ECEESPE2025 Oral Communications Oral Communications 4: Pituitary, Neuroendocrinology and Puberty Part 1 (6 abstracts)
Exploration of pituitary stem cells heterogeneity and their contribution in gonadotroph tumors
Álvaro Flores-Martínez 1 , Marie Chanal 1 , Marine Daura 1 , Benoit Samson 1,2 , Alexandre Vasiljevic 1,3 , Lasolle Hélène 1,4 , Mirela Ilie 1 , Emmanuel Jouanneau 1,5 , Ghislain Durif 2 , Olivier Gandrillon 2 , David Bernard 1 , Raul M. Luque 6 , Franck Picard 2 , Gerald Raverot 1,4 & Philippe Bertolino 1
1Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon 1 University, Lyon, France; 2LBMC, ENS de Lyon, CNRS UMR 5239, Inserm U1293, Université Claude Bernard Lyon 1, Lyon, France; 3Pathology Department, “Groupement Hospitalier Est” Hospices Civils de Lyon, Bron, France; 4Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, “Groupement Hospitalier Est” Hospices Civils de Lyon, Bron, France; 5Neurosurgery Department, “Groupement Hospitalier Est” Hospices Civils de Lyon, Bron, France; 6Maimónides Biomedical Research Institute (IMIBIC); University of Cordoba, Department of Cell Biology, Physiology and Immunology, Córdoba, Spain
JOINT3502
Pituitary tumors (PiTs) are heterogeneous intracranial neoplasms with limited personalized treatment options. Despite significant advances in understanding their genetics, epigenetics, and the cellular composition of their microenvironment, the underlying processes driving their tumorigenesis and heterogeneity remain poorly understood. The use of single-cell omics and tumour-derived cultures has confirmed the existence of various stem cell (SC) populations in all PiT-subtypes, raising questions about their role in tumorigenesis. Interestingly, while physio-pathological insults activate mouse pituitary SC (PSC) differentiation into endocrine pituitary lineages, their functional contribution has never been addressed in the context of murine tumours or human pituitary adenomas. Here, we questioned the heterogeneity and function of intratumoural PSCs using animal models, single cell-/spatial-omics, and patient-derived primary cultures. Through these approaches, we first confirmed that tumour growth, whether resulting from the orthotopic injection of tumour-cells or the consequences of aging, drives a remodelling of the SC-rich marginal zone (MZ). This was supported by the identification of MZ-budding structures containing SOX2+ cells and their expression of tumour-associated SCs (TA-SCs) markers. Following this observation, we confirmed the presence and the heterogeneity of SCs between 44 gonadotroph tumours (0.02%-4.78% SOX2+ cells). Bioinformatic analysis of single-nuclei sequencing (SnPatho-Seq) performed on three tumours with the highest SC numbers confirmed the presence of two SC populations with unique features and a series of differentiating stem-state identities. These findings were further confirmed by spatial-transcriptomic analysis (Visium/Xenium) and immunohistological validations, pointing to the existence of two major SOX2-expressing SC populations, respectively defined as Stem Cells and TA-SCs. Trajectory and pseudotime analyses confirmed that TA-SCs were differentiating into cell-states primed to the three major pituitary lineages: PIT1, TPIT and SF1, a result further validated by histological analysis. Finally, we addressed the mechanistic cues that control the TA-SC state. Regulon analysis identified STAT1/3 as a transcriptional pathway strongly activated in TA-SCs, a result supported by the identification of intratumoural SOX2-SCs showing a phospho-STAT3 activation. To assess the functional impact of JAK-STAT pathway modulation in vitro, we tested the effect of pharmacological inhibitors on SC-enriched cultures derived from patients. These inhibitors significantly decreased stemness markers while increasing the expression of endocrine differentiation markers. Altogether, these findings provide evidences that TA-SCs may contribute to pituitary tumorigenesis. Moreover, our results support that JAK-STAT inhibition impact SC maintenance and differentiation, suggesting this pathway as a potential therapeutic target to modulate TA-SC behaviour in PITs.Fundings: FRIEMM, Ligue-Cancer (CD26/CD69), HCL (PJC), ANR-23-CE45-0017, ANR-17-CONV-0002, ANR-18-CE45-0023, ANR-22-PESN-0002, CD24-00240, PRE2020-05930.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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