Sangeeta N. Bhatia
Cancer metastasis results in 90% of cancer-related deaths, yet few existing therapeutics directly target it, largely due to a general lack of knowledge with regards to the underlying mechanisms that mediate malignant dissemination. Despite a growing appreciation for the role that the microenvironment plays in promoting or inhibiting metastasis, challenges in detecting early stages of metastases continue to hamper efforts to dissect molecular events responsible for the process.
Our lab has applied a variety of techniques to screen for the presence of metastases in animal models and additionally to dissect the quality of the microenvironment in these areas. In one approach, a novel microarray screening platform consisting of 768 combinations of ECM components was designed and utilized to assay cell populations for their adhesion, proliferation, and marker expression using automated fluorescent microscopy in conjunction with automated cell counting and image analysis. This platform was used in conjunction with a mouse model of lung adenocarcinoma metastasis developed by the Jacks laboratory (KrasLSL-G12D/+;p53flox/flox) where distinct stages of metastasis are defined by characteristic cell lines derived from these mice. Hierarchical clustering of the adhesion profiles reveal metastasis-specific conserved alterations in ECM adhesion signatures, and identify a role for combinations of ECM composed of fibronectin with any of galectin-3, galectin-8, or laminin. Subsequently, the integrin α3β1 was shown to mediate adhesion to the fibronectin-galectin combinations in vitro and promote metastasis in mice bearing the autochthonous tumors or in humans with lung cancer.1 Finally, we demonstrate that galectin-3, whose expression has strong clinical associations with advanced malignancy and poor outcome, is present at the site of metastases, and is produced early during tumorigenesis by the tumors and CD11b+ leukocytes. Galectin-3 contains exhibits a specific affinity for the oncofetal T-Antigen, and we find that metastatic populations exhibit elevated T-Antigen on their surfaces, resulting from altered glycosyltransferase activity, that promotes metastasis.2 While altered glycosylation has long been associated with cancer, our data provides a mechanistic explanation for clinical associations between malignancy and elevated galectin-3 levels and suggests development of therapeutics targeting galectin-glycan interactions as a novel approach for treating metastatic disease. Collectively, this approach represents a novel phenotypic screening platform for use in the study of disease mechanisms as well as to identify novel biomarkers.
- Reticker-Flynn, NE, Braga Malta, DF, Winslow, MM, Lamar, JM, Xu, MJ, Underhill, GH, Hynes, RO, Jacks, TE, and Bhatia, SN (2012): A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis. Nature Communications 3, Article number: 1122
- Reticker-Flynn, N and Bhatia, SN. Altered glycosylation promotes lung cancer metastasis through interactions with galectins in the metastatic niche. (under review)