Translational Oncology最新文献

Background: Accurate estimation of recurrence risk for cervical cancer plays a pivot role in making individualized treatment plans. We aimed to develop and externally validate an end-to-end deep learning model for predicting recurrence risk in cervical cancer patients following surgery by using multiparametric MRI images.

Methods: The clinicopathologic data and multiparametric MRI images of 406 cervical cancer patients from three institutions were collected. We designed a novel deep learning model called "ConvXGB" for predicting recurrence risk by combining the convolutional neural network (CNN) and eXtreme Gradient Boost (XGBoost). The predictive performance of the ConvXGB model was evaluated using time-dependent area under curve (AUC), compared with the deep learning radio-clinical model, clinical model, conventional radiomics nomogram and an existing histology-specific tool. The potential of the ConvXGB model in predicting the recurrence-free survival (RFS) and overall survival (OS) was assessed.

Results: The ConvXGB model outperformed other models in predicting recurrence risk, with AUCs for 1 and 3 year-RFS of 0.872(95% CI, 0.857-0.906) and 0.882(95% CI, 0.860-0.904) respectively in the test cohort. This model showed better discrimination, calibration and clinical utility. Grad-CAM analysis was adopted to help clinicians better understand the predictive results. Moreover, Kaplan-Meier survival analysis revealed that patients who were stratified into high-risk group by the ConvXGB model were significantly susceptible to higher cumulative recurrence risk rates and worse outcome.

Conclusion: The ConvXGB model allowed for predicting postoperative recurrence risk in cervical cancer patients and for stratifying the risk of RFS and OS.

Bladder cancer (BLCA) genomic profiling has identified molecular subtypes with distinct clinical characteristics and variable sensitivities to frontline therapy. BLCAs can be categorized into luminal or basal subtypes based on their gene expression. We comprehensively characterized nine human BLCA cell lines (UC3, UC6, UC9, UC13, UC14, T24, SCaBER, RT4V6 and RT112) into molecular subtypes using orthotopic xenograft models. Patient-derived, luciferase-tagged BLCA cell lines were cultured in vitro and engrafted into bladders of NSG mice. Tumor growth was monitored using bioluminescence imaging and mRNA-based molecular classification was used to characterize xenografts into molecular subtypes. RNAseq analysis and basal, luminal, and epithelial-mesenchymal transition (EMT) marker expression revealed distinct patterns; certain cell lines expressed predominantly basal or luminal markers while others demonstrated mixed expression. SCaBER expressed high basal and EMT markers and low luminal markers, consistent with a true basal cell. RT4V6 was a true luminal cell line, displaying only high luminal makers. UC13, T24 and UC3 only showed increased expression of EMT markers. RT112, UC6, UC9 and UC14 expressed basal, luminal, and EMT markers. Immunohistochemical analysis validated our findings. Ki67 was assessed as a continuous percentage of positively stained cells. Morphological assessment of xenografts included H&E and α-SMA staining. These findings will allow for the rational use of appropriate models to develop targeted therapies to overcome or manipulate mechanisms of treatment resistance in BLCA.

Background: Liquid biopsy (LB) is a laboratory test performed on a fluid sample aiming at analyzing molecular data derived from circulating cells and related entities, or from nucleic acids. This umbrella review aims to map and evaluate the evidence supporting the use of LB in medicine across different medical specialities and conditions.

Methods: We searched three repositories from database inception up to October 1, 2023 and we included meta-analyses of observational studies reporting data on the use of LB, compared to gold standard, and its accuracy (area under the curve, AUC).

Results: Among 726 articles initially screened, 42 systematic reviews were included. Most of the outcomes explored (202/211) were related to cancer. We found that 75/211 had an excellent accuracy (AUC >0.90), with one comparison with an AUC equal to 1, i.e., Cell-Free Human Papillomavirus DNA (cfHPV-DNA) for HPV-positive oropharyngeal squamous cell carcinoma. However, considering published meta-analyses, all the outcomes were graded as very low on the GRADE criteria, and the heterogeneity was never reported.

Discussion: The literature about LB is rapidly increasing and some promising data about precision oncology are now available. However, this umbrella review on existing meta-analyses highlighted some critical issues for providing quantitative estimations on the different roles of LB.

