Division of Molecular Medicine

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Introduction

Our research group has been working on breast cancer for the past decade. Our initial interest was in establishing the long-term outcomes in women treated for breast cancer and the molecular correlates of these outcomes. Towards this objective, we have assembled a cohort of more than 440 women with confirmed breast cancer who were recruited at first presentation between 2008 and 2013. These women have been followed up over the past 9 years through a dedicated group called “Aadhara”. Our loss to follow-up rate of 4% is unmatched outside the clinical-trial setting in India. The complete clinical history along with formalin-fixed tumor specimens as well as matched blood specimens for most of the patients in the cohort were collected. Digitized images of these tumors are archived at our research institute. The median follow-up as of Mar 31st, 2017, has crossed 72 months. We have been the recipient of two 10-year philanthropic grants in addition to other extramural grants that have enabled such long-term uninterrupted activity. We were one of the first groups to have utilized formalin-fixed tumor material for molecular methods and we have a complete molecular pathology facility with a full range of molecular platforms.

Our initial questions concerned the basis of the higher Hormone receptor (HR) negative tumors in India; in particular, exploring epigenetic mechanisms of HR loss and understanding the biology of HR-mediated signaling.  Since a large proportion of our women present at later stages, we have developed an approach akin to the gene-expression-based OncotypeDX to identify the HR-positive tumors with poor prognosis regardless of lymph-node status. We are currently exploring the mechanisms and pathways of endocrine resistance mediated by epigenetic modifications. In addition to the patient specimen-centric work, we have established experimental mammalian cell culture facilities and individually ventilated –caging-systems to establish patient-derived Xenografts (PDX). Using these approaches, we have explored mechanisms of chemoresistance and metastasis mediated via tumor-stroma interactions by integrins and found specific roles for various integrins. Our recent work is focused on evaluating the role played by microRNAs in the regulation of nuclear hormone receptors. We have explored the role of microRNAs that bring about alterations to cell polarity in cancer cells and modulation of the stromal immune signature in hormone receptor-positive breast cancer. We are now exploring the crosstalk between multiple nuclear hormone receptors in the context of circulating steroid hormones with a specific emphasis on premenopausal breast cancer. In this context, we have initiated building another prospective cohort of breast cancer in 2019 and enrolled more than 200 patients thus far who are also being followed up at their treatment centers. 

Our research is focused on the investigation of structure function correlation of physiologically important protein molecules and their relation to disease. We are interested in various medical conditions such as hemoglobinopathies, thalassemia, iron deficient anemia, multiple sclerosis, neurodegenerative disorders and depression. The major biophysical techniques used by the group include absorption and emission spectroscopy and mass spectrometry. To screen the clinically important biomarker in the biological fluid, we use mass spectrometry based proteomics. In addition, we are also involved in the discovery of diagnostic tools using mass spectrometry. The group collaborates with Indian Institute of Science in Bioinformatics and Molecular Modeling research.

Our group is involved in understanding the Pediatric Kidney Diseases Nephrotic Syndrome, Acute Kidney Injury. Chronic Kidney Disease and Congenital Anomalies of Kidney and Urinary tract. Our interest is to understand the fundamental genetic mechanisms, molecular and immunological factors involved in the development of kidney disease. For this purpose, we are using various high throughput techniques such as Next-Generation Sequencing, MAGPIX-based multi-analyte detection, flow cytometry analysis of immune cells, immortalized podocyte cell based assays, immunofluorescent assays, etc., to understand the disease progression, identify biomarkers and molecular signatures for prognosis, diagnosis and patient stratification. Out ultimate aim is to translate the research data for clinical setting.

Patterning of developing embryos requires signaling via different molecules in spacio-temporally regulated manner. Hedgehog is one such highly conserved signaling protein required for embryonic patterning and is also hyper-activated in several cancers. Mechanism of Hedgehog release, transport and reception to activate different target genes for tissue patterning and cancer progression involves intricate processes at molecular and cellular levels. Several evidences including our previous work suggest that Hedgehog proteins are secreted on exovesicles. We find that Hedgehog proteins are secreted on at least two types of exovesicles with distinct proteins and miRNAs. Apart from exovesicles, there are other reported extracellular forms of Hedgehog proteins. However, currently the need for secretion of Hedgehog in different extracellular forms remains unclear.

Our group is interested in probing the basic biology of exovesicular release of Hedgehog and miRNA packaging. We are also seeking clarity on the physiological implications of the associated proteins and miRNAs on Shh function during tissue patterning as well as in diseases such as cancer where exovesicles-mediated tumor-stroma interactions have critical implications for tumor progression or regression.