Sackler Team Explores Cadherin Loss in Cancer Development

Garlick Release

Boston (November 1, 2011)

A study has uncovered a new link between development of a common type of cancer, squamous cell carcinoma (SCC), and low activity of E-cadherin protein, which keeps cells bound together in healthy tissue. In a paper published in the Journal of Investigative Dermatology, a cross-disciplinary team of researchers from Tufts University report that the loss of E-cadherin in SCC tumor cells resulted in elevated activity of two specific regulatory proteins that further lead to E-cadherin loss. This loop contributes to cancer development. These regulatory proteins could be novel targets for drug therapy in SCC.

“One of the hallmarks of SCC is the loss of the “glue” – the E-cadherin protein – between cancerous cells. The loss of this protein is one of the steps that precedes the development of cancer,” said first author Addy Alt-Holland, PhD, MSc, assistant professor of endodontics at Tufts University School of Dental Medicine (TUSDM). She also works with Jonathan Garlick in the division of cancer biology and tissue engineering at TUSDM.

For their study, the researchers generated three-dimensional engineered tissues from human skin cells that had decreased E-cadherin (control) or simultaneously decreased E-cadherin and either of the two regulatory proteins (experimental). Surface transplantation of the control tissues to mice resulted in the development of aggressive SCC, while transplantation of the experimental tissues resulted in low-grade benign skin tumors.

“Our results show that controlling the activity of either of these two regulatory proteins, FAK and Src kinases, can prevent the loss of E-cadherin and re-establish the glue between cells, pre-empting the development of aggressive cancer. Thus, our results could help in the development of new treatments for skin and similar cancers, such as oral cancers,” said Alt-Holland.

“This study furthers our understanding in the molecular events that regulate the early events in SCC development,” said senior author Jonathan Garlick, DDS, PhD, head of the division of cancer biology and tissue engineering at Tufts University School of Dental Medicine. “Our three-dimensional tissues are a biologically-meaningful system to study cancer development as it occurs in humans, and this research demonstrates their clinical relevance.”

Garlick is also a professor of oral and maxillofacial pathology at TUSDM, a member of the cell, molecular & developmental biology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts, and director of the Center for Integrated Tissue Engineering at TUSDM, which is dedicated to furthering the understanding of regenerative medicine through the investigation of three-dimensional tissue models.

According to the National Cancer Institute, skin cancers are the most common type of cancer in the United States, and SCC is the second most common type of skin cancer. It represents 15% of skin cancers, most often occurring in the head and neck. Prolonged, exposure, usually over years, to harmful sun rays, smoke, and industrial chemicals could lead to development of this disease.

Additional authors on the study are Adam Sowalsky, PhD, a graduate of the Sackler School of Graduate Biomedical Sciences, now a research fellow at Beth Israel Deaconess Medical Center; Yonit Szwec-Levin, DMD, assistant professor in the department of endodontics, TUSDM; Yulia Shamis and Harold Hatch, both PhD students at the Sackler School; and Larry Feig, PhD, professor in the department of biochemistry at Tufts University School of Medicine and member of both the biochemistry and neuroscience program faculties at the Sackler School.

This study was published in the November 2011 issue of the Journal of Investigative Dermatology and supported by grants from the National Institute of Dental and Craniofacial Research (DE011250 and DE017413), and the National Institute of General Medical Sciences (GM047717), both of the National Institutes of Health.

Alt-Holland A, Sowalsky A, Szwec - Levin Y, Shamis Y, Hatch H, Feig L, Garlick J. 2011. Suppression of E-cadherin function drives the early stages of Ras – induced squamous cell carcinoma through up-regulation of FAK and Src. J Invest Dermatol.  131: 2306–2315. Abstract in PubMed

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