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1.
Proc Natl Acad Sci U S A ; 117(11): 6103-6113, 2020 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-32123069

RESUMEN

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hepatocitos/patología , Neoplasias Hepáticas/genética , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Estudios de Cohortes , Supervivencia sin Enfermedad , Factor de Transcripción E2F1/antagonistas & inhibidores , Factor de Transcripción E2F1/metabolismo , Femenino , Perfilación de la Expresión Génica , Hepatectomía , Células Madre Embrionarias Humanas , Humanos , Hidroxiquinolinas/farmacología , Hidroxiquinolinas/uso terapéutico , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Estimación de Kaplan-Meier , Hígado/crecimiento & desarrollo , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Ratones , Persona de Mediana Edad , Pronóstico , Piridinas/farmacología , Piridinas/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Transducción de Señal/genética , Proteína smad3/antagonistas & inhibidores , Proteína smad3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Gut ; 71(8): 1656-1668, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34588223

RESUMEN

OBJECTIVE: Hepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models. DESIGN: We established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells. RESULTS: Prom1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation. CONCLUSION: Our study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Antígeno AC133/genética , Antígeno AC133/uso terapéutico , Animales , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Ratones , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/patología , Análisis de la Célula Individual
3.
NAR Cancer ; 5(3): zcad040, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37502711

RESUMEN

Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.

4.
J Clin Invest ; 131(11)2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33878034

RESUMEN

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/enzimología , Fucosiltransferasas/metabolismo , Glucosa/metabolismo , Neoplasias Hepáticas Experimentales/enzimología , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/enzimología , Animales , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Fucosiltransferasas/genética , Glucosa/farmacología , Glicosilación , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentales/diagnóstico , Neoplasias Hepáticas Experimentales/genética , Ratones , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/patología , Pronóstico , Galactósido 2-alfa-L-Fucosiltransferasa
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