ArticleJournal of experimental & clinical cancer research : CR2024
Membrane RRM2-positive cells represent a malignant population with cancer stem cell features in intrahepatic cholangiocarcinoma.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- A new inject-embed 3D culture method enables the spheroid and aggregate formation from single or dual liver cancer cell types.Cancer cell international · 2026Article
- The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance.Journal of translational medicine · 2025Review
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14 authors.
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Abstract
backgroundIntrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features.
methodsTranscriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1-3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1-3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells.
resultsThe unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis.
conclusionsRRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features.
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