Signalling networks in inflammation and cancer



Santos Mañes

Group Leader



Research summary

Inflammation is essential for effective defence of the organism against harmful stimuli such as pathogens, irritants or tissue damage. Discovery of the detailed processes of inflammation has revealed a close relationship between the inflammatory reaction and the immune response. Indeed, a hallmark of inflammation is the directed migration (chemotaxis) of inflammatory cells (mostly leukocytes) through blood vessel walls to the site of injury. Nonetheless, a deregulated response to tissue damage might lead to autoimmunity and chronic inflammatory diseases, and can also promote cancer.



Mira E, Carmona-Rodríguez L, Pérez-Villamil B, Casas J, Fernández-Aceñero MJ, Martínez-Rey D, Martín-González P, Heras-Murillo I, Paz-Cabezas M, Tardáguila M, Oury TD, Martín-Puig S, Lacalle R, Fabriás G,  Díaz-Rubio E, Mañes S. SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α. Nature Communications 2018; 9:389

Rackov G, Hernández-Jiménez E, Shokri R, Carmona-Rodríguez L, Mañes S, Álvarez-Mon M, López-Collazo E, Martínez-A C, Balomenos D. p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β. J Clin Invest 2016; 126: 3089-10

Ogando J, Tardáguila M, Díaz-Alderete A, Usategui A, Miranda-Ramos V, Martínez-Herrera DJ, de la Fuente L, García-León MJ, Moreno MC, Escudero S, Cañete JD, Toribio ML, Cases I, Pascual-Montano A, Pablos JL, Mañes S. Notch-regulated miR-223 targets the aryl hydrocarbon receptor pathway and increases cytokine production in macrophages from rheumatoid arthritis patients. Sci Rep 2016; 6: 20223

García-Castro A, Zonca M, Florindo-Pinheiro D, Carvalho-Pinto CE, Cordero A, Gutiérrez del Fernando B, García-Grande A, Mañes S, Hahne M, González-Suárez E, Planelles L. APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer. Carcinogenesis 2015; 36: 574-84

Lacalle RA, de Karam JC, Martínez-Muñoz L, Artetxe I, Peregil RM, Sot J, Rojas AM, Goñi FM, Mellado M, Mañes S. Type I phosphatidylinositol 4-phosphate 5-kinase homo- and heterodimerization determines its membrane localization and activity. FASEB J 2015; 29: 2371-85


Mañes Image2RedInflammation is a defence response of the organism to harmful internal and external stimuli. Detailed study of inflammation processes revealed a close relationship between the inflammatory reaction and the immune response. We thus expanded our initial focus on leukocyte migration to study factors and cell-cell interactions that regulate the many facets of inflammation, including differentiation of inflammatory leucocytes and changes in the endothelium that irrigates the site of injury. In 2015-2016, we worked in three areas:

  1. Characterization of the CXCR4 interaction with the actin-binding protein filamin-A.
    CXCR4 is a chemokine receptor involved in several human pathologies, including HIV-1 infection and tumour metastasis. Inherited mutations in CXCR4 also cause a rare immunodeficiency termed WHIM syndrome. WHIM mutations generate receptors with impaired endocytosis after agonist binding, leading to receptor hyperactivation. We demonstrated that interference with the CXCR4/filamin-A interaction restores internalization of WHIM mutant receptors, which provides a new therapeutic strategy for this rare, incurable disease.
  2. Macrophage differentiation in neurological and autoimmune diseases.
    Innate immune cells, particularly macrophages, are major conductors of the inflammatory reaction. Depending on their polarization, macrophages can activate a “healing programme”, which in cancer boosts tumour progression, or a “tissue destruction programme”, as occurs in autoimmune rheumatoid arthritis (RA). We found that upregulation of microRNA (miR)-223 distinguishes macrophages from RA patients with active disease from less inflammatory macrophages from osteoarthritic patients. miR-223 targets the aryl hydrocarbon receptor pathway, increasing production of pro-inflammatory cytokines and inflammation.
  3. Normalization of tumour-associated vasculature.
    The endothelium is a semipermeable barrier that regulates transfer of oxygen, endoand xenobiotics, as well as tumour and immune cell diapedesis. Progressing tumours are characterized by aberrant angiogenesis but are unexpectedly highly hypoxic. The consequence is dysfunctional tumour vasculature, which reduces perfusion of tumour tissue. We showed that extracellular superoxide dismutase (SOD3) normalizes tumour vasculature, thus increasing delivery of chemotherapeutic drugs and enhancing tumour immunity.

Mañes Image1Red

 Grupo SManesRed 

Santos Mañes Principal investigator
Emilia Mira Senior scientist
Rosa Ana Lacalle Senior scientist
Raquel Blanco Postdoctoral scientist
Laura del Barrio Postdoctoral scientist
Lorena Carmona-Rodríguez Predoctoral scientist
Ana Martín Leal Predoctoral scientist
Javier Santos Arenal Predoctoral scientist
Rosa M. Peregil Technician

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