Differential Inhibition of Visfatin-PAK4 as a Novel Strategy in Esophageal Squamous Cell Carcinoma for Therapeutic Purpose (Co-PI).
Indian Council of Medical Research
Research Summary
Cancer of the oral cavity, oral squamous cell carcinoma (OSCC), is the sixth most prevalent malignancy worldwide, and the third most common cancer in developing nations. The mortality rate for oral cancer is high because almost 60% of Stage III and IV OSCC patients show relapse within 2 years after remission. Development of drug resistance is a major impeding factor in the treatment outcome. Recently a sub-population of cancer cells called cancer stem cells (CSCs) have been identified as the culprits in relapse. Moreover, CSCs are reported to be important for tumor initiation and metastasis (the spread of the disease), making this subset an important candidate for prognostic prediction as well as targeted therapy.
Research in my lab focuses on understanding the basic biology of oral cancer stem cells. At the same time, we also incorporate translational research, which has a potential for clinical application.
Research Programs

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.
Current Research Grants
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2025 2022
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2024 2021
Exploration of the role of fodrin, a protein required in functional microtubule reorganization, in cancer and apoptosis (Co-PI).
Indian Council of Medical Research
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2022 2018
Virtual National Oral Cancer Institute Development of Animal Model Systems to study oral cancer progression
Department of Biotechnology [DBT]
Previous/ Completed Research Grants
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Evaluation of the role of TIF1γ in the regulation of self-renewal ability of OSCC stem cells
Department of Science & Technology [DST] 2016-2019Characterizing the signaling network that sustains oral cancer stem cells for developing a targeted therapy
Department of Science and Technology 2011-2014Identifying surface marker signature of oral cancer stem cells to develop a prognosis marker for oral squamous cell carcinoma using peptide-based CSC detection
Department of Biotechnology 2011-2014
Collaborations
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Collaborations
1. Dr. Nebu Abraham George, Assistant Professor, Surgical Oncology, RCC, Thiruvananthapuram.
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As a part of a multicentric project, VNOCI
1. Prof. Tapas K Kundu, Professor, Department of Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre For Advanced Scientific Research, Bangalore
2. Dr. Annapoorni Rangarajan, Associate Professor, Molecular Reproduction, Development and Genetics, INDIAN INSTITUTE OF SCIENCE, Bangalore
3. Dr. Birendranath Banerjee, Associate Professor, School of Biotechnology, KIlT School of Bhubaneswar, Orissa
4. Dr. Debnath Pal, Associate Professor, Computational and Data Sciences, INDIAN INSTITUTE OF SCIENCE, Bangalore,Karnataka
5. Dr. Subhashini Sadasivam , National Centre For Biological Sciences, Bangalore
6. Prof. Anupam Chatterjee, Professor, Biotechnology & Bioinformatics, North-Eastern Hill University, Shillong
7. Prof. Partha Pratim Majumder, Distinguished Professor, Genomics, National Institute of Biomedical Genomics, West Bengal
8. Prof. Ramaswamy Subramanian, Senior Professor, Technologies for the Advancement of Science (TAS), National Centre For Biological Sciences, Bangalore
9. Prof. Saumyadipta pyne, Professor, Indian Institute of Public Health, Hyderabad