Cancers, Vol. 10, Pages 452: Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells

Cancers, Vol. 10, Pages 452: Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells

Cancers doi: 10.3390/cancers10110452

Authors: Marie Alexandra Albaret Claudine Vermot-Desroches Arnaud Paré Jean-Xavier Roca-Martinez Lucie Malet Jad Esseily Laetitia Gerossier Johan Brière Nathalie Pion Virginie Marcel Frédéric Catez Geneviève De Souza Boris Vuillermoz Franck Doerflinger Emilie Lavocat Olivier Subiger Carine Rousset Corinne Bresson Elodie Mandon Anass Jawhari Pierre Falson Mélissa Jasmin Yohann Coute Hichem-Claude Mertani Pierre Saintigny Jean-Jacques Diaz

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.

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