Hypoxia, GALR2 and macrophage phenotype crosstalk in the microenvironment of head and neck squamous cell carcinoma (HNSCC)

• Grant number: 24/16531-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 15, 2025
• End date: December 30, 2025
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Carlos Rossa Junior
• Grantee: Ianny Brum Reis
• Supervisor: Arnaud Millet
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Institut Pour L'Avancée Des Biosciences, France
• Associated to the scholarship: 22/06041-0 - Efferocytosis in the microenvironment of Oral Squamous Cell Carcinoma: impact on immune response and tumor progression and dissemination, BP.PD

Abstract

Hypoxia is a critical feature of most solid cancers, affecting neoplastic cell processes such as survival, metabolism and phenotype. Hypoxic conditions trigger a cellular response aimed at adaptation for survival, which is largely mediated by stabilization of normally short-lived hypoxia-induced factors (HIFs). HIFs interact with other proteins and induce transcription of target genes containing a hypoxia-responsive element (HRE) motif in their promoter region. The two most studied isoforms of the heterodimeric HIFs are HIF-1¿ and HIF-2¿, but there is limited and controversial information on the role of HIF-2¿ in HNSCC. Another protein with controversial evidence regarding its role in HNSCC is GALR2. Interestingly, hypoxia and GALR2 may promote similar tumor progression-associated processes (cell survival, EMT/invasion, angiogenesis) and induce expression of similar genes (e.g., VEGF, TGF¿). There is evidence indicating that both hypoxia and GALR2 signaling affect the immune response, particularly the phenotype of macrophages. Macrophages are the most prevalent immune cell type in HNSCC, where they may make up to 50% of the tumor mass. Greater overall infiltration by macrophages and, particularly, of cells with an M2-like phenotype are correlated with worse prognosis and poorer response to treatment. Both hypoxia and GALR2 signaling may skew macrophages to the M2-like phenotype, thus it is conceivable that these two aspects (hypoxia and GALR2 signaling) interact in the HNSCC microenvironment. The hypothesis for the proposed experiments is that a crosstalk between hypoxia and GALR2 signaling (in neoplastic cells and macrophages) promote HNSCC progression and impair response to treatment. We intend to verify the association of hypoxia and GALR2 expression/signaling in HNSCC using patient-derived samples (ex-vivo approach) and through in vitro studies determine the influence of hypoxia and GALR2 signaling both independently and simultaneously on neoplastic cells and macrophages. The results of the proposed experiments will expand the findings of the research projects (post-doctoral project and research grant awards) associated with this application.