Bispecific antibodies (BsAbs) represent a promising strategy for cancer immunotherapy. Challenges in immunotherapy include inefficient early events in the immune response cycle, such as antigen presentation and T cell priming. Background stimulation of CD40 with agonistic antibodies is a promising strategy to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Assisted by Alphafold2(AlphaFold-Multimer), we developed a humanized CD40 agonistic antibody that exhibits activation only in the presence of cross-linking. It also demonstrates that the current AlphaFold2(AlphaFold2-Multimer) can predict antibody-antigen complexes. Due to the unique epitope, it demonstrates superior activation compared to APX005M (S267E). Building upon this, we created a novel bispecific antibody (anti-PD-L1/CD40 bispecific antibody, referred to as "BA4415") designed to activate CD40 signaling specifically in the context of PD-L1 while simultaneously blocking PD-1/PD-L1 signaling. Results from functional evaluations using effector cells revealed the superior biological activity of BA4415 compared to the combination of each monoclonal antibody. BA4415 demonstrated the ability to enhance T-cell cytokine release in vitro assays, exhibiting superior functional attributes compared to the anti-PD-L1 antibody. Furthermore, in humanized transgenic mice challenged with huPD-L1-expressing tumor cells, BA4415 induced superior anti-tumor activity. This novel anti-PD-L1/CD40 bispecific antibody holds potential for strong anti-tumor therapeutic efficacy by selectively restricting CD40 stimulation in tumors.

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with poorly understood underlying molecular mechanisms. Ferroptosis, a form of programmed cell death, is not fully elucidated in NPC.

Method: We conducted quantitative proteomics to detect dysregulated proteins in NPC tissues. The levels of endoplasmic reticulum membrane protein complex 2 (EMC2) in NPC tissue microarrays were evaluated by immunohistochemistry, and the prognostic value of EMC2 was analyzed in NPC patients. The role of EMC2 in ferroptosis and carcinogenesis was determined through in vitro and in vivo experiments. Quantitative proteomics, protease inhibition, ubiquitin detection, and rescue experiments were performed to explore the mechanism of EMC2-regulated ferroptosis.

Results: Significantly upregulated EMC2 was detected in NPC, and it was closely related to the characteristics of tumor progression. Elevated EMC2 was obviously correlated with poor survival in patients with NPC. EMC2 knockdown promoted ferroptosis, inhibiting cell viability, migration, and invasion, and enhancing the efficacy of cisplatin in NPC cells. Conversely, EMC2 overexpression contributed to ferroptosis repression, malignant progression, and reduced the efficacy of cisplatin. In addition, EMC2 knockdown suppressed xenograft tumor growth and enhanced ferroptosis in nude mice. Mechanistically, we identified transferrin receptor (TFRC) as a critical downstream protein. EMC2 interacted with TFRC and promoted its ubiquitin-proteasomal degradation. EMC2 regulated ferroptosis by mediating the level of TFRC.

Conclusions: EMC2 suppresses ferroptosis and promotes tumor progression, and the EMC2-TFRC axis is a novel ferroptosis regulatory pathway. EMC2 is a potentially biomarker and therapeutic target for NPC.

Cholangiocarcinoma remains a challenging primary hepatobiliary malignancy with dismal prognosis. Photodynamic therapy (PDT),a less invasive treatment, has been found to inhibit the proliferation and induce ferroptosis, apoptosis and necrosis in other tumor cells in recent years. Regrettably, the role and exact molecule mechanism of PDT is still incompletely clear in cholangiocarcinoma cells. Ferroptosis is a novel regulated cell death(RCD), which is controlled by glutathione peroxidase4(GPX4) with the characteristics of iron dependent and excessive intracellular accumulation of lipid peroxides. This novel form of RCD has attracted great attention as a potential new target in clinical oncology during recent years. In this study, we observed that hypericin mediated PDT(HY-PDT) could significantly inhibit the proliferation of the cholangiocarcinoma cells and suppress migration and the epithelial mesenchymal transition (EMT) as well. Then, we conducted transcriptome sequencing and bioinformatics analysis and observed that HY-PDT was most likely involved in ferroptosis, apoptosis, the EMT process and AKT/mTORC1 signaling pathways in cholangiocarcinoma cells. Next, a series of in vitro and in vivo experiments were performed to confirm that HY-PDT could trigger cholangiocarcinoma cells ferroptosis through inhibiting the expression of GPX4 protein. In terms of molecular mechanism, we found that HY-PDT induced ferroptosis by decreasing GPX4 expression via suppression of the AKT/mTORC1 signaling pathway. In addition, we also found that HY-PDT inhibit cholangiocarcinoma cells migration and the EMT process by inhibiting the AKT/mTORC1 pathway. Our study illustrated a new mechanism of action for HY-PDT and might throw light on the individualized precision therapy for cholangiocarcinoma patients.

Background: Despite advancements with intensity-modulated radiation therapy (IMRT), about 10 % of nasopharyngeal carcinoma (NPC) patients remain resistant to radiotherapy, leading to recurrence and poor prognosis. This study aims to identify radiosensitivity-related genes in NPC and develop a prognostic model to predict patient outcomes.

