Cancer Science最新文献

Cancer-stromal interactions play important roles in the biology of various cancers, including lung adenocarcinoma. We aimed to comprehensively analyze the lung cancer interactome and identify the key ligand-receptor pairs involved in the aggressiveness of lung adenocarcinoma. Transcriptome data were obtained from xenografts of 11 lung cancer cell lines that represented the major driver mutations in lung adenocarcinomas. A quantitative dataset was constructed in both stroma-to-cancer and cancer-to-stroma directions using the cancer-stromal interactome analysis method. The prognostic value of each factor was evaluated using multiple datasets. Analysis of 24,250 stroma-derived mouse transcripts and 26,289 human cancer-derived transcripts identified 1150 cancer-stromal interactions, from which we selected 117 interactions based on the intensity score of ligand-stromal transcript levels. Further prognostic analysis using public databases led us to identify 21 ligand-receptor pairs, including well-known as well as less well-characterized ligand-receptor pairs. Therefore, we selected tumor necrosis factor superfamily member 12/tumor necrosis factor receptor superfamily member 12A as possible factors contributing to the aggressiveness of lung adenocarcinoma via cancer-stromal interactions; immunohistochemical analysis confirmed that these factors were expressed mainly in the stroma and cancer cells, respectively, in both xenografts and primary lung adenocarcinoma. In human clinical specimens, high tumor necrosis factor receptor superfamily member 12A expression significantly correlated with tumor size, invasive diameter, and stage. Thus, tumor necrosis factor superfamily member 12 and its receptor tumor necrosis factor receptor superfamily member 12A signaling axis may be potential candidates for therapeutic intervention for lung adenocarcinoma.

First-line atezolizumab combination therapies were approved for the treatment of metastatic non-small cell lung cancer (NSCLC) based on results from the global phase 3 trials IMpower130, IMpower132, and IMpower150. These trials reported 12-month overall survival (OS) rates of 60%-67% with atezolizumab combination therapy. J-TAIL-2 (NCT04501497), a prospective, multicenter, observational study, evaluated atezolizumab combination therapy in routine clinical practice in Japan. Patients ≥ 20 years old with NSCLC received atezolizumab plus carboplatin and nab-paclitaxel (atezo + CnP), atezolizumab plus carboplatin or cisplatin plus pemetrexed (atezo + PP), or atezolizumab plus bevacizumab plus carboplatin and paclitaxel (atezo + bev + CP) in clinical practice. The primary endpoint was the 12-month OS rate. Secondary endpoints included OS, progression-free survival, and subgroup analyses, including IMpower-unlike (did not meet the main eligibility criteria of each IMpower trial) and IMpower-like patients. In total, 814 patients were enrolled (atezo + CnP, n = 217; atezo + PP, n = 211; atezo + bev + CP, n = 386). The IMpower-unlike group included patients with Eastern Cooperative Oncology Group performance status ≥ 2, autoimmune disease, or interstitial lung disease. Twelve-month OS rates (95% confidence interval [CI]) were 62.9% (55.8-69.2), 72.1% (65.2-77.9), and 68.3% (63.2-72.9) with atezo + CnP, atezo + PP, and atezo + bev + CP, respectively. OS hazard ratios (95% CI) in the IMpower-unlike vs. -like subgroups were 1.36 (0.91-2.05), 1.08 (0.70-1.68), and 1.49 (1.09-2.06), respectively. No new safety signals were observed. Real-world efficacy and safety for each atezolizumab combination were comparable to those in the relevant IMpower trials.

