Biology of Lung Cancer Metastasis

Cancer metastasis is a heterogeneous disease that is influenced by unique cellular origins, altered microenvironments, distinct physiologic restrictions, as well as specific genetic and epigenetic alterations. These factors all contribute to diverse biological and clinical courses, likely requiring tailored therapy for various cancer subtypes.

Lung cancers are particularly aggressive and can metastasize within months of diagnosis. Despite early detection and treatment, lung cancers spread to multiple tissues, most frequently to the brain. The mechanisms by which lung cancer cells invade and colonize distant organs remain largely unknown. Our goals are to identify molecular determinants of lung cancer metastasis, study their biological functions, and assess their clinical relevance.

To achieve this, we integrate  experimental modeling of both normal and aberrant biological phenomena  with bioinformatic analysis of human clinical samples, on various genomic/epigenomic platforms  (Figure 1). This multi-faceted approach is being applied to the following topics:

1. Deregulated cell fate in lung cancer metastasis.

Through bioinformatic analysis, we  uncovered a gene expression program that predicts poor outcome in patients with  lung adenocarcinoma, a major sub-class of non-small cell lung cancer (NSCLC). This program is driven by a transcriptional network which normally controls the differentiation of epithelial progenitor cells in the airways.  By transplanting human cancer cells into mice, we can generate a model of metastatic lung adenocarcinoma  (Figure 2).  We are now studying how this aberrant cell differentiation pathways is activated in lung tumors and characterizing the biological functions of its downstream genes in mice. We are also using genomic insights to track the origin and fate of tumor cells at various stages of lung adenocarcinoma progression.

2. Cues from the microenvironment.

Disseminating cancer cells also encounter paracrine signals from their microenvironments. Depending on the context, tumor cells may interface with the vasculature, immune cells, and other tissue specific cell types. Many of these interactions are akin to physiological reponses triggered during normal tissue injury and repair.  We are employing in vivo imaging techniques, transgenic reporter mice, and ex-vivo assays (Figure 3) to understand how invading lung cancer cells can take advantage of normal tissue remodelling signals to enable their metastatic colonization.

3. Linking metastasis with resistance to therapy.

The resistance of some cancers to therapy often correlates with metastatic relapse. Yet it is unclear how these two phenomena are mechanistically linked. A particularly intriguing example is the secondary metastasis observed in lung adenocarcinoma patients after they have undergone systemic chemotherapy. Is this acquired resistance due to tumor cell intrinsic alterations, factors from the new metastatic niche, or inefficient drug delivery to the affected organ site? Using biological insights gained through our experimental approach, we are attempting to solve these questions in the hopes of exploring new therapeutic possibilities.

4. Comparing different types of lung cancers.

Part of the challenge in diagnosis lung cancer patients, is the existence of different lung cancer subtypes, each with unique clinical properties. For instance NSCLCs such as adenocarcinomas, squamous cell carcinomas, and large cell carcinomas, arise from different regions of the airways.  These are also likely to harbor distinct molecular changes.  We are interrested in determining the unique molecular and cellular origins of each lung cancer subtype, to uncover more accurate prognostic modalities.