Abstract 3164: Impact of cN-II and CD73 inhibition on cancer cell migration
Authors: Octavia Cadassou, Muhammad Zawwad Raza, Emeline Cros-Perrial, Célia Armanet, Laura Gudefin, Kamel Chettab, Serge Manié, Charles Dumontet, Lars P. Jordheim
Journal: Cancer Research (2018)

Abstract Deregulation of nucleotide metabolism can lead to biological disturbances such as genetic instability, energetic homeostasis deregulation and pro-proliferative signaling, that are among the “Hallmarks of Cancer” described by Hanahan and Weinberg. Thus, this complex process has become in hotspot in cancer research. To fully apprehend to what extent nucleotide metabolism can be targeted for new anti-cancer therapies, the involved molecular actors and their function in cancer cell biology need to be better understood. Purine metabolism involves various intracellular and extracellular enzymes including cN-II (cytosolic nucleotidase-II) and CD73 that are two 5'-nucleotidases respectively able to dephosphorylate intracellular and extracellular nucleoside monophosphates into corresponding nucleosides. Considering nucleotide/nucleoside trafficking and their roles in cell biology, it is a possible that cN-II and CD73 are involved together in processes that increase cancer cells aggressiveness. We abolished cN-II and/or CD73 expressions in two human carcinoma cell lines (MDA-MB-231 and NCI-H292), using the CRISPR/Cas9 technique, and evaluated the impact of cN-II and CD73 on cell migration, under an extracellular nucleotide stress (by performing wound healing assays on the Incucyte device). The obtained results showed that cN-II alone or together with CD73, was able to modify cell migration, in absence and in presence of an extracellular nucleotide stress. Indeed, cN-II deficiency was associated with accelerated cell migration, in control conditions. Moreover, exposure to adenosine decreased migration for all the models, with a stronger effect on cN-II deficient cells. We further investigated on the expression or activity of migration regulators, and found that 5'-nucleotidases deficiency was associated with altered transcriptional expression of gelatinases (MMP-2 and MMP9) and their negative regulator (TIMP2). The study of signaling pathways that are known to be related to cell migration are currently studied. These in vitro observations justify upcoming in vivo studies that aim to correlate these results with metastasis occurrence after xenografts in immunodeficient mice. For the first time, our results define cN-II as involved in cell migration, confirming that this 5'-nucleotidase could represent an interesting target to reduce pro metastatic behaviors in cancer cells. Nevertheless, it remains to be defined whether the relation between 5'-nucleotidases and cell migration involves their catalytic activity (and thus nucleotide pools balance) or if it is due to the physical interaction with complexes that are already known to regulate this process. Citation Format: Octavia Cadassou, Muhammad Zawwad Raza, Emeline Cros-Perrial, Célia Armanet, Laura Gudefin, Kamel Chettab, Serge Manié, Charles Dumontet, Lars P. Jordheim. Impact of cN-II and CD73 inhibition on cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3164.