Title : Decoding the universal proliferative engine of pituitary adenomas: From single-cell insights to cross-subtype therapeutic innovation
Abstract:
Objective: Pituitary adenomas (PAs) are clinically heterogeneous tumors with subtype-specific hormonal profiles, yet current therapies remain largely reactive and fail to address their proliferative core. This study challenges the dogma of subtype-driven tumorigenesis by identifying a universal proliferative center across PA subtypes, aiming to redefine therapeutic strategies through mechanism-based targeting.
Methods: Single-cell RNA sequencing was performed on 43 PA samples (125,390 high-quality cells) spanning all major hormonal subtypes. Cell clustering, marker gene analysis, and functional enrichment were employed to characterize subtype-overlapping proliferative populations. Regulatory networks were inferred via transcription factor (TF) prediction (X2K platform) and pathway annotation.
Results: We identified a pan-subtype proliferative center universally present across all PA subtypes, despite their divergent cellular origins. This cluster exhibited robust activation of cell cycle progression (HSA-1640170), DNA replication (ORC1/6,TYMS), and chromatin remodeling (ANP32A/B, PTMA) pathways. A conserved regulatory axis involving CDK1, MYC, and E2F1 emerged as the central driver, orchestrating downstream effectors through transcriptional and post-translational networks. Strikingly, this center’s molecular architecture remained consistent across subtypes, suggesting a unified proliferative mechanism independent of lineage-specific origins.
Conclusion: Our findings reveal a previously unrecognized proliferative center that transcends PA subtype classifications, unifying hormonally distinct tumors through a CDK1-MYC-E2F1-centric regulatory program. This discovery implies that divergent PA subtypes may converge on a shared proliferative "core" during tumor progression, offering two key translational hypotheses: First, the core regulators (CDK1, ANP32A/B) could serve as pan-subtype therapeutic targets, potentially disrupting proliferation across all PA variants. Second, quantifying this center’s activity may improve risk stratification beyond current subtype-based paradigms. To sum, our data provide a foundational framework for redefining PA biology and guiding future therapeutic development focused on this conserved center.
