Effect of Hoxb7 gene editing with CRISPR/Cas9 in lung cancer metastasis

• Grant number: 24/21803-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: August 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Cesar Seigi Fuziwara
• Grantee: Pedro Lucas da Silva Oliveira
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/17282-5 - Transcriptional and post-transcriptional control in aggressive cancer and metastasis, AP.JP

Abstract

Lung cancer stands as the second most common cancer and the leading cause of cancer-related mortality worldwide. In 2022, 2,480,675 new cases of lung, tracheal, and bronchial cancer were diagnosed, and 1,817,469 deaths were attributed to lung cancer. Its high mortality is closely linked to late-stage diagnoses, as early tumors often present no symptoms that would warrant investigation. Molecular alterations activating the MAPK pathway through mutations in KRAS (~33%), EGFR (~14%), and BRAF (~10%) are generally associated with the oncogenesis of lung cancer, the most prevalent histological subtype being adenocarcinoma. This subtype is characterized by a high metastatic rate, leading to rapid disease progression and patient death. However, our molecular understanding of the metastatic process remains insufficient to develop permanent curative interventions for lung cancer patients. Consequently, the search for novel mechanisms driving tumor aggressiveness has gained significant attention, including the role of microRNAs, epigenetic modifications, and the acquisition of stem cell-like and pluripotent phenotypes. Indeed, our research group has demonstrated that the activation of chromatin remodelers, such as the PRC2/EZH2 complex, along with the inhibition of pulmonary microRNAs and transcription factors, is associated with metastasis. Transcriptomic analyses of pulmonary metastases excised from the liver of mice revealed the activation of several Hox gene clusters. Hox genes are critical for determining the anterior-posterior axis during embryonic development, and their dysregulation has been implicated in tumorigenesis and tumor aggressiveness. Therefore, this project aims to investigate the role of Hox gene activation in metastatic lung cancer, focusing particularly on studying the effects of Hoxb7 gene editing using CRISPR/Cas9 in metastasis.