Boston University Medical Campus
Genetics Program

Sam Thiagalingam, Ph.D.

Research Interests
Elucidation of genetic & epigenetic alterations in cancer and neurological disorders as diagnostic/ prognostic markers and targets for therapy and metastasis of cancer.

Our major research focus is on the use cancer genomics, employing primarily breast and colon cancers as model systems, to shed light on genomic instability, genetic and epigenetic aberrations and metastasis of cancer. We hope to elucidate the molecular basis of the multi-step cancer progression through these studies. Furthermore, we are also interested in unravelling the correlation between the epigenome and the pathogenesis of major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BD).
It is well established that TGF-β plays dual roles during breast carcinogenesis; an early tumor suppressive and a late-stage pro-oncogenic role that accompanies a progressive increase in the locally secreted TGF-β levels. Interestingly, increase in the TGF-β levels in advanced breast cancers and enhanced Smad2/3 signaling in metastatic breast cancer suggest that at least selected parts of the TGF-β signaling pathway/sub-network might promote advanced breast cancer progression. Furthermore, TGF-β has been shown to induce epithelial to mesenchymal transition (EMT) in breast cancers which has also been correlated with induction of intravasation of in situ carcinoma cells through the basement membrane, survival in the circulation, extravasation into distal tissues and formation of micrometastases. The results from our recent studies suggest that aberrant signaling events regulate epigenetic alterations to define altered gene function during breast cancer progression. Furthermore, by disrupting hyperactive TGF-β signaling in breast cancer cells, we have successfully reversed the metastatic properties of breast cancer cells suggesting that these approaches are amenable to therapeutic applications.

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. Therefore, we 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. We are in the process of investigating the temporal relationship between epigenetic inactivation of the SMAD8 gene and the stage(s) of breast cancer and are planning to determine the identities and roles of differentially regulated genes due to defective Smad8 signaling that mediate genesis and metatstasis of breast cancer.
We have also continued to maintain an interest in understanding the connection between genomic instability and cancer at the molecular level. It has been universally believed that defective spindle assembly checkpoint (SAC) causes aneuploidy. Interestingly, our studies uncovered a novel apoptotic checkpoint pathway regulated by the kinetochore proteins. We plan to continue these studies by performing a detailed analysis of the roles of individual kinetochore proteins in the maintenance of genomic stability.
Our studies involving genetic and epigenetic analysis of lung cancer and the examination of the literature in the cancer field have led us to propose an academically simplified scheme to explain the complexity in cancer progression as a process that consists of a series of a cascade of interconnected functional sub-network modules of various alterations in a multi-modular molecular network (MMMN) encompassing multiple targets within each module. Our long-term goal is to contribute to the elucidation of the multi-modular molecular network (MMMN) cancer progression models as the road map to dissect the complexity inherent to cancer (Figure 1). Currently, we are in the process of using breast cancer as a prototype to perform proof of principle analyses to construct a MMMN cancer progression model.
The fact that genetic makeup alone cannot explain the molecular basis of major psychiatric disorders such as SCZ and BD was instrumental for us to direct our attention to epigenetic alterations as the major cause of pathogenesis. Our studies showed that both hyper- as well as hypo- promoter DNA methylation changes of the genes RELN and MB-COMT respectively play critical roles in defining their altered functionality in major psychiatric disorders, SCZ and BD. Therefore, because of the possibility of gene-environment interactions mediated epigenetic modulation of gene function, we are involved in establishing a logical relationship between epigenetic changes and schizophrenia and bipolar disorder.