Dataset Information

Uncovering biological heterogeneity in endometrial carcinoma molecular subtypes by proteomic analysis

ABSTRACT: While endometrial cancer (EC) has an overall favorable prognosis, some patients do poorly and may benefit from refinements of current classification systems. Molecular classification stratifies ECs into four prognostic groups: POLEmut, MMRd (mismatch repair deficient), p53abn, and NSMP (no specific molecular profile), where POLEmut has the best prognosis and p53abn has the worst prognosis. We used proteomic profiling to provide additional prognostic or predictive information for EC patients, across or within molecular subtypes. Global proteome profiling of formalin fixed, paraffin embedded samples, that had clinicopathologic and outcome data, was performed on 184 ECs encompassing all four molecular subtypes, including replicate samples of the same tumor, and both biopsy and final hysterectomy specimens. To ensure representation of each subtype, we profiled an approximately equal distribution in the 148 unique tumors; 34 (23%) POLEmut, 40 (23%) MMRd, 35 (24%) p53abn and 39 (26%) NSMP, rather than the population-based distributions. There was high reproducibility in the proteomic profiles of intra-tumor replicate samples, and between matched biopsy and hysterectomy tumor samples. Consensus clustering identified four clusters with different prognosis, named ‘Adhesion’, ‘Immune’, ‘Proliferation’, and ‘Metabolic’ based on proteins enriched in each cluster. We correlated protein expression with common mutations, molecular subtypes, and outcomes. Proteomic analysis of EC identified candidate prognostic markers that may further refine current molecular classification and help guide treatment decisions. These data offer insights into new therapeutic interventions that could be developed to target proteins and pathways identified by EC proteomic profiling.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Uterine Endometrial Cancer Cell

DISEASE(S): Endometrial Carcinoma

SUBMITTER: Gian Luca Negri

LAB HEAD: Gregg Morin

PROVIDER: PXD057700 | Pride | 2025-10-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	McAlpine_BMBP_SS_Endometrial_B10_F1.raw	Raw
	McAlpine_BMBP_SS_Endometrial_B10_F10.raw	Raw
	McAlpine_BMBP_SS_Endometrial_B10_F11.raw	Raw
	McAlpine_BMBP_SS_Endometrial_B10_F12.raw	Raw
	McAlpine_BMBP_SS_Endometrial_B10_F2.raw	Raw

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Publications

Proteomic analysis uncovers biological diversity in molecularly defined endometrial carcinomas.

Cochrane Dawn R DR Negri Gian Luca GL Huvila Jutta J Kalantari Forouh F Farnell David A DA Mohammad Nissreen N Thompson Emily E Yang Winnie W Lum Amy A Spencer Sandra E SE Riley Ryan R Jamieson Amy A Leung Samuel S Chiu Derek D Chow Christine C Lim Jamie L P JLP Köbel Martin M Kommoss Stefan S Kommoss Friedrich F Gilks Blake B Hoang Lien L Huntsman David G DG Morin Gregg B GB McAlpine Jessica N JN

Neoplasia (New York, N.Y.) 20250917

While endometrial cancer has an overall favorable prognosis, some patients have poor outcomes and may benefit from further refinements of the current classification systems. Molecular classification stratifies endometrial cancer patients into four prognostic subtypes: POLEmut, MMRd (mismatch repair deficient), p53abn, and NSMP (no specific molecular profile), where patients with POLEmut have the best prognosis and p53abn has the worst prognosis. We used proteomic profiling to assess if additiona ...[more]

PMID: 40966993

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Project description:With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed – the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions. Furthermore, an overrepresentation of Alzheimer’s disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study revealed novel vascular ageing-associations of AD in the brain capillary endothelium, and provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.