Molecular targets in health and disease: focus on PI3-kinase

ACCarrera

 

Ana C. Carrera

Group Leader

Contact

 

Research summary

Two biological problems have occupied the activity of our team (~12 to 15 members): cancer and inflammation. Our recent work is based in the assumption that the same biological activities that control physiological responses also control pathology when deregulated. The team is currently working on class I phosphoinositide 3-kinase (PI3K), with special emphasis on examining the specific function of each of the four class I PI3K isoforms in physiology and disease.

 

Publications

Olazabal-Morán M, González-García A, Carrera AC. Functions of Nuclear Polyphosphoinositides. . Handb Exp Pharmacol 2020; 259: 163-181

Vallejo-Díaz J, Chagoyen M, Olazabal-Morán M, González-García A, Carrera AC The Opposing Roles of PIK3R1/p85α and PIK3R2/p85β in Cancer. Trends Cancer 2019; 5(4):233-244.

Carrera AC & Anderson R. The cell biology behind the oncogenic PIP3 lipidsJ Cell Sci 132 2019; jcs228395

Varona R, Ramos T, Escribese MM, Jimeno L, Galán A, Würtzen PA, Vega F, Marín A, Martín S, Carrera AC, Blanco C, Barber D PPersistent regulatory T-cell response 2 years after 3 years of grass tablet SLIT: Links to reduced eosinophil counts, sIgE levels, and clinical benefitAllergy 2018; 74(2):349-360

Vallejo-Díaz J, Olazabal-Morán M, Cariaga-Martínez AE, Pajares MJ, Flores JM, Pio R, Montuenga LM, Carrera AC. Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma. Oncotarget 2016; 7:85063-78

Millán-Uclés Á, Zuluaga S, Marqués M, Vallejo-Díaz J, Sanz L, Cariaga-Martínez AE, Real FX, Carrera AC.  E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing. Oncotarget 2016; 7:84054-71

Funding

Ministerio de Ciencia innovacion logo Comunidad de Madridlogo AECC

 

 

decreased invadopodia in p85b def cellsOur group studies the molecular mechanisms by which signalling proteins control cell behaviour, and when altered, human cancer. In recent years we have focused on the enzymes that control PIP3 (phosphatidylinositol 3-phosphate), a little-abundant molecule in “resting tissues” but one which is required when cells need to divide or migrate - including in cancer. We have been involved in the following studies:

1) The action of PI3-kinase beta on hESC stemness/differentiation decision

PI3-kinase beta, one of the enzymes generating PIP3, localizes to the nucleus and regulates DNA replication, segregation and repair. We are studying its function in human stem cell (hESC) stemness/differentiation decisions.

2) Regulation of PTEN phosphatase activity under near-physiological conditions

PTEN phosphatase, which reduces PIP3 levels, is altered in many human tumours, most commonly during the metastatic phase. The main therapeutic approach for limiting PIP3 action in cancer has been to inhibit PI3-kinase enzymes. Nonetheless, boosting tumour PTEN phosphatase activity could be an alternative. We are involved in the study of how PTEN phosphatase activity is modulated after growth factor receptor activation, and whether boosting PTEN phosphatase may provide an anti-tumoral strategy.

3) PIP3 actions in TUMOR microenvironment: hypoxia and oxidative stress

In the course of our studies on the growth of human tumours as xenografts in mice, we noticed that interference with the action of PI3-kinases alters the response of cells to oxygen deprivation. Since solid tumours often grow in low oxygen conditions (hypoxia), we are investigating the crossroads between PIP3 regulation and the expression of the HIF transcription factors that mediate cell adaptation to low oxygen levels. The cells of solid tumours also show high levels of reactive oxygen species (ROS), partly due to their altered metabolism, conditions to which these cells have to adapt if they are to survive. A high percentage of lung tumours show activation of the NFE2L2 pathway, which protects them from ferroptosis death. The latter type of cell death is caused by the accumulation of oxidised lipids at the membrane; we are trying to define the role of NFE2L2 in lung cancer and interfere with its activity (Asociacion Española Contra el Cáncer).

 

defects in nucleocytoplasmic traffic in PIK3CB def cells

 grupoCarreraRed 

Name
Position
Contact
Ana Clara Carrera Principal investigator
Ana María González-García Postdoctoral scientist
Antonio Garrido Tárrio Postdoctoral scientist
África Millán Ucles Postdoctoral scientist
Sundhansu Yadav Postdoctoral scientist
Manuel Olazabal Morán Predoctoral scientist
Miriam Sánchez Ortega Predoctoral scientist
Carmen Hernández Agüero Technician
Lorena Sanz González Technician

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