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

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...

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Autores: Ruiz-Fernandez-de-Cordoba, B. (Borja)|||/items/d8fd5d77-c85e-4c43-b6df-2b85dffa2816, Moreno-Moreno, H. (Haritz)|||/items/06a1cdf7-f60a-447e-9af7-0d68a02f4713, Valencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51f, Perurena, N. (Naiara)|||/items/0eb7aaca-5d38-49f0-a3c9-795763b8ffde, Ruedas, P. (Pablo)|||/items/e078e59f-02db-47e0-b6bc-d0b5b90c03a7, Walle, T. (Thomas)|||/items/c7678f08-39b8-417e-91b9-c5f6e9f722f6, Pezonaga-Torres, A. (Alberto)|||/items/5553d07b-6624-4483-b3d0-5f5140449000, Hinojosa, J. (Juan)|||/items/e1b8e596-9e37-4300-95d1-ab7b4dce4fda, Guruceaga-Martínez, E. (Elizabeth)|||/items/71d8df8b-4fab-4004-a38e-4057dddc85b2, Pineda-Lucena, A. (Antonio)|||/items/aabeed59-b8b3-4787-a803-a5fc7136ef9f, Abengozar-Muela, M. (Marta)|||/items/d95a49c9-6792-45d4-9f5b-326f0b0c6de2, Cochonneau, D. (Denis)|||/items/844eabcb-ff76-4256-a428-14cfa3e19f76, Zandueta, C. (Carolina)|||/items/87152e96-d7de-40b4-abe6-efa4a6fdac79, Martinez-Canarias, S. (Susana)|||/items/b468a404-1a10-4fd9-a479-7c62c85a4ad1, Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30, Ajona, D. (Daniel)|||/items/33f1d5ec-5a97-4d7f-a428-499e5075fc78, Ortiz-Espinosa, S. (Sergio)|||/items/366128c7-0213-4250-90c8-37cf8c008553, Morales-Urteaga, X. (Xabier)|||/items/0d40624e-57e2-4b06-a13a-90287a57b241, Ortiz-de-Solorzano, C. (Carlos)|||/items/b2c0bd13-68a7-437c-b67f-2e5f1a9f0324, Santisteban-Eslava, M. (Marta)|||/items/563d2cef-8a22-4110-97f4-8e16eac15419, Ramos, L.I. (Luis Isaac)|||/items/e153b271-46de-465e-b0c6-b429180a23c8, Guembe-Echarri, L. (Laura)|||/items/97f8ce8d-95cd-4a82-9a07-254d1f89f0e6, Strnad, V. (Vratislav)|||/items/ae58c8b3-42f2-4a49-abca-04c0b811a772, Heymann, D. (Dominique)|||/items/395262da-ffb6-402e-a5d2-25c71d4ed668, Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f, Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95, Rodriguez-Ruiz, M.E. (María Esperanza)|||/items/bb89f8c4-6380-4de3-8dd0-877dbf28ef44, Andrea, C.E. (Carlos Eduardo) de|||/items/e487698b-8d56-4c3e-8cba-40e33c78083a, Vicent-Cambra, S. (Silvestre)|||/items/20c60fd9-edba-4dba-942c-3669eb079816, Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e, Lecanda, F. (Fernando)|||/items/3fac5441-504d-4927-979a-5460140b12ec, Martinez-Monge, R. (Rafael)|||/items/4f936ddc-91ab-4824-b659-c6c6dab6698b
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/116323
Acceso en línea:https://hdl.handle.net/10171/116323
Access Level:acceso abierto
Palabra clave:Breast Cancer
Locoregional failure
Descripción
Sumario: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.

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