the mechanisms through which EPS8 enhances cell growth (Fig. 4).

Fig. 4. EPS8 stimulates AKT-dependent and independent pathways to activate expression of MMP-9 and other uncharacterized molecules, leading to enhanced cell growth, motility and invasion. RTK – receptor tyrosine kinase, MAPKs – mitogen-activated protein kinases, TFs – transcription factors.

References

  1. Yeudall WA, Miyazaki H. Expert Rev Anticancer Therapy. 7, 351-360 (2007)
  2. Yeudall WA, et al. Oral Oncol 41, 698-708 (2005)
  3. Yeudall WA, et al. Mol. Carcinogen. 18, 89-96 (1997)
  4. Wrighton KH, et al. Int J Cancer 112, 760-770 (2004)
  5. Wang H, et al. Carcinogenesis 30, 165-174 (2009)
  6. Miyazaki H, et al. Cancer Res 66, 4279-4284 (2006b)
  7. Miyazaki H, et al. Oral Oncology 42, 240-256 (2006a)
  8. Christofakis E, et al. Oral Oncol 44, 920-926 (2008)
  9. Cardinali M, et al. Mol. Carcinogen. 18, 78-88 (1997)

Honors

  • 2007: Omicron Kappa Upsilon
  • 2006: Who's Who in America
  • 2005: Founding Fellow, International Academy of Oral Oncology
  • 2004: Visiting Professor, Faculty of Dentistry, Thammasat, Chulalongkorn and Chiang Mai Universities, Thailand
  • 1996-Present: Editorial Board, Oral Oncology

Funded Research

  • NIH/NCI. Chemoresistance and motility: role of p53 and NF-kB2 in cancer. (PI: S. Deb).
  • IC/DEP Research Program. Dendrimer-based delivery of siRNA for squamous carcinoma therapy.
  • Massey Cancer Center. Mechanisms that regulate intermediate filament protein expression during tumor progression.
  • Massey Cancer Center. MDM2-EF1α interaction in the etiology of lung cancer. (co-PI with S.P. Deb)

Selected Publications

  1. Wang H, et al. Role for EPS8 in squamous carcinogenesis. Carcinogenesis 30, 165-174 (2009)
  2. Paccione RJ, et al. Keratin downregulation in vimentin-positive cancer cells is reversible by vimentin RNAi, which inhibits growth and motility. Mol Cancer Ther 7, 2894-2903 (2008)
  3. Yeudall WA. Squamous cell carcinoma. Encyclopedia of Cancer. Ed. M. Schwab. Springer, Berlin. pp 2798-2801 (2008)
  4. Christofakis E, et al. Roles of CXCL8 in squamous carcinoma proliferation and migration. Oral Oncol 44, 920-926 (2008)
  5. Tripathi A, et al. Docking and hydropathic scoring of polysubstituted pyrrole compounds with anti-tubulin activity. Bioorgan Med Chem 16, 2235–2242 (2008)
  6. Molinolo A, et al. Dissecting the Akt/mTOR signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res 13, 4964-4973 (2007)
  7. Arthur C, et al. Autophagic cell death, polyploidy and senescence induced in breast tumor cells by the substituted pyrrole JG-03-14, a novel microtubule poison. Biochem Pharmacol 74, 981-991 (2007)
  8. Yeudall WA, Miyazaki H. Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention? Expert Rev Anticancer Therapy. 7, 351-360 (2007).
  9. Miyazaki H, et al. Downregulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res 66, 4279-4284 (2006)
  10. Miyazaki H, et al. Growth factor-sensitive molecular targets identified in primary and metastatic head and neck squamous cell carcinoma using microarray analysis. Oral Oncology 42, 240-256 (2006)
  11. Edmiston JS, et al. Inability of TGFβ to cause SnoN degradation in esophageal cancer cells leads to resistance to TGFβ induced growth arrest. Cancer Res 65, 4782-4788 (2005)
  12. Yeudall WA, et al. Uncoupling of epidermal growth factor-dependent proliferation and invasion in a model of squamous carcinoma progression. Oral Oncol 41, 698-708 (2005)
  13. Wrighton KH, et al. Aberrant p53 alters DNA damage checkpoints in response to cisplatin: downregulation of CDK expression and activity. Int J Cancer 112, 760-770 (2004)