Abstract
Simple SummaryLow-grade, early-stage endometrial cancer (EC) is the most frequent malignant tumor of the uterine corpus. Our study aimed to assess dysregulated pathways in this specific subset of EC through proteomic analysis. We describe and validate the dysregulation of the SLIT/ROBO signaling pathway, as well as cellular death processes such as necroptosis and ferroptosis. We identify several immune-related pathways, with a dominance of innate immune response associated pathways. Our findings reveal the singular biology of low-grade, early-stage ECs and could guide future research in the field.Low-grade, early-stage endometrial carcinoma (EC) is the most frequent malignant tumor of the uterine corpus. However, the molecular alterations that underlie these tumors are far from being fully understood. The purpose of this study is to describe dysregulated molecular pathways from EC patients. Sixteen samples of tumor tissue and paired healthy controls were collected and both were subjected to mass spectrometry (MS)/MS proteomic analysis. Gene ontology and pathway analysis was performed to discover dysregulated pathways and/or proteins using different databases and bioinformatic tools. Dysregulated pathways were cross-validated in an independent external cohort. Cell signaling, immune response, and cell death-associated pathways were robustly identified. The SLIT/ROBO signaling pathway demonstrated dysregulation at the proteomic and transcriptomic level. Necroptosis and ferroptosis were cell death-associated processes aberrantly regulated, in addition to apoptosis. Immune response-associated pathways showed a dominance of innate immune responses. Tumor immune infiltrates measured by immunofluorescence demonstrated diverse lymphoid and myeloid populations. Our results suggest a role of SLIT/ROBO, necroptosis, and ferroptosis, as well as a prominent role of innate immune response in low-grade, early-stage EC. These results could guide future research in this group of tumors.
Highlights
Endometrial carcinoma (EC) is the most frequently diagnosed gynecologic malignancy in the European Union, with more than 73,000 new cases estimated to have been diagnosed in 2020 [1]
Aside from apoptosis related pathways, which are frequently dysregulated in malignancies, we identified necroptosis and ferroptosis as potential cell death pathways altered in low-grade, early-stage endometrial carcinomas (EEC) (Figure S2c)
Our results suggest that this increased susceptibility to ferroptosis is quenched by the up-regulation of inhibitors such as GPX4, AIFM2 (FSP1) and glutathione synthetase (GSS), which could potentially be targeted in low-grade EEC [33,34]
Summary
Endometrial carcinoma (EC) is the most frequently diagnosed gynecologic malignancy in the European Union, with more than 73,000 new cases estimated to have been diagnosed in 2020 [1]. A new molecular classification of EC has been proposed based on the genomic features of the tumors [6]. Genetic alterations, such as POLE mutation, copy number alterations, and microsatellite instability, can be used to classify EC and guide post-surgical adjuvant treatment for women with more aggressive tumors. Studies have revealed novel associations between protein expression and the genomic profiles of tumors [10]. Most of these studies included the endometroid and serous subtypes of EC, revealing major molecular differences between these tumors
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