Early Career Research Award – DST SERB

Understanding Wnt Pathway and LncRNAs interaction for the identification of novel therapeutic targets in triple-negative breast cancers Breast cancer is the leading cancer in women, with about 1.7 million cases per year worldwide. Although the efficacy of breast cancer therapies has improved considerably, patients with triple- negative breast cancer (TNBC) maintain the poorest prognosis. TNBC patients have a high incidence of disease recurrence and overall, the highest mortality amongst breast cancer patients. TNBCs will often display an aberrant activation of an important developmental pathway – the WNT pathway. Our and our collaborator's group and others have shown that key Wnt pathway players, such as Wnt transmembrane receptors, are overexpressed in TNBC and can actively contribute to pro-tumorigenic processes. To date, TNBC-targeted therapies have not been successfully developed. In parallel, WNT-targeting compounds against breast cancers are still currently in clinical trials. The advances in the development of sequencing technologies have allowed us to start characterizing the molecular landscape of TNBC. Although various genes involved in the Wnt pathway have been well characterized, several aspects of their function and regulation are not yet fully understood. It has been recently proposed that long non-coding RNAs (lncRNAs) are dysregulated in many cancers and may be linked to aberrant WNT activity. In this proposed study we aim to characterize the interplay between lncRNAs and Wnt pathway activation in TNBC. We have generated a large collection of Wnt activity TNBC fluorescent reporter cell lines that display various levels of Wnt activity. We have found very dynamic and heterogeneous WNT activity levels within the TNBC models. We will use RNA-seq technology to identify novel WNT-regulating lncRNA in the WNT subpopulations from TNBC models with differential WNT activation status. The biological functions of novel lncRNAs will be characterized in our TNBC models and further validated in patient samples from our curated breast cancer cohort. Taken together, our study aims to unravel the lncRNA mediated regulation of Wnt signaling with the ultimate goal of identifying novel targetable mechanisms in TNBCs.

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DST-RSF, Indo-Russia International Collaboration Research Grant

Unraveling the molecular mechanism of lncRNAs involvement in Glioblastoma

Based on existing literature and our preliminary data, we hypothesize that LINC-ROR should have very important role in glioblastoma cells. Little is known about fine molecular mechanisms of LINC-ROR action inside tumor cells. We suggest that interaction of LINC- ROR with survivin protein and likely involvement of LINC-ROR in regulation of MDM2 level by unknown mechanism could be crucial molecular switch in regulation of glioblastoma proliferation and survival. Therefore, dissection of molecular mechanisms of LINC-ROR in glioblastoma is very important, since LINC-ROR, according to our predictions, could become new target molecule in future glioblastoma treatment. In this project we aim at further confirmation of critically important participation of LINC-ROR in glioblastoma survival and proliferation, as well as at characterization of molecular mechanisms of LINC-ROR function in glioblastoma.

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Indian Council of Medical Research (ICMR)

Identifying the role of P53 regulated long non-coding RNAs (LncRNAs) by Crispr/Cas9 in ovarian cancer

Cellular DNA is subject to constant stress and cells have developed robust mechanisms to correct and maintain genome integrity. In cancer, these mechanisms are impaired which accounts for the complex genomic alterations. Although, all the DNA repair genes have been identified and how they repair damaged DNA is for the most part understood, their regulation is still not completely clear. P53 which is important in maintaining genome integrity is the most frequent mutated gene in cancer. The earliest cellular signals in response to genotoxic stress and their relationship to p53 are poorly understood. LncRNAs present in non-coding genomic regions is emerging as major regulators of many genes involved in normal biological processes. There is some data to suggest that LncRNAs may be important in regulating directly the genes involved in DNA damage response. Further, there is emerging evidence of the role of LncRNAs in the pathogenesis of cancer. Therefore, an evaluation of LncRNA's and their role in cancer, especially in relation to DNA damage response is important.

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This is particularly so, as many of the commonly used drugs directly interact with DNA and do not allow normal repair causing cellular apoptosis. In ovarian cancer, p53 is mutated at a high frequency, and in breast significantly. In addition, in both cancers, defects in homologous recombination are common and occur at a frequency of up to 50%. It is, therefore, pertinent to ask whether which LncRNAs are expressed in response to DNA damaging drugs in both cancers and their relationship with p53.