Analysis of senescence in pituitary tumors from different lineages and the potential role of senolytic drugs as targeted therapies.
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Andonegui-Elguera Sergio, Gonzalez-Serrano Maria J, Mercado-Medrez Sophia, Hinojosa-Alvarez Silvia, Martinez-Mendoza Florencia, Ramirez-Ramos Itzel, Reyna-Coahutle Leilani A, Sanchez-Carbajal Arzu Y, Hernandez-Bustos Stefany R, Alegria-Ortega Alejandro, Gonzalez-Mejlem Jose M, Garcia-Saenz Manuel R, Gomez-Apo Erick, Escobar-España Aurea, Gonzalez-Torres Carolina, Gaytan-Cervantes Javier, Palma-Guzman Alam, Guinto Gerardo, Guinto-Nishimura Gerardo Y, Lopez-Felix Blas E, Zepeda-Fernandez Erick U, Estrada-Estrada Erick M, Correa-Correa Victor, Gonzalez-Zavala Pedro A, Asenscio-Montiel Marco A, Garcia-Vargas Miguel A, Cantu-Chavez Emmanuel, Chavez-Herrera Victor R, Arreola-Rosales Rocio L, Vadillo Eduardo, Chavez-Gonzalez Antonieta, Fajardo-Orduña Guadalupe R, Montesinos Juan Jose, Monroy-Garcia Alberto, Cortes-Morales Victor A, Mendez-Rosito Diego, Garcia-Lopez Isai, Ramirez-Landeros Joshua, Garcia-Fuentes Diego A, Vergara-Lopez Alma, Torres-Flores Hugo, Taniguchi-Ponciano Keiko, Marrero-Rodriguez Daniel, Mercado Moisés
Аннотация
METHODS: We performed spatial transcriptomics (ST) in dopamine agonist resistant prolactin secreting PT, as well as single nucleus RNAseq (snRNAseq) in growth hormone secreting and non-functioning of gonadotropic differentiation PT to describe the senescence, proliferative and stemness landscapes. Bioinformatic analyses included clustering, senescence scoring (SenePy), cell cycle inference (ccAFv2), differentiation potential (CytoTRACE2), and EMT signature evaluation. Primary tumor cell cultures were established to validate senescence (β-galactosidase activity) and to assess the senolytic effect of dasatinib.
RESULT: All PT included in the study were transcriptomically heterogeneous, showing between three and ten transcriptional clusters. Senescence analysis reveals two main clusters regardless of PT lineage: One with a high and the other one with low senescence score. Most spots contain terminally differentiated cells at phase G1/G0 of the cell cycle. Distinct alteration in different signaling pathways were found in clusters with low senescence score: PI3K-cascade-FGFR1 and inositol phosphate metabolism among prolactin secreting tumors, phosphatidyl inositol signaling system and serine/threonine kinase activity the in GH-secreting PT, sphingolipid signaling pathway and serine/threonine kinase alterations among non-functioning of gonadotropic differentiation PT. Dasatinib treatment of primary cell cultures of pituitary tumors of different lineages showed significant dose-dependent cell death, accompanied by caspase-3/7 activation and morphological changes consistent with apoptosis.
CONCLUSION: Our data show that PT may contain senescent and terminally differentiated cells without any EMT evidence, and dasatinib could represent an alternative for therapy resistant PT.