TIF1γ 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. Our observations show that this molecule has an oncogenic function in oral cancer by regulating self-renewal ability of oral cancer stem cells. Moreover, TIF1γ is required for the induction of self-renewal by several self-renewal pathways other than TGF-β. The known function of TIF1γ is its E3 ubiquitin ligase activity, for degrading its substrates. Since none of the known substrates can explain its role in cancer stem cell regulation, we are exploring the interactome of TIF1γ by proteomic approach to find its substrate responsible for self-renewal regulation. Moreover, our results also suggest a transcriptional regulatory role apart from its E3 ubiquitin ligase activity. Attempts are also made to understand how this molecule regulates self-renewal at the transcriptional level.

CSCs reside in a special microenvironment called “CSC niche”, which is maintained as a result of orchestration of different signaling pathways instigated through cell-cell interaction, secreted growth factors or cytokines. The niche helps in the maintenance of self-renewal ability, therapeutic resistance and tumorigenecity of CSCs. Hence disrupting the “CSC niche” will be the effective way to target CSC population. Followed by our observations of phosphoproteomic analysis and proteomic analysis of surface molecules using CSC-enriched spheres, we are exploring the significance of EphA2/EphrinB1 pathway in the regulation of CSCs. Our results suggest the involvement of this pathway in defining the “CSC niche”.

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.

Recently, DBT has started a multicentre study, “Virtual National Oral Cancer Institute” to develop molecular signatures of oral cancers arising due to different reasons form different parts of India. For this work, I am collaborating with 7 centres in India, and RGCB provides the orthotopic models of oral cancer and imaging platform to test the hypothesis developed by other centers.
Majority of the oral carcinoma cases are of OSCC of tongue or floor of the mouth. We have developed orthotopic models for both these kinds of oral carcinoma. These models are being used for understanding the oral cancer biology.