The early stage in tumor progression to a state of invasiveness and metastasis is characterized by epithelial dysregulation and instability that drives loss of cellular adhesion and increased cell mobility and proliferation. In many cases, signaling pathways important in lung development are critical for mediating these processes. The biological processes required for this progression include alterations in the TGF-Beta signaling pathway, and genomic copy number alterations of CDK4 and MDM2, and mutations in key oncogenic regulators. Our laboratory has identified TGF-βReceptor II repression as a biomarker of lung adenocarcinoma invasiveness and has developed in-vivo and in-vitro system to examine the mechanisms by which TGFβ enhances lung tumor progression.
WHO/IASLC/ATS Lung adenocarcinoma classification emphasizes the distinction of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) from their invasive counterparts. Lung adenocarcinoma can progress from an indolent in situ carcinoma to an invasive, aggressive, metastatic tumor. Molecular biomarkers of invasion can distinguish invasive from non-invasive tumors, a distinction that is typically difficult to make in small biopsies and cytology specimens and is becoming increasingly important as the recognition of early stage adenocarcinoma increases with the widespread implementation of lung cancer screening programs in the United States. Our current research focuses on identification of a unique genomic signature that can distinguish between indolent and invasive tumors in early stage lung adenocarcinoma. Using genomic and functional approaches, we are focussed on identifying genes responsible for invasive behavior of tumors. Our current research identified genes like Aurora kinases, as master regulator of invasiveness. Our goal is to target such genes as an intervention therapy.
Equally important in mediating adenocarcinoma progression is the contribution by the tumor microenvironment. The microenvironment is a complex system comprised of stromal fibroblasts, macrophages, lymphocytes, other bone marrow-derived cells (BMDCs), and extracellular matrix (ECM) that in a reciprocal fashion, can contribute to tumor regression or progression. Key regulators of the tumor microenvironment regulation of tumor progression include the TGF-Beta signaling pathway, thrombospondin-1 (Tsp-1), and the composition of the tumor immune contexture. Our current research focuses on cross talk between TGFBR2- CCL5 signaling pathway to understand their contribution in tumor progression as well as invasion and metastasis.
We are using animal model and animal imaging to study onset and progression of lung adenocarcinoma. Taken together, these advances in the understanding of tumor mediated and microenvironment mediated processes that regulate adenocarcinoma progression and metastasis will drive advances in translational approaches to improve diagnosis and treatment of lung cancer.