Molecular Oncology Lab

Research Description

My group is interested in exploring the genetic/epigenetic changes that initiate cancer and its progression by employing novel strategies and approaches. We also aim to investigate the molecular events that drive cancer progression and resistance towards chemotherapeutic drugs, in hopes that these discoveries can lead to the development of more effective therapies that target the specific causative pathways/alterations.

Prostate Cancer

Molecular characterization of Indian Prostate Cancer
Our research group in collaboration with GSVM medical college, Kanpur; King George’s Medical University, Lucknow and All India Institute of Medical Sciences, New Delhi for the first time screened Indian prostate cancer (PCa) cohort for the known genetic alterations. Our group for the first time characterized Indian PCa patients’ specimens for ERG, ETV1, ETV4 and RAF kinase genetic rearrangements, SPINK1 over-expression and PTEN deletion by employing immunohistochemistry (IHC) and Fluorescence in-situ Hybridization (FISH). We revealed high recurrence of TMPRSS2-ERG (~50% recurrent) and SPINK1 over-expression (~12% recurrent) among Indian PCa patients. Most importantly, we found higher incidence of RAF genetic rearrangements among Indian prostate cancer patients (~6% in Indian PCa as compared to ~2% in Caucasian), indicating that these patients may respond to the FDA-approved RAF kinase inhibitors or MEK inhibitors which are already available in the clinic
(Prostate, 2015). This work represents the first comprehensive molecular subtyping of prostate cancer cohort from the Indian subcontinent, which has a huge potential for direct diagnostic, tailored therapeutic intervention and translational impact.

Prostate Cancer_1

(A) IHC staining for ERG rearrangement and SPINK1 in Indian PCa patients. (B) Summary of molecular subtypes in prostate cancer. (C) Circos depicting racial disparity associated with molecular subtypes of prostate cancer (Trends in Cancer, 2016).

Exploration of Novel Molecular Drivers and Mechanistic Circuitry of Indian Prostate Cancer
Prostate cancer has been known to evolve from diverse genetic alterations including mutations, gene fusions/rearrangements, amplifications/deletions, and other aberrations that perturb gene expression levels. The major drift in field of prostate cancer genomics has been the sub-classification of tumors into distinct molecular subtypes. Emerging high throughput technologies such as Next Generation Sequencing will dictate the developments in personalized genomic medicine in the near future. Although majority of Our group’s major focus of research is to fully understand the entire spectrum of genetic/epigenetic aberrations that occur in cancer patients specifically in the Indian subcontinent. Our previous efforts successfully delineated the common molecular subtypes for Indian PCa patients using a targeted IHC/FISH-based approaches. We to explore the comprehensive mutational landscape of these patients representing the entire disease-spectrum (primary to metastatic disease), understand the pathobiology of the newly identified mutation(s) and identify actionable alterations.
Prostate Cancer_2

Bhatia & Ateeq, 2019, Trends Mol. Med.

Considering racial disparities and clinical-treatment options available in India, exploring mutational-profiles of patient representing prostate cancer disease progression is critical for understanding the pathobiology and in redefining therapeutic targets for these patients. Major focus of our current research includes:
  • Genome wide screen of frequently mutated and hotspot regions associated with prostate cancer risk in Indian patient samples.
  • Integrative Sequencing for comprehensive identification of clinically significant alterations in Indian Prostate Cancer.
  • Development of prostate cancer patient-derived organoids from biopsies and utilize them genomic characterization and potential drug screen.
  • Characterization of exosome-encapsulated coding and non-coding RNAs secreted during prostate cancer using liquid biopsies.

Investigating the role of Homeobox genes in prostate cancer progression
Homeobox genes are the master regulators encoding transcription factors (TFs) which play a crucial role in the embryonic development. These TFs contain a conserved DNA binding domain known as homeodomain. Dysregulation of homeobox gene family including HOX and NKX3.1 have been reported in PCa progression. Distal-less homeobox (DLX) gene family members have been identified as early diagnostic biomarkers in PCa patients, whose oncogenic potential still remains elusive. We intend to unravel the molecular mechanism behind DLX gene family mediated PCa oncogenicity, which will open up avenues for novel therapeutic interventions targeting this molecular subtype of PCa.

Colorectal Cancer

Colorectal cancer (CRC) is the third most prevalent cancer worldwide and is one of the most severe malignancies associated with gastrointestinal tract. The transformation of normal colon epithelium to a cancerous phenotype entails multiple genetic and/or epigenetic alterations which promote oncogenesis. The key molecular events involved in CRC progression are activation of Wnt signalling, EGFR overexpression, loss of chromosome 18q and TP53 inactivation.

Serine Protease Inhibitor Kazal Type-1 (SPINK1) overexpression is known to play critical role in CRC progression. Moreover, Spink3, a mouse homolog of human SPINK1, was found to be upregulated in colitis associated cancer and was linked with enhanced tumor multiplicity and tumor volume. Our group demonstrated the oncogenic role of SPINK1 in CRC, wherein knockdown of SPINK1 was accompanied by increase in the expression of metallothioneins in SPINK1+ colon adenocarcinoma cells (Oncogenesis 2015). Global gene expression profile of SPINK1 knockdown cells indicated alterations in several metabolic processes, suggesting its possible role in metabolic regulation. .
Colon Cancer
Schematic of role of SPINK1 in colorectal cancer progression.

We thus aim to examine the metabolome of SPINK1+ colorectal cancer, which might aid in the identification of dysregulated metabolites critical in SPINK1-mediated oncogenesis in colorectal cancer.

Repository of Patients’ Derived Primary Tumor Xenograft

In order to take our discoveries of therapeutic targets to the next level and to examine target’s potential utility, we are employing a variety of in vivo preclinical mouse models. We will also establish a bioluminescent imaging mouse model, a non-invasive imaging system that allows discrimination of cancer cells from normal cells in an in vivo mouse model.

We are also establishing a biorepository of the primary tumor xenograft models (directly derived from the cancer patients, also known as Patient Derived Xenografts), which will be instrumental in accurately identifying clinically active agents and effective drug combinations, particularly in extrapolating the differences in drug treatment between mice models and humans.

                                                                                                                                            © Webpage maintained by: Anik Mitra