Cellular and molecular responses to hypoxia

Insufficient supply of oxygen (hypoxia) is a characteristic of many lethal pathologies with unmet medical needs such as the growth of solid tumours, chronic obstructive pulmonary disease (COPD), ischaemic diseases and obesity. Cells are equipped with oxygen sensor systems that trigger a programmed response when oxygen is limited.

Hypoxia-inducible factors (HIF1, HIF2 and HIF3) are central regulators of this cellular response to oxygen fluctuations. The focus of our current research is the role of HIF-dependent oxygen sensory pathways in cancer, lung disease and obesity. In particular, we are primarily interested in the reprogramming of cellular metabolism, which is one of the fundamental biological functions performed by HIF factors.

1.- HIF factors and renal cell carcinoma: HIF factors are induced in hypoxic areas in the inner nucleus of solid tumours, but clear cell renal carcinoma (ccRCC) – in which Vhl is lost (the main HIF repressor in normoxia) – shows a constitutive expression of HIF regardless of oxygen levels in the tumour. In these tumours, HIF1 shows its antiproliferative capacity in an autonomous cell form, while HIF2 acts as an oncoprotein. Therefore, ccRCCs are being studied extensively to try to understand the role of HIF in cancer biology. Our studies have shown that HIF2a isoform acts as an mTORC1 activator through the SLC7A5 amino acid transporter, which is essential to maintaining tumour growth in ccRCC. We have recently found a new connection between glucose and lipid metabolisms and HIF factors, which has a notable impact on ccRCC progression. Independent of these ccRCC tumour metabolism projects, we have recently initiated a project for the identification of new molecular connections between HIF-dependent pathways and tumour immunology.

2.- HIF factors and respiratory tract dysfunction in lung disease: Lung diseases such as chronic obstructive pulmonary disease (COPD) and sleep apnoea-hypopnoea syndrome (SAHS) are the most common fatal respiratory diseases, and are predicted to be the world’s third leading cause of death by 2020. They are characterised by an insufficient level of oxygen in the blood (hypoxaemia), continuous in COPD and intermittent in SAHS, and are associated with oxidative lung damage, an exaggerated inflammatory response in the lung and at the systemic level. Notably, although lung tissue – bronchial epithelium – is a first barrier to oxygen, the role of HIF oxygen sensitivity responses in pulmonary pathophysiology is still largely unknown. Based on our recent studies on HIF pathways as proliferative marker activators in bronchial epithelium, including mTORC1, we are currently studying, in collaboration with other IIS-Princesa researchers (Dr Julio Ancochea), the role of HIF-dependent oxygen sensor pathways in (i) lung protection and repair (ii) ventilation and (iii) their potential to identify new biomarkers for the diagnosis and prognosis of fatal respiratory diseases.

3.- HIF factors in white adipose tissue and obesity: obesity and associated disorders have become the most prominent pathologies of the 21st century. This is particularly relevant in the ageing population, which is more prone to obesity. We have characterised the molecular changes that occur in humans and mice during the progressive increase of visceral white adipose tissue (WAT). We found a specific metabolic reprogramming through HIF1α during the expansion of WAT in mice. Since genetic approaches to the study of visceral WAT biology are still limited, we have established in vivo techniques to explore the role of autonomous metabolism in the expansion of WAT. By directing short-hairpin lentiviral sequences locally to a WAT store in the epididymis, and using the other side as a control, we have investigated the role of several metabolic pathways in the enlargement of white adipocytes.

Team members

area-1_Linea-2_G9_Dr_AragonesGroup leader:

Julián Aragonés López

Universidad Autónoma de Madrid – Hospital Universitario Santa Cristina

  Other team members. Hospital Universitario La Princesa:

  • Antonio Bouthelier de Pedro
  • Ainara Estibaliz Elorza Peregrina
  • Esther Fuertes Yebra
  • Florinda Meléndez Rodríguez
  • Claudia Mesa Ciller
  • Ángel Ordoñez Navadijo
  • Manuel Ortiz de Landázuri Busca
  • Inés Soro Arnaiz
  • María del Mar Torres Capelli
  • Andrés Amalio Urrutia Elorduy
  • Qilong Oscar Yang Li
Aragonés López. Potentiation of mitochondrial activity in adipose tissue as therapeutical strategy for obesity and type 2 diabetes: interplay between oxygen sensing and neuregulin signaling. 534/C/2016. Marató TV3. 2016-2019.

