Scientific publications

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

Jan 27, 2022 | Magazine: Cancer Discovery

Borja Ruiz-Fernandez de Cordoba  1 , Haritz Moreno  2 , Karmele Valencia  3 , Naiara Perurena  4 , Pablo Ruedas  1 , Thomas Walle  5 , Alberto Pezonaga-Torres  1 , Juan Hinojosa  1 , Elisabet Guruceaga  6 , Antonio Pineda-Lucena  7 , Marta Abengozar-Muela  8 , Denis Cochonneau  9 , Carolina Zandueta  10 , Susana Martinez-Canarias  1 , Alvaro Teijeira  11 , Daniel Ajona  12 , Sergio Ortiz-Espinosa  2 , Xabier Morales  13 , Carlos Ortiz de Solorzano  14 , Marta Santisteban  15 , Luis I Ramos-Garcia  16 , Laura Guembe  17 , Vratislav Strnad  18 , Dominique Heymann  19 , Sandra Hervas-Stubbs  20 , Ruben Pio  21 , Maria E Rodriguez-Ruiz  22 , Carlos E de Andrea  23 , Silvestre Vicent  24 , Ignacio Melero  11 , Fernando Lecanda  25 , Rafael Martinez-Monge  26


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.

CITATION Cancer Discov. 2022 Jan 27;candisc.0932.2021.  doi: 10.1158/2159-8290.CD-21-0932.

Our authors

Borja Ruiz Fernández de Córdoba
Haritz Moreno Moreno
Laboratory technician Solid Tumor Research Program
Elizabet Guruceaga Martínez
Bioinformatics Research Technician Bioinformatics Platform
Carolina Zandueta Pascual
Research Technician Solid Tumor Research Program
Dr. Daniel Ajona Martínez-Polo
Dr. Xabier Morales Urteaga
Research Technician Image Platform
Laura Guembe Echarri
Research Collaborator Morphology Platform
Dr. Sandra Hervás Stubbs
Researcher | Principal Investigator Adoptive Cell Therapy Research Group