Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Among the different types of lung cancer, small cell lung cancer (SCLC) is the most aggressive form with a 5-year survival rate of less than 5%. No efficient therapeutic strategy exists for SCLC except for the rare cases when the disease is detected early. Although some of the genes commonly mutated in human SCLC are known, including the RB and p53 tumor suppressors, the molecular mechanisms of SCLC initiation and progression are still only partially understood, which hampers the development of novel targeted therapies as well as the ability for early detection.
Our overarching goal is to develop novel strategies for targeted therapy as well as early detection and prevention through understanding the mechanisms of SCLC development. To this end, we developed and used a genetically engineered mouse model that recapitulates the genetic alterations apparent in human small cell lung cancer (SCLC). Using this mouse model, we interrogated molecular and cellular mechanisms that drive SCLC initiation, progression, and maintenance. We focus the efforts of the laboratory on the following areas:
- The role of signaling pathways in the progression and chemo-resistance of SCLC We aim to determine the functions of the signaling pathways, e.g. Hh, Wnt/-Catenin and Notch that are activated in chemo-resistance cells. To this end, we utilize mouse genetics and biochemical approaches to characterize the pathways in the context of tumor development and chemo-response. Further analysis of the molecular events, after blocking the pathway genetically or pharmacologically will allow me to uncover molecular mechanisms downstream of those signaling pathways that play important roles in the maintenance of SCLC before and after chemotherapy. Our research will assess whether these pathway may serve as novel therapeutic targets in patients.
- Roles of the tumor cell plasticity in chemo-tolerance of SCLC The plasticity of tumor cells has been implicated in metastasis and chemo-tolerance, the hallmarks of SCLC. Primary cells from mouse SCLC consist of heterogeneous populations of cells. The cancer cells display remarkable plasticity associated with increased tolerance to chemotherapy drugs. We currently aim to determine potential roles of the tumor cell plasticity in chemo-tolerance and the mechanisms underlying the heterogeneity, specifically the role of signaling pathways. Preliminary gain-of-function experiment suggests that Notch pathway promote the tumor plasticity. Using in vivo and in vitro gain-of- and loss-of-function experiments, we aim to test how signaling pathway regulates this functional plasticity of SCLC cells. Together, the proposed experiments will probe how the plasticity of SCLC cells may allow them to evade current chemotherapeutic treatments, which may help to improve therapeutic strategies in patients.
- Novel molecular determinants of SCLC progression Discovery and validation of key drivers in SCLC progression can be achieved by comparing tumor cells with pre-neoplastic precursor cells or metastatic cells. Using novel mouse model capable of lineage tracing, we are now able to isolate our target cells. To identify gene expression profiles of a minute population of cells of interest, we utilize gene-chip array and RNA-sequencing that are coupled with the data of advanced genomics studies (e.g. array CGH, exome sequencing). This project aims to take an unbiased approach to uncover novel molecules that may be critical for the development of SCLC. These proposed experiments will greatly enhance our understanding of the mechanisms underlying SCLC initiation and progression.