IGF1R as a pharmacological target in allergic asthma and cancer-promoting factor in the lung tumor microenvironment

  1. Elvira Alfaro Arnedo
Supervised by:
  1. José Manuel García Pichel Director
  2. Iciar Paula López García Director

Defence university: Universidad de La Rioja

Year of defence: 2021

  1. Isabel Varela Nieto Chair
  2. Carmen Torres Manrique Secretary
  3. Rubén Pío Osés Committee member
  1. Agriculture and Food
Doctoral Programme:
  1. Programa de Doctorado en Ciencias Biomédicas y Biotecnológicas por la Universidad de La Rioja y la Universidad de Zaragoza

Type: Thesis


Background: IGF1R (Insulin-like Growth Factor 1 Receptor) is a ubiquitous tyrosine kinase that modulates multiple cellular functions including proliferation, growth, differentiation and survival. Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Lung cancer is a leading cause of malignant diseases, given the long-term ineffectiveness of current therapies and late-stage diagnoses, and tumor progression is influenced by cancer cell interactions with the tumor microenvironment (TME). Although IGF1R was found to be involved in asthma and reported to affect the TME, pharmacological inhibition of IGF1R in asthma and its role in the lung TME have not previously been investigated. Methods: C57BL/6J mice were challenged by house dust mite (HDM) extract or PBS for four weeks and therapeutically treated with the IGF1R tyrosine kinase inhibitor (TKI) NVP-ADW742 (NVP) once allergic phenotype was established. The correlation of IGF1R with established clinical biomarkers of allergic asthma was also studied. On the other hand, we assessed IGF1R genomic alterations and expression in non-small-cell lung cancer (NSCLC) patient tissue samples as well as IGF1R serum levels. Moreover, we performed tumor heterotopic transplantation and pulmonary metastases in IGF1R-deficient mice using melanoma and Lewis lung carcinoma (LLC) cells. Results: Lungs of HDM-challenged mice exhibited a significant increase in phospho-IGF1R levels, incremented AHR, airway remodeling, eosinophilia and allergic inflammation, as well as altered pulmonary surfactant expression, being all of these parameters counteracted by NVP treatment. HDM-challenged lungs also displayed augmented expression of the IGF1R signaling mediator p-ERK1/2, which was greatly reduced upon treatment with NVP. Furthermore, serum IGF1R levels in patients with allergic asthma were significantly increased as compared to healthy subjects and correlated with IgE levels and circulating eosinophils. On the other hand, increased amplification and mRNA expression, as well as increased protein expression (IGF1R /p-IGF1R) and IGF1R levels were found in tumor samples and serum from NSCLC patients, respectively. Moreover, IGF1R deficiency in mice reduced tumor growth, proliferation, inflammation and vascularization, and increased apoptosis after tumor heterotopic transplantation. Following induction of lung metastasis, IGF1R-deficient mice exhibited a decreased presence of leukocytes in bone marrow and BALF, and attenuated IL6 and TNFα serum levels. IGF1R-deficient lungs also demonstrated a reduced tumor burden, and decreased expression of tumor progression markers, p-IGF1R and p-ERK1/2. Additionally, IGF1R-deficient lungs showed increased apoptosis and diminished proliferation, senescence, vascularization, epithelial-mesenchymal transition (EMT) and fibrosis, along with attenuated inflammation and immunosuppression upon induction of lung metastasis. Conclusions: These findings demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and that IGF1R promotes metastatic tumor initiation and progression in the lung TME. In addition, IGF1R is suggested to be a candidate biomarker in allergic asthma and in early prediction of drug response and clinical evolution in NSCLC patients.