MON-051 Spatial Transcriptomics Reveals Metabolically Altered Senescent Clones In Aggressive, Therapy-resistant Lactotroph Pitnet

Abstract Disclosure: D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. S. Andonegui-Elguera: None. E. Sosa-Eroza: None. E. Gomez-Apo: None. A. Escobar-España: None. A. Moscona Nissan: None. G. Guinto-Nishimura: None. B. Lopez-Felix: None. E. Zepeda-Fernandez: None. C. Victor: None. P. Gonzalez-Zavala: None. M. Asenscio-Montiel: None. M. Garcia-Vargas: None. E. Cantu-Chavez: None. R. Arreola-Rosales: None. M. Mercado: None. Lactotroph pituitary neuroendocrine tumors (PRL-PitNET) are the most common functioning pituitary neoplasm, accounting for 50% of all pituitary tumors. About 15% behave aggressively with rapid growth despite dopamine agonist (DA) therapy. Lactotroph carcinomas resemble aggressive PRL-PitNET but feature craniospinal or distant metastases. This study aimed to identify molecular markers of aggressiveness and DA resistance using spatial transcriptomics, as well as whole exome and transcriptome sequencing in patients with aggressive, DA-resistant PRL-PitNET. Ethical approval was obtained from our institutional review board, and patients were recruited with signed informed consent.The evaluated tumors contained a few stem cells, a high number of tumor cells, and a relatively low number of endothelial cells and macrophages. Each tumor showed from 3 to 10 transcriptional clusters. Interestingly, when senescence was analyzed, tumors showed only two main clusters, one with high a senescence score and a second one with a low score. The trajectory correlated with the senescence score, indicating a transition from a high to a low senescent profile. We found a close association between the metabolic alterations and the senescence landscape. Particularly, high-score senescence clusters showed alterations in glycerolipid, phospholipid, glycerophospholipid and phosphatidylinositol metabolic processes. The high senescence metabolically altered clusters showed alteration in PI3K-AKT signaling, linking metabolism with pathways regulating senescence in aggressive PRL-PitNET. We also performed cell potency and epithelial-mesenchymal transition (EMT) analysis to identify if there was any de-differentiation process or any EMT process, showing no cell state regression. The cell proliferation analysis showed that most spots in all tumors were predominantly in G1/G0 phase of the cell cycle. Exome-seq showed SF3B1 and TP53 pathogenic variants in one tumor each. Altogether, metabolically altered, senescent clones correlate with pharmacologically-resistant and aggressive PRL-PitNET. It remains to be elucidated whether these alterations are induced by DA or are inherent to these neoplasms. Presentation: Monday, July 14, 2025