Sam Thiagalingam, Ph.D.
Associate Professor of Genetics & Genomics,
Medicine, and Pathology & Laboratory Medicine.
Dolphin Trust Investigator.

Ph.D. 1992, Johns Hopkins University
Post-doctoral Fellowship, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

(617)638-6013
(617)638-4275, fax
E323

samthia@bu.edu
http://people.bu.edu/samthia/

Our overall research strategy is to use cancer genomics, employing primarily breast and lung cancers as model systems, to shed light on genomic instability, genetic and epigenetic aberrations and metastasis of cancer and invent new tools for the diagnosis, prognosis, management and therapy of cancer. We approach these overall goals by undertaking research under the following topics: (i) The Smad signaling connection to cancer metastasis; (ii) The role of p53 in genome stability; and (iii) Genetic susceptibility and molecular markers of lung cancer.

Despite the acceptance that the TGF-ß/ Smad signaling pathways play critical but opposing roles in both tumor suppression and metastatic cancer promotion, the molecular basis for these paradoxical effects remains elusive. Except for the elucidation of an association between genetic alterations in the SMAD4 gene and gastrointestinal and pancreatic cancers, the nature and contributions of the other SMAD gene alterations in cancers is largely unknown. We have developed a novel technique known as Targeted Expressed Gene Display (TEGD) to survey various SMAD genes for differential expression. The loss of SMAD8 expression in multiple types of cancers, including 31% of both breast and colon cancers directly correlated with epigenetic silencing by DNA hypermethylation. In advanced cancers, TGF-ß ceases to function in tumor suppression and could adopt the converse role of enhancing metastatic spread. Our data elucidates an important connection between Smad4 inactivation and up-regulation of pro-angiogenic/ metastatic effects in advanced cancers. We are currently investigating the connection between inactivation of the various Smads and cancer to identify additional markers for accurate diagnosis and prognosis as well as ideal nodal points of therapeutic intervention of cancer.

We have continued to explore alternate modes of inactivation of p53. Our identification of hBUB1 as a modulator of p53 provided a molecular basis for the ability of p53 to maintain genomic stability. Furthermore, our experimental data strongly suggest that the hBUB1 kinase is a regulator of p53 activity during the mitotic checkpoint. We are currently investigating whether the inactivation of either p53 or hBUB1 in tumors could be a major mechanism for aneuploidy.

We are also studying the molecular basis of the genesis of sporadic lung cancer caused by tobacco smoke derived carcinogens. The lack of histologically well defined early neoplasms despite relatively distinct late neoplasms for lung cancer has frustrated effective prevention, diagnosis and therapy of the disease. Based on our preliminary findings, we are proposing a global modular molecular network model which suggests that NSCLC progression to distinct histological subtypes is associated with defined genetic and epigenetic alterations that occur at multiple steps. In the long-term, we are hoping to identify various target genes that may serve as nodal points for therapeutic intervention, diagnosis, prognosis and management of lung cancer.

Recently, we have also become interested in studying the genetics and epigenetics of neurological disorders and have published the first preliminary systematic study on epigenetic alterations in schizophrenia. We hope to inject a new paradigm into the field of psychiatric genetics and epigenetics through these and future studies.