TIF1γ (TRIM33), an E3 ubiquitin ligase, is a negative regulator of TGF-β signaling with its well-established role in hematopoiesis. In cancer context, it is considered as a tumor suppressor with its negative regulatory role on TGF-β , which promotes tumor progression. In our lab we have shown that TIF1γ regulates self-renewal ability of oral cancer cells and causes the recurrence of the disease. We have unraveled its role in the transcriptional regulation of self-renewal genes. We have seen that TIF1γ is essential for the induction of self-renewal by many pathways. Currently, we are focusing on the upstream regulators of this pathway. We are also attempting to identify the post-translation modifications, like phosphorylation or acetylation that activates the molecule. Another important aspect to be explored is the role of the mutations of the gene that are prevalent in oral cancer patients.

CSCs reside in a special microenvironment called "CSC niche", maintained as a result of orchestration of different signaling pathways instigated through cell-cell interactions or secreted molecules. The niche helps in the maintenance of self-renewal ability, therapeutic resistance, and in turn regulate the relapse of the disease. We have been elucidating the role of EphA2/EphrinB1 signaling in CSC regulation in oral cancer. Our results implicate that the surface localization of the ligand and the receptor play a role in the regulation of oral cancer CSCs and recurrence. The mutations of these genes could be important in the modulation of this pathway.

The function of Host Defense Peptides (HDPs), an integral part of the innate immune system, has been recently reassigned to immunoregulation from the membranolytic antimicrobial activity. Contrary to the assumption that the antitumor activity of HDPs depends on their membranolytic activity, we observed that HDP-induced signaling through immunomodulators leads to apoptosis in cancer cells. We established that the peptide binds to IL6/IL6R/gp130 complex to modulate its downstream signaling. In contrast to the IL6 blockers that inhibit JAK/STAT activity, SSTP1 shifts the proliferative IL6/JAK/STAT signaling to the apoptotic IL6/JNK/AP1 pathway. Further, we show that cancer cells expressing high IL6Rα levels, like triple-negative breast cancer (TNBC), undergo apoptosis in response to low concentrations of SSTP1, which do not induce hemolysis, the result of the nonspecific membranolytic activity. Thus, our study highlights the importance of HDPs with identified targets for translation to clinical use.

Single cell biology by and large depends on the detection and isolation of subpopulations from heterogeneous cell populations.  Even though antibodies are conventionally used for this purpose, their relevance in certain context is limited, especially when the target is an intracellular molecule. For the first time we have shown a simple, cost-effective and efficient method of live sorting of cells based on the expression of an intracellular marker using a fluorophore-tagged binding peptide. Our results prove that our peptide TM2 can be used to separate cells with differential expression of HIRA.
Fluorescent-based optical imaging using Near Infrared (NIR) dyes tagged to tumor specific target is an optimal tool for surgical margin prediction. We have shown that TM1-IR680, is ideal for surgical margin prediction, in a preclinical analysis. Interestingly, the peptide was sensitive enough to detect lymph nodes that harbored dispersed tumor cells before colonization, which was impossible to identify by conventional histopathology.

The biology of oral cancer can be studied using in vitro and in vivo mouse models. We have successfully generated 3D co-culture model on alginate matrix where we could incorporate tumor fibroblasts and tumor cells. We are in the process of generating organoid model for oral cancer, which can be effectively used for drug screening. We have also established the generation of xenografts, orthotopic models and humanized orthotopic PDX models.