Student Theses and Dissertations

Kim J. Png

Date of Award

2012

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Tavazoie Laboratory

Abstract

Metastasis is a highly complex, multi stage process that is clinically daunting, causing the majority of deaths from solid malignancies. A previous study identified three microRNAs that robustly suppresses breast cancer metastasis to lung and bone – miR-126, miR-206 and miR-335. While miR-335 suppressed metastasis through inhibition of cell-autonomous metastatic phenotypes of cell migration and invasion, the role of miR-126 in metastasis remained unknown. Here, endogenous miR-126 is shown to regulate the non-cell autonomous phenotype of endothelial recruitment to metastatic breast cancer cells. Through coordinate targeting of IGFBP2, PITPNC1 and MERTK, miR-126 inhibits endothelial recruitment, which is required for metastatic angiogenesis and metastatic colonization. IGFBP2 secreted by metastatic cells promotes endothelial recruitment through binding of IGF-1 in the extracellular space, activating IGF type-I receptor on endothelial cells. In contrast, MERTK receptor cleaved from metastatic cells acts as a decoy receptor for GAS6, sequestering GAS6 away from endothelial MERTK receptor, which normally signals to inhibit endothelial recruitment. Co-injection of endothelial cells with breast cancer cells noncell autonomously rescues their miR-126-induced defect in metastasis, revealing a role for cancer cell-endothelial interactions in metastatic initiation. These findings reveal endothelial recruitment and endothelial interactions in the tumour microenvironment to be integral features of metastatic breast cancer. All three previously discovered breast cancer metastasis suppressor microRNAs display deregulated expression in cancer through unknown mechanisms. These findings reveal that the human miR-335 locus undergoes both genetic deletion and epigenetic promoter hypermethylation in metastatic derivatives obtained from independent patients’ tumours. Additionally, matched primary tumour-metastases pairs revealed the silencing of miR-335 expression to occur at least partially through genetic deletion. Genetic deletion of miR-335 also correlates with ovarian cancer recurrence, suggesting that miR-335 may play a regulatory role in ovarian cancer. The miR-126 locus, however, is not subjected to either genetic deletion or epigenetic promoter hypermethylation. Early evidence suggests that miR- 126 expression is inhibited through a processing defect in the biogenesis of mature miR-126 from pre-miR-126. These findings reveal individual metastasis suppressor microRNAs to be regulated by divergent mechanisms – generic (genetic or epigenetic) and microRNA-specific (processing) regulatory mechanisms.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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