Background and aims The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs’ niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF.
Design We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study.
Results CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy.
Conclusions EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.
- pancreatic cancer
- stem cells
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TZ, JL and YX contributed equally.
Contributors JH and JL conceived and designed the experiments; TZ and YX performed most of the experiments; JL, WB, KZ, WJ, SY, HoWang and HaWang performed some experiments; YG, CH and SY provided technical support; TZ, SG, XW provided patient samples and technical support. JH, JL, TZ and YX analysed and discussed the data. JL and TZ wrote and completed the paper. JH supervised the entire project.
Funding This work was supported by the National Natural Science Foundation of China (grants 82030092, 81720108028, 82072657, 81802432, 82072716, 81802433, 82072659, 81871968 and 81871978), the programmes of Tianjin Prominent Talents, Tianjin Eminent Scholars, Tianjin Natural Science Fundation (20JCQNJC01330, 18JCJQJC47800, 19JCJQJC63100 and 19JCYBJC26200), Tianjin Postgraduate Research and Innovation Project (2019YJSB104), and Tianjin Research Innovation Project for Postgraduate Students (2019YJSB104). The research in S. Yang’s laboratory is supported by the National Cancer Institute (R01 CA175741) and the Elsa U. Pardee Foundation (R01 CA175741)
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All the patients provided written consent for the use of their specimens and disease information for future investigations according to the ethics committee of Tianjin Medical University Cancer Institute and Hospital, China, and in accordance with the recognised ethical guidelines of Helsinki (ID number of the ethics approval: Ek2017141). Animal experiment procedures were approved by the ethics committee of Tianjin Medical University Cancer Institute and Hospital, in compliance with the principles and procedures of the NIH Guide for the Care and Use of Laboratory Animals.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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