Journal Article Research Support, Non-U.S. Gov't Ppublish 21 citations
PubMed: 35191482 DOI: 10.1158/2159-8290.CD-21-0932
Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer.
Cancer Discov 12(5):1356-1377
Authors: Borja Ruiz-Fernández de Córdoba, Haritz Moreno, Karmele Valencia, Naiara Perurena, Pablo Ruedas, Thomas Walle, Alberto Pezonaga-Torres, Juan Hinojosa, Elisabet Guruceaga, Antonio Pineda-Lucena, Marta Abengózar-Muela, 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 Pío, María E Rodríguez-Ruiz, Carlos E de Andrea, Silvestre Vicent, Ignacio Melero, Fernando Lecanda, Rafael Martínez-Monge
Affiliations
- Solid Tumors Program. Division of Oncology, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- Bioinformatics Core Facility, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.
- Program of Molecular Therapies, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.
- Departament of Pathology, Clínica University of Navarra, Pamplona, Spain.
- Nantes Université, CNRS, US2B, UMR 6286, Nantes, France.
- Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine, Saint Herblain, France.
- Immunology and Immunotherapy, CIMA, Pamplona, Spain.
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
- Image Core Facility, CIMA, Pamplona, Spain.
- Oncology, Clínica University of Navarra, Pamplona, Spain.
- Radiation Oncology, Clínica University of Navarra, Pamplona, Spain.
- Morphology Core Facility, CIMA, Pamplona, Spain.
- Department of Radiation Oncology, University of Erlangen, Erlangen, Germany.
- Department of Oncology and Metabolism, Medical School, Sheffield, UK.
- School of Medicine, Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain.
Abstract
ABSTRACT
Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1/CD203a (ENPP1) to be closely associated with LRF. ENPP1hi circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of polymorphonuclear myeloid-derived suppressor cells and neutrophil extracellular trap (NET) formation. Genetic and pharmacologic ENPP1 inhibition or NET blockade extends relapse-free survival. Furthermore, in combination with fractionated irradiation, 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.
SIGNIFICANCE
CTC exploit the ENPP1/HP axis to promote local recurrence post-surgery and post-irradiation by subduing myeloid suppressor cells in breast tumors. Blocking this axis impairs tumor engraftment, impedes immunosuppression, and obliterates NET formation, unveiling new opportunities for therapeutic intervention to eradicate local relapse and ameliorate patient survival. This article is highlighted in the In This Issue feature, p. 1171.
MeSH
Radiotherapy, Cells, Haptoglobins, Myeloid-Derived Suppressor Cells, Breast Neoplasms, Neoplasms, Breast, Prognosis
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