Aragonés López, Julián. Role of HIF oxygen response factors in pulmonary pathology and non-invasive diagnostic/prognostic biomarkers in respiratory disease. SAF2013-46058-R. MINECO. 2014-2016.

Aragonés López, Julián. CONSEPOC: Inflammation and hypoxia: mechanisms of development and progression of COPD and SAHS. S2010/BMD-2542. CAM. 2012-2015.

Ortiz de Landazuri Busca, Manuel. RECAVA: Cardiovascular Research Network. RD12/0042/0065. ISCIII. 2013-2016.

Ortiz de Landazuri Busca, Manuel. Inflammation and hypoxia: mechanisms of development and progression of COPD and SAHS. S2010/BMD-2542. CAM. 2012-2015.

Elorza, Ainara, Soro-Arnaiz, Ines, Melendez-Rodriguez, Florinda, Rodriguez-Vaello, Victoria, Marsboom, Glenn, de Carcer, Guillermo, Acosta-Iborra, Barbara, Albacete-Albacete, Lucas, Ordonez, Angel, Serrano-Oviedo, Leticia, Miguel Gimenez-Bachs, Jose, Vara-Vega, Alicia, Salinas, Antonio, Sanchez-Prieto, Ricardo, Martin del Rio, Rafael, Sanchez-Madrid, Francisco, Malumbres, Marcos, Landazuri, Manuel O., Aragones, Julian. HIF2 alpha Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5. Mol. Cell 2012. 48: 681-691. FI: 15.280(Q1). PMID: 23103253. DOI: 10.1016/j.molcel.2012.09.017.

Palazón A, Martínez-Forero I, Teijeira A, Morales-Kastresana A, Alfaro C, Sanmamed MF, Perez-Gracia JL, Peñuelas I, Hervás-Stubbs S, Rouzaut A, de Landázuri MO, Jure-Kunkel M, Aragonés J, Melero I. The HIF-1 alpha Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy. Cancer Discov. 2012. 2: 608-623. FI: 10.143(Q1). PMID: 22719018. DOI: 10.1158/2159-8290.CD-11-0314.

Tello, Daniel, Balsa, Eduardo, Acosta-Iborra, Barbara, Fuertes-Yebra, Esther, Elorza, Ainara, Ordonez, Angel, Corral-Escariz, Maria, Soro, Ines, Lopez-Bernardo, Elia, Perales-Clemente, Ester, Martinez-Ruiz, Antonio, Antonio Enriquez, Jose, Aragones, Julian, Cadenas, Susana, Landazuri, Manuel O. Induction of the Mitochondrial NDUFA4L2 Protein by HIF-1 alpha Decreases Oxygen Consumption by Inhibiting Complex I Activity. Cell Metab 2011. 14: 768-779. FI: 13.668(Q1). PMID: 22100406. DOI: 10.1016/j.cmet.2011.10.008.

Miro-Murillo, Marta, Elorza, Ainara, Soro-Arnaiz, Ines, Albacete-Albacete, Lucas, Ordonez, Angel, Balsa, Eduardo, Vara-Vega, Alicia, Vazquez, Silvia, Fuertes, Esther, Fernandez-Criado, Carmen, Landazuri, Manuel O., Aragones, Julian. Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression. PLoS One 2011. FI: 4.092(Q1). PMID: 21811636. DOI: 10.1371/journal.pone.0022589.

Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragonés J, Mazzone M, Mairbäurl H, De Bock K, Jeoung NH, Mollenhauer M, Georgiadou M, Bishop T, Roncal C, Sutherland A, Jordan B, Gallez B, Weitz J, Harris RA, Maxwell P, Baes M, Ratcliffe P, Carmeliet P. Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. Gastroenterology 2010. 138: 1143-438. FI: 12.032(Q1). PMID: 19818783. DOI: 10.1053/j.gastro.2009.09.057.