Background and aimsThe 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.DesignWe 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.ResultsCXCL12 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.ConclusionsEHF 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.

Background: Colon adenocarcinoma (COAD) is one of the most prevalent cancers worldwide and has become a leading cause of cancer death. Although many potential biomarkers of COAD have been screened with the bioinformatics method, it is necessary to explore novel markers for the diagnosis and appropriate individual treatments for COAD patients due to the high heterogeneity of this disease. Epithelial-to-mesenchymal transition (EMT)-mediated tumor metastasis suggests poor prognosis of cancers. Ferroptosis is involved in tumor development. EMT signaling can increase the cellular sensitivity to ferroptosis in tumors. The aim of our study is finding novel prognostic biomarkers to determine COAD patients for predicting efficiency of metastasis status and targeting precise ferroptosis-related therapy.Methods: A novel gene signature related to metastasis and ferroptosis was identified combing with risk model and WGCNA analysis with R software. The biological functions and predictive ability of the signature in COAD were explored through bioinformatics analysis.Results: We established a four-gene prognostic signature (MMP7, YAP1, PCOLCE, and HOXC11) based on EMT and ferroptosis related genes and validated the reliability and effectiveness of this model in COAD. This four-gene prognostic signature was closely connected with metastasis and ferroptosis sensitivity of COAD. Moreover, WGCNA analysis further confirmed the correlation between PCOLCE, HOXC11, and liver and lymphatic invasion of COAD.Conclusion: The four genes may become potential prognostic biomarkers to identify COAD patients with metastasis. Moreover, this four-gene signature may be able to determine the COAD suitable with ferroptosis induction therapy. Finally, PCOLCE2 and HOXC11 were selected individually because of their novelties and precise prediction ability. Overall, this signature provided novel possibilities for better prognostic evaluation of COAD patients and may be of great guiding significance for individualized treatment and clinical decision.

Background Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. Methods We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. Results High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. Conclusions Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.