title: Cell of origin and fusion variants of Eml4-Alk in non-small cell lung cancer
creator: Chocarro Pérez de Azanza, Sara
subject: ddc-570
subject: 570 Life sciences
description: Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal forms of cancer worldwide. EML4-ALK is a fusion gene that arises from a chromosomal translocation between the echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) genes. This fusion gene has been found in approximately 5-7% of NSCLC cases, making it an important therapeutic target for this disease. Therefore, this thesis aimed to understand the molecular and biological mechanisms underlying EML4-ALK variants in NSCLC, in order to provide insights into the development and progression of this disease which could lead to more effective therapies.  To study the most prevalent Eml4-Alk variants in NSCLC, I made use of an available adenoviral system to induce the endogenous V1 rearrangement in mouse lungs, and generated a similar system to induce the V3 fusion gene. The results of this thesis revealed that the Eml4-Alk V3 rearrangement induced a diverse range of lung adenocarcinomas, including papillary lesions, solid and lepidic adenocarcinomas, as well as squamous cell carcinomas (SCC). Interestingly, SCC had not been previously observed in the Eml4-Alk V1 model.  Careful examination of the mice uncovered that the V3 model induced a significantly reduced overall survival rate compared to V1, correlating with a more aggressive phenotype of this variant observed in patients. This study also demonstrated that V1 cells undergo DNA damage and apoptosis early upon transformation, which could be the reason of the delayed death of V1 mice. Further results suggested that this early phenotype in V1 mice was most probably related to the Tp53 pathway, since loss of Trp53 induced a reduction in the overall survival rate and increased the number of tumors in V1 mice but not V3 mice.  NSCLC is a heterogeneous disease with diverse molecular subtypes and one of the critical factors that contribute to the variability in NSCLC is the cell of origin. Understanding the cell of origin of NSCLC helps to identify the molecular mechanisms and signaling pathways that drive the cancer's development, progression, and response to therapy and to identify new biomarkers for early detection and prognosis. In this thesis, I observed that V3 tumors were derived from club and alveolar type 2 (AT2) cells, consistent with previous findings in V1, and that those with an AT2 origin seem to be more aggressive. Additionally, time course single-cell RNA sequencing of the development of V1 club tumors revealed that club cells use their intrinsic regeneration mechanisms during the process of tumor development.  Taken together, these findings provide important insights into the complexity of EML4-ALK variants in NSCLC and the diverse ways in which these variants contribute to the development of this disease. They highlight the need for further investigation into the mechanisms underlying EML4-ALK variants, in order to guide the development of more effective treatments for NSCLC.
date: 2024
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserver/33702/1/Thesis%20Sara%20Chocarro.pdf
identifier: DOI:10.11588/heidok.00033702
identifier: urn:nbn:de:bsz:16-heidok-337027
identifier:   Chocarro Pérez de Azanza, Sara  (2024) Cell of origin and fusion variants of Eml4-Alk in non-small cell lung cancer.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33702/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng