Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [64Cu][Cu(ATSM)] PET and proteomic studies

Jade Fantin (1) , Jérôme Toutain (1) , Elodie A. Pérès (1) , Benoit Bernay (2) , Sarina Maya Mehani (1) , C Hélaine (1) , Mickael Bourgeois (3, 4) , Carole Brunaud (1) , L Chazalviel (1) , Julien Pontin (2) , Aurélien Corroyer-Dulmont (1, 5) , Valable Samuel (1) , Michel Chérel (3, 4) , Myriam Bernaudin (1)

1 ISTCT - Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux
2 Plateforme PLATIN’, US EMPlateforme PLATIN’, US EMerode, Normandie Université, Unicaen, Caen, France
3 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
4 GIP ARRONAX [Nantes]
5 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]

Background Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. Results First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [ 64 Cu] [Cu(ATSM)] PET revealed a significant uptake by cortical BM (p < 0.01), while no uptake is observed in striatal BM 23 days after tumor implantation. Pimonidazole, HIF-1α, HIF-2α, CA-IX as well as GFAP, CTR1 and DMT1 immunostainings are positive in both BM. Conclusion Overall, [ 64 Cu][Cu(ATSM)] imaging and proteomic results showed the presence of hypoxia and protein expression changes linked to hypoxia and oxidative stress in BM, which are more pronounced in cortical BM compared to striatal BM. Moreover, it emphasized the interest of [ 64 Cu][Cu(ATSM)] PET to characterize TME of BM and depict inter-metastasis heterogeneity that could be useful to guide treatments.

Mots clés: Brain metastasis; Lung cancer; Hypoxia; HIF; Oxidative stress; Cu-ATSM; Imaging; Proteomic; Preclinical; Rodent; Copper-64; PET

Domaines: Sciences du Vivant [q-bio]

Jade Fantin, Jérôme Toutain, Elodie A. Pérès, Benoit Bernay, Sarina Maya Mehani, et al.. Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [64Cu][Cu(ATSM)] PET and proteomic studies. EJNMMI Research, 2023, 13 (102), ⟨10.1186/s13550-023-01052-8⟩. ⟨hal-04308804⟩