Intracellular and extracellular promoters of metastasis to different organs

Abstract

Metastasis is the cause of the vast majority of cancer-related deaths, yet much remains unknown about this complex process, from how tumor cells complete the many steps of the metastatic cascade to how they can adapt to survive in multiple, vastly different secondary sites. I have therefore conducted two studies into different aspects of metastasis. First, I investigated the scaffold protein IQGAP1, which promotes primary tumor growth and invasiveness in several cancers. However, the role of IQGAP1 in metastasis has been unclear. We used IQGAP1 knockdown and knockout to investigate its role in the metastatic cascade in melanoma and breast cancer. I found that reduction of IQGAP1 expression inhibited the formation of metastases, without limiting primary or metastatic tumor growth. Furthermore, IQGAP1 knockout significantly decreased extravasation of tumor cells from circulation.

These data demonstrate that IQGAP1 promotes metastasis in vivo through regulation of extravasation and suggest that it may represent a valid therapeutic target for inhibiting metastasis. Second, I examined how cells from the same primary tumor can adapt to several different secondary environments. A critical component of every metastatic niche is the extracellular matrix (ECM), which provides structural support, migration control, and growth and survival signals. However, a comprehensive comparison of the ECM components of metastatic niches at various secondary sites had not yet been conducted. I isolated metastases from the brain, lungs, liver and bone marrow, which were all derived from parental MDA-MB-231 human breast cancer cells. We then enriched these tumor samples for ECM proteins and used quantitative mass spectrometry to analyze their ECM composition. Strikingly, the niches created at each site were distinct.

Using these data, I compared protein abundance across all metastatic sites to determine which ECM proteins were most significantly elevated in each particular tissue relative to the others. Following this analysis, I knocked down tumor cell expression of SERPINB1, a protein characteristically elevated in brain metastases, and observed reduced metastasis to the brain. Together, these studies offer insight into the fundamental biology of metastasis and metastatic niches, as well as provide potential targets of metastatic breast cancer for imaging and therapy.