Research
Metastasis is often depicted as an orderly cascade of events whereby malignant cells spread from a primary tumor to eventually colonize distant organs. In fact, the evolution of different cancers towards metastatic disease is a heterogeneous process 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 in some instances metastasize within months of diagnosis. Despite early detection and intervention, lung cancers relapse to multiple tissues such as lymph nodes, lungs, bones, adrenal glands, and most frequently, the brain. The high death rate from different thoracic malignancies has greatly stimulated research into their molecular origins. Nevertheless, 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 mouse modeling and live imaging, with the analysis of human clinical datasets and genomic/epigenomic platforms (Figure 1). This multi-faceted approach is being applied to the following research topics:
1) Lung adenocarcinoma metastasis and developmental pathways.
By transplanting human cancer cells into mice, we can generate a xenograft model of metastatic lung adenocarcinoma, a major sub-class of non-small cell lung cancer (NSCLC). This enables both in vivo and in vitro studies of human lung adenocarcinoma cells that metastasize to clinically relevant tissues (Figure 2). We further uncovered a transcriptional program that predicts poor outcome in early stage patient cohorts. This program includes novel metastasis gene candidates, and is driven in part by hyperactivation of the WNT/TCF pathway. The canonical WNT pathway plays significant roles in development, stem cell biology, and the initiation of certain types of cancer. In lung adenocarcinomas, this pathway is seemingly associated with tumor progression and multi-organ metastasis. We are studying how this WNT program is activated in lung tumors, and characterizing the biological functions of downstream metastasis gene targets. Finally, we are investigating the putative role of other pathways that normally regulate stem cells and lineage fate in promoting lung adenocarcinoma metastasis.
2) Cues from the microenvironment.
While some pathways are intrinsic to malignant cells and regulate their overall metastatic competence following tumor initiation, disseminated cancer cells can also encounter paracrine signals originating from unique microenvironments. Our in vivo model of lung adenocarcinoma metastasis recapitulates tumor-stroma interactions that are consistent with human disease (Figure 3). Depending on the context, tumor cells may interface with the vasculature, immune cells, and other tissue specific cell types. We are employing in vivo imaging techniques, transgenic reporter mice, and ex-vivo assays to identify niches in the microenvironment where specific molecular cues are exchanged with disseminated lung cancer cells to enable metastatic colonization.
3) Linking metastasis with resistance to therapy.
The eventual resistance of some cancers to systemic 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 or targeted therapy. 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 lung cancers.
With improving knowledge and experimental models, we are also interested in comparing the malignant properties of various lung cancer subtypes. NSCLCs such as adenocarcinomas, squamous cell carcinomas, and large cell carcinomas of the lung, as well as small cell lung cancers, all have distinct biological etiologies, which may require different genetic determinants for metastatic progression.
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Publications
Selected Publications:
Nguyen, D.X., Chiang, A.C., Zhang, H.F.X., Kim, J.Y., Kris, M.G., Ladanyi, M., Gerald, W.L., and Massagué J. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell, 138(1): 51-62 (2009). Commentary: Nat Rev Cancer. 2009 Sep;9(9):610.
Bos, P.D., Zhang, H.F.X., Nadal, C., Shu. W., Gomis. R.R., Nguyen, D.X., Minn, A.J., Van de Vijver, M., Gerald, W.L., Foekens, J.A., and Massagué, J. Genes that mediate metastasis through the blood-brain barrier. Nature, 459: 1005-9 (2009).
Nguyen D.X., Bos P.D., and Massagué, J. Metastasis: from dissemination to organ specific colonization. Nature Reviews Cancer, 9(4): 274-284 (2009).
Nguyen, D.X. and Massagué, J. Genetic Determinants of Cancer Metastasis. Nature Reviews Genetics: 8 (5), 341-352 (2007).
Gupta, G.P*, Nguyen, D.X.*, Chiang, A.C., Bos, P.D., Kim, J.Y., Nadal, C., Shu, W.,
Gomis, R.R., Todorova-Manova, K., and Massagué, J. Mediators of vascular remodeling
co-opted for sequential steps in lung metastasis. Nature, 446: 765–770 (2007). *Authors contributed equally.
Commentary: Nature. 446: 735-6 (2007).
Minn, A.J., Gupta, G.P., Padua, D., Bos, P.D, Nguyen, D.X., Kreike, B., Nuyten, D., Zhang, Y., Wang, Y., Foekens, J.A., van de Vijver. M., and Massagué, J. Lung Metastasis Genes Couple Breast Tumor Size and Metastatic Spread. PNAS, 104, 6740–6745 (2007).
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