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Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer

2022; American Association for Cancer Research; Volume: 12; Issue: 5 Linguagem: Inglês

10.1158/2159-8290.cd-21-0932

2159-8290

Borja Ruiz‐Fernández de Córdoba, Haritz Moreno, Karmele Valencia, Naiara Perurena, Pablo Ruedas, Thomas Walle, Alberto Pezonaga-Torres, Juan Hinojosa, Elizabeth Guruceaga, Antonio Pineda‐Lucena, Marta Abengózar, Denis Cochonneau, Carolina Zandueta, Susana Martínez-Canarias, Álvaro Teijeira, Daniel Ajona, Sergio Ortiz‐Espinosa, Xabier Morales, Carlos Ortiz‐de‐Solórzano, Marta Santisteban, Luis I. Ramos-García, Laura Guembe, Vratislav Strnad, Dominique Heymann, Sandra Hervás‐Stubbs, Rubén Pı́o, María E. Rodríguez-Ruiz, Carlos E. de Andrea, Silvestre Vicent, Ignacio Melero, Fernando Lecanda, Rafael Martı́nez-Monge,

Nanoplatforms for cancer theranostics

Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF. Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.