CATALYZING CANCER METASTASIS: A STUDY OF THE ENZYMATIC DRIVERS OF TUMOR DISSEMINATION AND GROWTH

Abstract

Section I: E-selectin binding to Fut3/6-modified Glg1 is essential to bone metastasis via the induction of a Mesenchymal-Epithelial Transition and activation of Wnt signaling.

The initial survival and growth of disseminated tumor cells (DTCs) in distant organs is one of the most important but least understood steps of the metastatic cascade. Previous studies have demonstrated the importance of the epithelial-mesenchymal transition (EMT) in promoting cancer stem cell properties, while the reverse process of mesenchymal-epithelial transition (MET) is required for metastatic outgrowth. However, it is unknown how MET and cancer stem cell traits can be simultaneously induced when tumor cells disseminate to a distant organ. Here we show that bone endosteal E-selectin promotes bone metastasis by inducing MET and activating Wnt signaling. We further demonstrate that α1-3 Fucosyltransferases Fut3/6 fucosylate Glg1-N165 to serve as the E-selectin ligand on bone metastatic tumor cells. These findings provide new insights into the functional role of E-selectin as a component of the vascular niche critical for the initial colonization of bone metastasis.

Section II: Aldh1a3 activity functionally links chemoresistance to metastasis in ER- breast cancer

Cancer stem cell markers such Aldefluor reactivity and CD44hi/CD24lo are routinely used to isolate aggressive and “stem-like” subpopulations from heterogeneous tumors. Despite the association of these markers with self-renewal, chemoresistance, and metastasis, the fundamental question of whether these markers are drivers of cancer progression has not been answered. Here we used functional selection to generate a novel model of breast cancer replicating each stage of progression. Profiling of cancer stem cell markers revealed that only Aldefluor reactivity and chemoresistance correlate to tumorigenic / metastatic propensity. Further analysis identified that Aldh1a3 is the unique isoform that generates Aldefluor positivity, and Aldh1a3 activity functionally links metastatic ability in vivo with enhanced chemoresistance in vitro. Finally, we show that Aldh1a3 is a strong clinical predictor of poor distant metastasis-free survival in Estrogen receptor negative patients receiving chemotherapy.