Cancer-Associated Fibroblast Proteins as Potential Targets against Colorectal Cancers
Ruchi Shah, Katherine A. Johnson, Anna E.L. Lippert, Sean G. Kraus, Philip B. Emmerich, Cheri A. Pasch, Wei Zhang, Kristina A. Matkowskyj, Aaron M. LeBeau, Dustin A. Deming
Abstract
In colorectal cancer (CRC), attempts to identify cancer cell-specific markers to guide antibody-mediated therapeutics have failed to uncover markers that are both exclusive to cancer tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment and upregulate unique surface markers, are not found in healthy tissues. Here, we evaluated the expression patterns of CAF-associated proteins α-smooth muscle actin (αSMA), fibroblast activation protein (FAP), podoplanin (PDPN), matrix metalloproteinase-2 (MMP2), transgelin (TAGLN), and THY1. While αSMA and THY1 were abundant in cancer tissues, high abundance in normal tissues limited their targeting potential. FAP was present in 94.5% of primary and metastatic CRC tissues and absent in 93.7% of adjacent normal colon and liver tissues assessed. These results indicate that FAP is a promising target for antibody conjugates with potential for broad application in CRC. Co-expression analyses showed that CRCs simultaneously expressing high levels of PDPN, MMP2, and THY1 were enriched for immune-related signatures, indicating potential for antibody-mediated immune engagers. Overall, this work highlights the potential of CAF proteins to act as therapeutic targets for novel anticancer agents and become important therapeutic biomarkers.