Abstract B17: Disrupting tumor growth through targeting TEM8

Tumor Endothelial Marker 8 (TEM8) is an integrin-like cell-surface receptor originally identified being specific to tumor endothelial cells in colorectal cancer (CRC) blood vessels. Further investigation showed upregulated TEM8 expression in tumor vessels of various tumor types, as well as in certain tumor cells. We observe an increase in TEM8 expression in metastatic cancer cell lines compared to their non-metastatic counterpart in both colon and breast cancer cell lines. In order to investigate whether TEM8 is required for tumor growth and metastasis we have developed a humanized anti-TEM8-toxin-conjugated antibody. The antibody shows preclinical effectiveness in a CRC model in vivo. We have also utilized the CRISPR-Cas9 technology to create TEM8 knockout cell lines, which show impaired proliferation and invasion in vitro and reduced tumor growth in vivo compared to control cell lines. Intriguingly, microarray analysis showed a significant increase in TEM8 mRNA levels in breast cancer cells seeded on collagen modified by the crosslinking enzyme lysyl oxidase (LOX). We have previously shown that LOX plays a role in tumor progression, metastasis, and pre-metastatic niche formation through its ability to modulate matrix stiffness. Importantly, both high TEM8 and LOX expression is correlated with decreased survival in ER- breast cancer patients. Collagen VI, a TEM8 ligand, and their interaction have been implicated in being important for migration and for stimulating Wnt-signaling in breast cancer stem cells. Using global quantitative mass spectrometry we observe an increase in collagen VI in the extracellular matrix of CRC tumors overexpressing catalytically active, but not catalytically inactive, LOX compared to low-LOX expressing tumors. Furthermore, using publicly available databases TEM8 and collagen VI are found to be co-expressed in CRC patient datasets. Thus, we speculate that another possible mechanism of LOX mediated tumor and metastasis progression is through TEM8. Further, that combined targeting of TEM8 and LOX may inhibit primary and metastatic tumor growth. Citation Format: Anette M. Hoye, Sofie Tolstrup, Thomas R. Cox, Jeremy P. Mauldin, Arthur E. Frankel, Janine T. Erler. Disrupting tumor growth through targeting TEM8. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B17.