Methods: We analyzed 179 NPC samples from Fujian Cancer Hospital using RNA sequencing. Differentially expressed genes (DEGs) were identified between radiotherapy-sensitive and resistant samples. Machine learning algorithms and Cox regression were used to construct a prognostic risk model, validated in the GSE102349 dataset. Additional analyses included functional pathway, immune infiltration, and drug sensitivity.

Results: A risk model based on six genes (LCN8, IGSF1, RIMS2, RBP4, TBX10, ETV4) was developed. Kaplan-Meier analysis showed significantly shorter progression-free survival (PFS) in the high-risk group. The model's AUC values were 0.872, 0.807, and 0.802 for 1-year, 3-year, and 5-year predictions. A nomogram including clinical factors was created, and enrichment analysis linked the high-risk group to radiotherapy resistance mechanisms.

Conclusions: This study established a novel radiosensitivity-related prognostic model, offering insights into NPC prognosis and radiotherapy resistance mechanisms.

Undifferentiated pleomorphic sarcoma (UPS) is the most frequent and the most aggressive sarcoma subtype for which therapeutic options are limited. The identification of new therapeutic strategies is therefore an important medical need. Epigenetic modifiers has been extensively investigated in recent years leading to the development of novel therapeutic agents. Dual BET/EP300 inhibitors have shown synergistic antitumor activity and have recently entered clinical development. To date, no data related to potential of BET/EP300 inhibition as a treatment in UPS have been reported. To investigate the therapeutic potential of BET/EP300 inhibition, we evaluated the antitumor activity of three compounds in vitro via MTT, apoptosis and cell cycle assays. The most potent inhibitor was evaluated in vivo in two animal models and the mechanisms of action were investigated by RNA sequencing, Western blotting and immunofluorescence staining. A CRISPR knockout screen was performed to identify resistance mechanisms. Among the three compounds tested, the dual inhibitor NEO2734 was the most potent, decreased the viability of UPS cells in vitro through a regulation of E2F targets and cell cycle and decreased the tumor growth in vivo. Moreover, we identified GPX4 as a gene involved in resistance and showed synergy between BET inhibition and ferroptosis induction. The present study demonstrated that dual BET/EP300 inhibitors have a relevant antitumor activity in a subgroup of UPS characterized by expression of MYC-targets pathway and identified a potent combination therapeutic strategy that deserves further investigation in the clinical setting.

E2F1 is a critical transcription factor that regulates cell cycle progression, is expressed at high levels in most cancer cells, and activates the biogenesis of proteins related to the cell cycle. Over recent years, researchers have demonstrated that E2F1 could also facilitate cellular apoptosis under conditions of cellular stress, thus creating a double-edged sword associated with both the regulation of cellular survival and death. However, the mechanisms responsible for these actions remain poorly understood. In this study, we demonstrated that serum stress could activate the acetylation of E2F1 at K125. Further analysis indicated that the acetylation of E2F1 at K125 could facilitate its interaction with the promoter of FAS and upregulate the levels of Fas. Furthermore, the acetylation of E2F1 attenuated its interaction with p53, thus leading to the transactivation of BAX. The upregulation of Fas and Bax activated the cleavage of caspase-3 and facilitated the apoptosis of HCC cells experiencing serum stress. Collectively, our findings indicated that the acetylation of E2F1 at K125 under serum stress leads to a functional change and a new role as an executor of cell death instead of an oncoprotein.

Background: Lysophosphatidylcholine acyltransferase 3 (LPCAT3) promotes ferroptosis through the incorporating polyunsaturated fatty acids into membrane phospholipids, however, its role in serous ovarian cancer remains unclear. Here explored cancer proliferation and metastasis after modulating LPCAP3.

Methods: LPCAT3 protein in ovarian cancer tissues was detected using bioinformatic and immunohistoche mical assays. Cell behaviors were observed after up- or down-regulating LPCAT3. Lipid metabolites were determined, and then the pathway enrichment analysis was performed.

Results: The expression level of LPCAT3 in serous ovarian cancer tissues was lower than that in other types of ovarian cancer, and high expression was associated with a longer survival time. Overexpressing LPCAT3 reduced cell proliferation, migration and invasion via enhancing ferroptosis and decreasing the survival signaling; these behaviors were enhanced in LPCAT3-downknocked cells, where a higher abundance of arachidonic acid was observed followed by up-regulation of the downstream survival signaling. In vivo, up-regulation of LPCAT3 decreased tumor growth, but down-regulation enhanced tumor growth and metastasis.

Conclusions: LPCAT3 modulated metabolism of arachidonic acid, thereby regulating ferroptosis and the survival signaling to determine cancer growth and metastasis.