Molecular Oncology and Biomarkers Program
Associate Professor, Medicine, Hematology/Oncology
Associate Professor, Pathology
Georgia Cancer Center
1410 Laney Walker Blvd., CN-3112
Office Phone: 706-721-0295
Lab Phone: 706-721-7024
Non-small cell lung carcinoma (NSCLC) is a leading cause of death worldwide. A critical barrier to progress in treating NSCLC patients is that while targeted therapies using receptor tyrosine kinase inhibitors are effective in EGFR mutated tumors, no such effective therapy has been found for KRAS mutated tumors. Our goal is to improve the treatment of NSCLC by defining the biologic interactions of TIMP-1 in KRAS lung adenocarcinoma. Our specific interest is in the molecule TIMP-1 and its role in the tumor microenviroment in causing lung metastasis.
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 (reviewed in J Carcinog Mutagen 2015, 6:225). 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 tumor growth. 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 context of invasion and metastasis.
TIMP-1 and the tumor microenvironment
The close correlation between MMP2 expression and increased angiogenesis at the edge of lung carcinoma metastasis to the brain was previously reported (Int J Clin Exp Pathol 2010;3(8):775-781). Subsequently we have used lung adenocarcinoma cells to determine the effects of TIMP-1 on tumor growth. Transfected cells overexpressing TIMP-1 resulted in highly aggressive, more vascularized tumors when injected into the mouse brain and in a series of in vitro assays (J Neuropathol Exp Neurol. 2015, 74(4):293-304). We have identified the anti-apoptotic function TIMP-1 as well as enhanced angiogenesis as the basis for its tumor promoting activity. Additionally, we have presented evidence that TIMP-1 overexpression results in increased levels of Bcl-2, resulting in inhibition of apoptosis via inactivation of BAD following its phosphorylation at serine 112. This inhibition of apoptosis occurs through the p90RSK/BAD axis via interaction between TIMP-1 and Bcl-2 (Plos One. 2015, 10: e0137673).
TIMP-1 and epigenetic/post-translational alterations
More recently, we have sought to determine the downstream effects of TIMP-1 overexpression or knockdown, identifying TIMP-1 interactions with miRNA and its effects on downstream signaling. We are also studying the effects of TIMP-1 modulation on epithelial-mesenchymal transition on lung adenocarcinoma cell lines with KRAS mutations.
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
Ghoshal-Gupta S, Kutiyanawalla A, Lee BR, Nurani A, Ohja J, Mondal A, Kolhe R, Rojiani AM and Rojiani MV: Modulation of miRNA Profile in Lung Adenocarcinoma Cell Lines Following TIMP-1 Downregulation (Submitted- OncoTarget)
Hopley RT, Haller E, Rojiani MV, Rojiani AM: Morphologic and Elemental Analysis of Primary Melanosis of the Dentate Nucleus: Correlation with Neuromelanin (In-Press - J Neuropath and Exp Neurol)
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 10(9):0137673. doi:10.1371/journal.pone.0137673
Wiranowska M, Rojiani AM, Rojiani MV (2015) Matrix Metalloproteinases-Modulating the Tumor Microenvironment. J Carcinog Mutagen 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)
Papiez J, Rojiani MV, Rojiani AM: Vascular Alterations in Schwannomas Int J Clin Exp Pathol. 2014; 7(7): 4032–4038
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. (2004) Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies. Annals of Surgical Onc. 11:413-419
Muir D, Johnson J, Rojiani MV, Inglis B, Rojiani AM, Maria BL (1996) Assessment of infiltration by glioma cell tumors engrafted within the rat spinal cord. J Neurooncology 30:199-211
Pan J, Roskelley C, Luu-The V, Rojiani MV and Auersperg N. (1992) Reversal of divergent differentiation by Ras oncogene-mediated transformation. Cancer Res 52: 4269 – 4272
NIH/NCI R01CA197477-A1 5/1/2016 – 4/31/2021 (Co-I)