Abstract
Disclosure: K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. S. Andonegui-Elguera: None. E. Sosa-Eroza: None. E. Gomez-Apo: None. A. Escobar-España: None. G. Guinto-Nishimura: None. B. Lopez-Felix: None. E. Zepeda-Fernandez: None. E. Estrada-Estrada: None. E. Cantu-Chavez: None. R. Arreola-Rosales: None. D. Marrero-Rodríguez: None. M. Mercado: None. Resistant and sensitive GH pituitary neuroendocrine tumors resolved by spatial transcriptomics Acromegaly results from a growth hormone secreting pituitary neuroendocrine tumor (GH-PitNET) in more than 98% of cases. GH-PitNET are the second most common functioning pituitary adenomas. Acromegaly is a chronic and systemic condition that significantly compromises life expectancy and quality of life as a consequence of its metabolic, cardiovascular, cerebrovascular and respiratory comorbidities. Surgical removal of the adenoma is the treatment of choice, yet over 30% of these patients require adjuvant pharmacological treatment with first generation somatostatin receptor ligands (fgSRL) to achieve disease control. SRL normalize IGF-1 levels in 30-50% of patients; thus, a significant proportion of patients are resistant to this treatment. The molecular mechanisms underlying such resistance to fgSRL are largely unknown. This study aimed to identify molecular markers of aggressiveness and SRL resistance using spatial transcriptomics in patients with GH-PitNET. WE also performed bulk RNAseq on a second group of SRL-resistant and SRL-sensitive GH-PitNET. Ethical approval was obtained from our institutional review board, and patients were recruited with signed informed consent. High intratumoral heterogeneity was observed in patients with SRL-sensitive tumors with 8 and 10 transcriptomic clusters, whereas the SRL-resistant patients had 8 and 9 transcriptomic clusters. Differential gene expression revealed a distinct profile of SRL-sensitive and SRL-resistant patients. The 3 predominantly expressed genes were HLA-A, LMO3 and PCP4L1 in SRL-resistant patients, and CBLN1, NF1 and PRL in SRL-sensitive patients. Enrichment analysis showed that ECM-receptor interaction, MAPK signaling pathway and WNT signaling pathway are altered in SRL-resistant, whereas Sphingolipid signaling pathway, various types of N-glycan biosynthesis and Cell adhesion molecules are altered in SRL-sensitive PitNET. Similar findings were observed in the second group. We then performed a cell cycle analysis, showing that most spots/clusters are in G0/G1 cell cycle phase with very low number of spots in S, G2/M and early G1, this results in disregard of the SA-response status. We previously showed that sphingolipid and MAPK signaling pathways are altered in aggressive and recurrent PitNET and could represent an attractive molecular target. Presentation: Monday, July 14, 2025