Director's Message

NCCS has been at the forefront of cancer research in the country for several years. Dr. Sharmila Bapat's team, one of the research groups studying the biology of cancer at NCCS, has recently been successful in developing a novel method to address the issue of diverse cell composition of tumours. Tumors are known to harbor cellular, molecular and functional intra-tumoral heterogeneity, which confounds our understanding of the perturbation(s) of basic biological processes in the context of cancer. This issue was addressed by Dr. Bapat and her group by using a flow cytometry-based approach for the deconstruction of a tumor into discrete tumor fractions, which relies on resolution of the cancer stem cell (CSC)-based hierarchy, genetic instability and differential cell cycling fractions. Since these are universal principles, this approach is applicable across different cancer / cell types. Further integration of this real-time definition of cellular heterogeneity with molecular profiling can lead to the assignment of cell-specific functional context(s) within tumors, as against derivation of biological functions based on averaged tumor data. Thus, gene expression studies across sorted cell fractions led to the establishment of a unique association of the surface marker CD53 with regenerative potential in CSCs as well as progenitors within the tumor regenerative hierarchy. Another interesting finding of their research was the association of cytoskeletal remodeling and epithelial to mesenchymal transition (EMT) with aneuploid fractions under conditions of stress, which emphasizes the contribution of genetic heterogeneity and Darwinian principles of selection during tumor metastases. Tumor deconstruction was also demonstrated to be a convenient tool to overcome limitations of the currently used simplistic drug screening strategies in which consideration of cell line-based cytotoxicity and/or in vivo tumor regression as end-points of drug efficacy fail to address residual regenerative potential following therapeutic regimes. This is important since at a clinical level, tumor heterogeneity represents a major therapeutic hurdle in targeting heterogeneous cell fractions that drive recalcitrant disease. Dr. Bapat and her group showed that applying the same principles of deconstruction improved the identification of cellular and molecular drug targets, and that this information could thus be used to achieve complete tumor regression. These developments could thereby provide a convenient tool for drug screening and repositioning, as well as for predicting responses to therapeutics and for formulating novel drug combinations.

The scientists at NCCS have also been studying communicable diseases, such as those caused by viruses. Dr. Debashis Mitra and his group has been working on different aspects of the HIV virus, related to host-virus interactions, immune response and drug discovery. The primary objective of their research is to understand the virus and its interactions with the host cell better, which could lead to improved antiviral strategies. This group has recently elucidated the role of the HSP70-binding protein, HspBP1, a co-chaperone molecule of HSP70, in HIV-1 pathogenesis. Their finding revealed that HspBP1 inhibits HIV-1 gene expression and viral replication by interacting with NF-?B enhancer sequences in the LTR promoter. They also determined that HspBP1 competes with p65 of the NF-?B heterodimer for recruitment on the ?B enhancer site. To summarize, HspBP1 appears to inhibit HIV-1 gene expression and replication by restricting p65 from binding to the NF-?B enhancer sequence on the viral promoter. The identification of this novel role of HspBP1 as a host intrinsic inhibitor of HIV-1, which negatively regulates HIV-1 gene-expression and replication, could be a promising lead towards identifying new anti-HIV therapeutic strategies. As is evident from the extensive research being done worldwide, this is the need of the hour since the current therapeutic strategy involving the use of a combination of anti-retrovirals has proven useful in controlling the virus but not in eradicating it from patients. Further, with the ultimate objective of identifying novel cellular targets for the inhibition of HIV-1, Dr. Mitra and his group have also screened a library of pharmacologically-active bio-molecules known to target cellular pathways, to identify novel anti-HIV molecules. They have been successful in identifying several promising bioactive molecules and further characterization of a few of these molecules and their targets is currently in progress.

Dr. Arvind Sahu and his group study other factors that play a role in protection from viral infections, such as host factors, especially the complement cascade of the immune system. These studies assume importance when we take into consideration that the pandemic influenza A(H1N1) 2009 virus (Swine Flu virus) is now circulating seasonally and causing a significant disease burden worldwide. Their data demonstrate that the presence of an intact complement is essential for clearing the pandemic influenza virus infection, wherein locally-synthesized complement plays a major role. Further, their results reveal that activation of the classical as well as alternative pathways of complement system is a requisite for efficient neutralization of the virus as well as optimum generation of C3a and C5a (complement fragments generated after complement activation), which is necessary for boosting the protective immune responses. Their findings thus reveal that deficiencies of components of the classical and alternative pathways enhance susceptibility to and the severity of a pandemic influenza virus infection.

Osteoimmunology is another area of research at NCCS. Dr. Mohan Wani and his research group study the role of interleukin-3 (IL-3) in the pathophysiology of bone and cartilage remodelling. Their recent findings revealed for the first time that IL-3 plays a chondroprotective role in osteoarthritis (OA). OA is a chronic disease of articular joints that leads to degeneration of both cartilage and subchondral bone. This group discovered that IL-3, a cytokine secreted by activated T cells, up-regulates the expression of chondrocyte genes Sox9 and col2a, which are important for matrix synthesis, and down-regulates the expression of matrix metalloproteinases, MMP-3 and MMP13, under inflammatory conditions in both mouse and human chondrocytes. Interestingly, they also found that IL-3 reduces the degeneration of articular cartilage and subchondral bone microarchitecture in mouse model of human osteoarthritis. Further, they found that IL-3 decreased IL-1?-induced matrix degradation in micromass pellet cultures of human mesenchymal stem cells. These studies have thrown light on the therapeutic potential of IL-3 in the amelioration of articular cartilage and subchondral bone microarchitecture degeneration associated with OA.

We aspire to expand our horizons to encompass more extensive academic and research collaborations with organizations within and outside India, and partnerships with the industry. NCCS has initiated steps towards achieving these goals by signing MoUs with neighbouring institutions like IISER-Pune, the S. P. Pune University, a university overseas and some private companies. Furthermore, drawing strength from the rich research and academic ecosystem already available in Pune, we also propose to establish a Pune Biotechnology Cluster (Pune BioCluster) in association with IISER-Pune, with the aim of seamlessly integrating the high quality work being done at various organizations in Pune in the field of biology. We strongly believe that the Pune BioCluster would augment inter-institutional interactions and synergize research-&-teaching activities, proving beneficial to many in academia and the industry.

Shekhar C Mande