Abstract
Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which they impact cancer biology remain largely unexplored. The aim of this study was to expose an externalized form of cytokeratin 8 (eK8) as a key player of colorectal tumorigenesis and characterize its mode of action. To achieve this, we generated a unique antagonist monoclonal antibody (D-A10 MAb) targeting an eight-amino-acid-long domain of eK8, which enabled us to ascertain the pro-tumoral activity of eK8 in both KRAS-mutant and wild-type colorectal cancers (CRC). We showed that this pro-tumoral activity involves a bidirectional eK8-dependent control of caspase-mediated apoptosis in vivo and of the plasminogen-induced invasion process in cellulo. Furthermore, we demonstrated that eK8 is anchored at the plasma membrane supporting this dual function. We, therefore, identified eK8 as an innovative therapeutic target in CRC and provided a unique MAb targeting eK8 that displays anti-neoplastic activities that could be useful to treat CRC, including those harboring KRAS mutations.
Highlights
The unexpected presence of intracellular proteins at the surface of some eukaryotic cells was recently described
D-A10 monoclonal antibodies (MAbs), we demonstrated that externalized form of cytokeratin 8 (eK8) mediates bidirectional signaling from colorectal tumors, one to the microenvironment leading to extracellular matrix degradation and another to the intracellular apoptotic machinery leading to tumoral cell death in vivo
Using xenografted mice bearing Isreco-1 or HCT116 tumors treated with different doses of M20, D-A10, or D-D6 MAb, we showed that the M20 antibody, as well as the D-A10 MAb, induced a continuous and significant reduction in tumor growth, while the D-D6 MAb did not produce this effect
Summary
The unexpected presence of intracellular proteins at the surface of some eukaryotic cells was recently described. These proteins are referred to as externalized proteins (eProts). The signals leading to their externalization remain unidentified since, in general, they neither exhibit a canonical transmembrane domain (TM) nor a signal sequence. They appear at the cell surface under pathological circumstances [1], and exhibit new properties related to cell signaling and invasive mechanisms. Externalized glucose-related protein 94 (eGRP94) interacts with and stabilizes ER-α36 [4], as well as human EGFR 2
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