Targeting Durotaxis in Pulmonary Fibrosis and Pancreatic Cancer

• Autores: Alba Santos Hipólito
• Directores de la Tesis: Santiago Lamas Peláez (dir. tes.), David Lagares Salto (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2020
• Idioma: inglés
• Número de páginas: 110
• Tribunal Calificador de la Tesis: Maria Molina Molina (presid.), Fernando Rodríguez Pascual (secret.), José Luis Alonso Castellano (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Biología molecular
  • Ciencias médicas
    • Medicina interna
      • Enfermedades pulmonares
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Organ fibrosis, characterized by a pathological deposit of extracellular matrix, is a major component of numerous human diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, diabetic nephropathy or pancreatic cancer among others. Finding effective anti-fibrotic therapies will require a better understanding of the molecular mechanisms that underlie the onset and progression of organ fibrosis.

    Tissue fibrosis is characterized by deposition and crosslinking of extracellular matrix proteins including collagen type I, leading to increased matrix stiffness. Recent studies have shown that matrix crosslinking is sufficient to drive and amplify fibrotic responses by promoting mechanoactivation of myofibroblasts, the effector cells in fibrosis. The mechanobiology of organ fibrosis as well as the mechanisms by which matrix stiffness promotes fibrosis remain poorly understood.

    In this thesis, we have investigated the role of matrix stiffness gradients at promoting the pathological recruitment of fibroblasts to sites of injury via a process known as “durotaxis”. Our central hypothesis is that durotaxis drives and amplifies tissue fibrosis by promoting fibroblast recruitment. First, we have studied the role of the FAK-Paxillin axis at controlling fibroblast durotaxis in lung fibrosis.

    Our data indicate that pharmacological inhibition of FAK-Paxillin interaction with JP-153 blocks fibroblast durotaxis but not chemotaxis and prevents the development of lung fibrosis in experimental models. In addition, we have investigated the role of microtubule acetylation in fibroblast durotaxis. Our results indicate that the enzyme α-TAT1 promotes the acetylation of α-tubulin on lysine 40 at the leading edge on durotaxing cells, and that genetic inhibition of α-TAT1 inhibits fibroblast durotaxis but not chemotaxis. Furthermore, α-TAT1-deficient mice showed protection from lung fibrosis in experimental models, indicating that targeting fibroblast durotaxis may represent a novel therapeutic strategy to treat lung fibrosis.

    Finally, we have demonstrated that tumor cells from patients with pancreatic cancer show increased durotactic capacity in vitro, suggesting a potential role for durotaxis at initiating the metastatic cascade.