Molecular Oncology & Biomarkers


 

Non-small cell lung carcinoma (NSCLC) is a leading cause of death worldwide. The Rojiani Lab is broadly seeking to understand the biology of NSCLC, with a specific interest in the molecule TIMP-1.  Our investigations have examined its biologic interactions within the tumor microenvironment, including its impact on the development of chemoresistance.  Our goal is to contribute to improved predictive and therapeutic interventions for the management of NSCLC by defining the biologic interactions of TIMP-1 in lung adenocarcinoma.  

 My laboratory focuses on the role of the tumor microenvironment in non-small cell lung carcinoma (NSCLC). In particular, we are examining the role of matrix metalloproteinases (MMPs) and their natural endogenous inhibitors, the TIMPs. Although TIMPs have classically been regarded as inhibitors of MMPs, over the years they have emerged as truly multifunctional proteins with MMP-independent roles in tumor growth apoptosis, angiogenesis, invasion and metastasis.  TIMP-1 has also been shown to be an important prognostic marker, as high serum levels of TIMP-1 have been associated with poor prognosis for a number of cancers. Our major interest lies in the multifaceted and paradoxical functions of TIMP-1 in apoptosis, EMT (epithelial to mesenchymal transition), angiogenesis and chemoresistance.  The tumor promoting activities of TIMP-1 have been attributed to its MMP-independent functions, including anti-apoptotic activity. Recognizing the role of many chemotherapeutic agents in inducing apoptosis and inhibiting angiogenesis, there is clearly a need to better define the complex interactions of TIMP-1, particularly in the tumor microenvironment.

We have determine the effects of TIMP-1 on tumor growth in NSCLC cells.  Transfected cells overexpressing TIMP-1 resulted in highly aggressive, more vascularized tumors when implanted in the mouse brain. . We have also presented evidence that TIMP-1 overexpression results in increased levels of Bcl-2, resulting in inhibition of apoptosis. Additionally, we have sought to determine the downstream effects of TIMP-1 knockdown, identifying TIMP-1 interactions with miRNA and its effects on downstream signaling. Most recently, we have reported on the development of chemoresistance in high TIMP-1 expressing NSCLC cell lines via increased expression of IL-6. Currently we are exploring the role of the extracellular matrix and cancer stem cells in TIMP-1-mediated chemoresistance.

Xiao W, Wang L, Howard J, Kolhe R, Rojiani AM, Rojiani MV:  TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC.  Cancers, August 2019; 11, 1184; doi:10.3390/cancers11081184 

Ghoshal-Gupta S, Kutiyanawalla A, Lee BR, Ojha J, Nurani A, Mondal A, Kolhe R, Rojiani AM and Rojiani MV: TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. Oncotarget, 2018; 9:8941-8956.

Kolhe R, Hunter M, Liu S, Jadeja R, Pundkar C, Mondal A, Mendhe B, Drewry M, Rojiani MV, Liu Y, Isales C, Guldberg R, Hamrick M, and Fulzele S:  Gender specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis." Nature Scientific Reports 2017 May 17;7(1):2029

Strickland-Marmol LB, Brem S, Rojiani AM, Rojiani MV:  Vascular morphometric parameters- correlation with histologic grade and VEGF expression in oligodendroglioma. Am J Cancer Res. 2017; 7(4) 973-981

Nalluri S, Ghoshal-Gupta S, Kutiyanawalla A, Gayatri S, Lee BR, Jiwani S, Rojiani AM and Rojiani MV: TIMP-1 inhibits apoptosis in lung adenocarcinoma cells via interaction with Bcl-2.  – PLoS ONE 2015; 10(9):0137673. doi:10.1371/journal.pone.0137673

Wiranowska M, Rojiani AM, Rojiani MV: Matrix Metalloproteinases-Modulating the Tumor Microenvironment. J Carcinog Mutagen 2015; 6:225. doi: 10.4172/2157-2518.1000225

Rojiani MV, Rojiani AM: TIMP-1 Overexpression In Lung Carcinoma Enhances Tumor Kinetics And Angiogenesis. J Neuropath Exp Neurol 2015 April; 74 (4) 293-304)

Rojiani MV, Alidina J, Esposito N, Rojiani AM: Expression of MMP-2 correlates with increased angiogenesis in CNS metastasis of lung carcinoma. Int J Clin Exp Pathol 2010; (8):775-781

Rojiani MV, Korabathina K, Siemann DW, Rojiani AM:  Cell Proliferation Index Determination by Immunohistochemical Detection of hCDC47 Protein. Appl Immunohistochem Mol Morphol. 2010; 18(3):278-82 11.

Riddle ND, Gorden L, Rojiani MV, Hakam A, Rojiani AM. CD44 and p53 immuno-expression patterns in NF1 neoplasms - indicators of malignancy and infiltration. Int J Clin Exp Pathol. 2010 Jun 12;3:515-21.

Bloomston M, Durkin A, Yang I, Rojiani MV, Rosemurgy A, Enkmann S, Yeatman T, and Zervos E: Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies. Annals of Surgical Onc. 2004; 11:413-419

Muir D, Johnson J, Rojiani MV, Inglis B, Rojiani AM, Maria BL: Assessment of infiltration by glioma cell tumors engrafted within the rat spinal cord.  J Neurooncology 1996; 30:199-211

Pan J, Roskelley C, Luu-The V, Rojiani MV and Auersperg N: Reversal of divergent differentiation by Ras oncogene-mediated transformation. Cancer Res 1992; 52: 4269 – 4272

 

 

NIH/NCI R01CA197477-A1  (Co-I)