Lung adenocarcinoma can progress from an indolent in situ carcinoma to an invasive, aggressive, metastatic tumor. The WHO/IASLC/ATS Lung adenocarcinoma classification emphasizes the distinction of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma from their invasive counterparts. 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.
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.
We identified a unique gene signature that could distinguish indolent tumors from invasive tumors in early stage lung adenocarcinoma. Our genomic analysis and functional assays identified Aurora kinases (A and B) as master regulators of invasiveness in early stage lung adenocarcinoma. Our research focuses on characterizing Aurora kinase driven invasiveness pathway and targeting them for 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.
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.