Research

1. Deciphering the role of Osteopontin (OPN) in tumor progression:     Prof. Kundu’s group have dissected the molecular mechanisms by which Osteopontin  OPN) and its associated genes regulate the metastatic potential of breast and other cancers. A better understanding of mechanism by which OPN promotes tumorigenesis may be useful in crafting novel OPN-based anti-cancer therapy. The role of OPN in promoting cancer progression is the subject of in depth investigation. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor growth and angiogenesis and may develop an effective therapeutic strategy for the management of cancer. 

2. Role of tumor microenvironment in tumor progression: Tumor microenvironment consists of various cellular players including extracellular matrix (ECM), hypoxia, fibroblasts, neuroendocrine (NE) cells, adipose cells, immune-inflammatory cells and the lymphatic vascular networks. These components play crucial role in tumor growth, immune evasion, metastasis and angiogenesis. Earlier, Prof. Kundu and group have demonstrated the role of hypoxia and TAMs in Osteopontin regulated tumor progression in breast cancer and melanoma models respectively. Recently, our groups have explored how Tumor Activated Macrophages (TAMs) promotes cancer stem cell (CSC) phenotype and CSC-mediated breast tumor growth. 

3. Cancer Stem Cells (CSCs) and their role in Tumor Growth and Metastasis: Tumor initiating cells having stem cell characteristics were first discovered in leukaemia and later in solid tumors that recently has become an important area in cancer research. These stem like tumor cells, termed as cancer stem cells (CSCs) govern tumor progression, angiogenesis and metastasis via modulating specific pathways that depends upon the type of the tissue. Prof. Kundu and group have recently shown that Notch1-MAPK signaling axis regulates CD133+ cancer stem cell-mediated melanoma growth, angiogenesis and lung metastasis and andrographolide, a druggable molecule suppresses CD133+ cancer stem cell-mediated lung metastasis in skin cancer.

4. Nanomedicine and Cancer Therapy: Breast cancer is a complex disease and most breast cancer treatments are limited to chemotherapy, radiation, and surgery. Substantial advances in breast cancer treatments have resulted in a significant decrease in mortality. However, existing breast cancer therapies often result in high toxicity and nonspecific side effects. Therefore, better targeted delivery and increased efficacy of drugs are crucial to overcome these effects. Application of nanotechnology or nanoparticle-mediated drug delivery can resolve some of these issues and these areas of research are expanding dramatically. Our group have synthesized and characterized cRGD peptide conjugated chitosan nanoparticles loaded with anticancer drug raloxifene or andrographolide. Enhanced uptake of Cy5.5 conjugated RGD CHNP was studied in triple negative and αvβ3 integrin over-expressing breast cancer cells. The decrease in cell viability was observed by MTT assay after treatment with drug encapsulated nanoparticles. RGD conjugated nanoparticles exhibit enhanced inhibition of cell viability in these breast cancer cells. In vitro and in vivo toxicity studied revealed that these nano-drugs are not toxic in normal cells and tissues. Finally, our group have demonstrated that andrographolide or raloxifene encapsulated RGD-CHNPs significantly inhibited the breast tumor growth suggesting that RGD conjugated chitosan nanoparticles could be an effective approach for targeted therapeutic delivery in different sub-types of breast cancer. 

5. Here, we report the crosstalk between the cancer cells and stromal fibroblasts that leads to tumor progression. The process is initiated by secretion of a chemokine like protein, osteopontin (OPN) from the cancer cells that differentiates the fibroblasts to myofibroblasts. Tumor-derived OPN achieves this transition by engaging CD44 and αvβ3 integrins on the fibroblast surface, which mediates signaling via Akt and ERK to induce Twist1-dependent gene expression. The OPN-driven CAFs then secrete CXCL12, which in turn triggers epithelial to mesenchymal transition (EMT) in the tumor cells. OPN, produced by the cancer cells, and CXCL12, secreted by activated fibroblasts, are necessary and sufficient to perpetuate the crosstalk. Knocking out OPN in carcinogen-induced mammary tumors or knocking down OPN in cancer cells and fibroblast coimplanted xenografts abrogates myofibroblast differentiation, Twist1, and CXCL12 expression. OPN expression is correlated with CAF-specific gene signature as shown by breast tumor tissue microarray consisting of 100 patient specimens. Bioinformatics analyses have confirmed that the expression of OPN is significantly correlated with the expression of myofibroblast-specific markers as demonstrated in human breast carcinoma dataset of 2509 patients. Our findings describe OPN and CXCL12 act as compelling targets to curb the tumor-promoting features of the stromal components and further suggested that OPN-regulated CXCL12 network might act as potential therapeutic target for the management of CAFmediated breast cancer progression.