Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs. METHODS: We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers. RESULTS: Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment. CONCLUSIONS: The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes. A Schematic illustration of the role of NR5A2 in cancer stem cells versus differentiated cancer cells, along with the action of the NR5A2 inhibitor Cpd3. B Overall survival of tumor-bearing mice following allocated treatment. A total of 18 PDX models were treated using a 2 x 1 x 1 approach (two animals per model per treatment); n=36 per group (illustration created with biorender.com ).

Design, synthesis and antitumor activity of aromatic urea-quinazolines.

Background: Gefitinib and sorafenib have been proved effective for the treatment of cancers in clinical practice for years. Materials & methods: We intended to integrate the structural features of gefitinib and sorafenib and construct structurally unique 7-aromatic ureido-4-anilinoquinazolines. Results: Most of the targets exhibited promising antitumor activities. 8u showed excellent antitumor activities against the three tested cell lines (IC50, 0.81-2.49 µM). The enzymatic, apoptosis assay of 8u were also performed to study their preliminary action of mechanism. Conclusion: 8u deserve further research as antitumor agents.

[The radiosensitization of nimotuzumab on CAL-27 cells after 125I seeds irradiation].

PURPOSE: To observe the inhibitory effect of nimotuzumab combined with low-dose continuous irradiation using 125I seeds on CAL-27 cells originating from human tongue squamous carcinoma, and explore the radiosensitization of nimotuzumab on human tongue squamous carcinoma CAL-27 irradiated with 125I seeds. METHODS: The exponential-phase CAL-27 cells were randomly divided into 4 groups: control group, 125I seeds irradiation group, nimotuzumab group, nimotuzumab plus 125I seeds irradiation group. CCK-8 assay was used to detect the inhibitory effect of 125I seeds irradiation on CAL-27 cancer cells, and flow cytometry assays were performed to calculate the apoptosis rate of cells and cell cycle from each group. The morphology of cells was compared using Hoechst 33258 staining. The data were analyzed with SPSS17.0 software package. RESULTS: 125I seeds inhibited the growth of CAL-27 cells in time-dose dependent manner. The apoptosis rate of cells irradiated by nimotuzumab combined with 125I seeds irradiation was higher than that treated with nimotuzumab and 125I seeds irradiation respectively, and nimotuzumab followed by radiation had a lower S phase cells(P<0.05). CONCLUSIONS: Nimotuzumab combined with 125I seeds irradiation killed CAL-27 cells by inducing apoptosis. Nimotuzumab and low-dose γ ray emitted from 125I seeds can significantly enhance the radiosensitivity of CAL-27.

[Thoracoscopic cardiac surgical procedures: a report of 674 cases].

OBJECTIVE: To evaluate the efficacy and safety of thoracoscopic cardiac surgical procedures under extracorporeal circulation. METHODS: From May 2000 to May 2006, 674 patients received thoracoscopic cardiac surgery under extracorporeal circulation. These procedures included atrial septal defect occlusion for 238 patients, ventricular septal defect occlusion for 380 patients and mitral valve replacement for 56 patients. Thirty degree thoracoscopes and femoral extracorporeal circulation were used. The aorta was cross-clamped and the myocardium was protected by coronary perfusion with cold crystal or blood cardioplegia. RESULTS: The operation succeed in 645 patients (96%, 645/674). Enlarging the incision was performed in 28 patients. Operation time was from 1.8 h to 5.6 h with the mean of (2.8 +/- 1.2) h. Cardiopulmonary bypass time was from 56 min to 198 min with the mean of (78 +/- 2.3) min. Aortic cross-clamp time was from 8 min to 96 min with the mean of (31 +/- 19) min. The volume of chest drainage was (140 +/- 46) ml. None but one postoperative death occurred, the mortality was 0.15%. Postoperative complications occurred in 48 cases (7%), including bleeding in 8 patients, leakage in 5 patients (reoperation in 2 patients) and hemo-pneumothorax in 33 patients. One patient died postoperatively from cerebral hemorrhage (0.15%, 1/647). CONCLUSION: Thoracoscopic cardiac surgical procedures for atrial septal defect occlusion, ventricular septal defect occlusion and mitral valve replacement is feasible and safe.