Conventional cancer therapies, including radiation therapy and chemotherapy, rely on inflicting DNA damage, yet they inevitably affect normal cells, leading to severe adverse effects. The advent of precision chemotherapy exploiting tumor-specific DNA repair defects has validated the effectiveness of this approach. The first successful example is PARP inhibitors, which selectively kill homologous recombination (HR) defective cancers, such as familial breast cancer possessing HR deficiency due to BRCA gene mutations. However, the broader landscape of DNA maintenance-including DNA replication, repair, and checkpoint pathways-harbors numerous mutations in tumors that remain untargeted. Here, we propose repurposing chain-terminating nucleoside analogs (CTNAs) to target such cancers' vulnerabilities. CTNAs, long utilized as anti-cancers and anti-viral drugs, inhibit replication and thereby suppress growth, but their activity has never been systematically aligned with specific cancer mutations associated with DNA maintenance defects. Based on our recent studies, we demonstrate that CTNAs elicit synthetic lethality in cells deficient for distinct DNA maintenance systems, amplifying replication stress, leading to cell death. We highlight the spectrum of CTNA-induced lesions and repair pathways required for cellular tolerance. This framework presents a versatile "repair-defect-guided" chemotherapy that expands the clinical utility of CTNAs and improves therapeutic effect by reducing side effects.

Succinylation has been shown to promote lung cancer development, but its mechanism remains incompletely understood. KAT2A, a succinyltransferase, acts as an oncogene in multiple cancers, but its role in mediating lung cancer progression is unclear. This study aimed to investigate the mechanism by which KAT2A regulates lung cancer progression via succinylation. KAT2A expression was analyzed using UALCAN, GEPIA, and Kaplan-Meier Plotter databases, and validated in lung cancer cell lines and patient-derived tissues. Quantitative real-time PCR, Cell Counting Kit-8 (CCK-8), EdU staining, and flow cytometry were performed to assess KAT2A's role in lung cancer cell proliferation and apoptosis. KAT2A's target proteins were predicted using LinkedOmics and STRING databases. Additionally, in vivo xenograft models were established to evaluate the effect of KAT2A knockdown on tumor growth. Results indicated that KAT2A expression was significantly elevated in lung cancer cells and tissues and was associated with poor prognosis. KAT2A knockdown inhibited proliferation and promoted apoptosis in lung cancer cells, whereas MYC overexpression reversed these effects. Mechanistically, KAT2A knockdown downregulated MYC by reducing succinylation at K370 and K386 residues. Mutation of these sites abrogated the proliferative effect of MYC overexpression and restored apoptotic activity. Furthermore, in vivo experiments demonstrated that KAT2A knockdown inhibited tumor growth and reduced MYC succinylation. Our findings demonstrate that KAT2A functions as an oncogene in lung cancer by enhancing MYC succinylation. This study identifies KAT2A as a promising therapeutic target for lung cancer.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited therapeutic options. Microtubule-associated serine/threonine kinase-like (MASTL), a pivotal regulator of mitosis, remains poorly characterized in HCC. This study aimed to elucidate the clinical significance, biological functions, and molecular mechanisms of MASTL in HCC progression. Bioinformatics analysis of TCGA and ICGC datasets revealed MASTL overexpression correlated with advanced tumor stage and served as an independent prognostic factor. Functional studies demonstrated that MASTL knockdown significantly disrupts HCC cell proliferation, increases the incidence of abnormal mitotic events, and amplifies DNA damage, collectively driving mitotic catastrophe (MC) and subsequent cell death. Mechanistically, MASTL regulated paclitaxel sensitivity by modulating ENSA phosphorylation and PP2A-B55α activity, with PP2A-B55α knockdown reversing MASTL deficiency-induced MC. Transcriptional regulation analysis identified E2F1 as a direct activator of MASTL expression, confirmed by ChIP-qPCR and dual-luciferase reporter assays. These findings establish MASTL as a critical oncogene in HCC through the E2F1-MASTL-PP2A-B55α axis, suggesting its potential as both a prognostic biomarker and therapeutic target for HCC. Future studies should explore MASTL inhibitors in combination with conventional chemotherapy to overcome drug resistance in HCC patients.

Radium-223 dichloride (Ra-223) improves survival in bone-metastatic castration-resistant prostate cancer (mCRPC). However, prospective real-world data are limited, particularly regarding treatment outcomes, predictors of completing six cycles, and integration with subsequent therapies. The KYUCOG-1901 study was a prospective multicenter observational study at 19 Japanese institutions. Patients with mCRPC and ≥ 2 bone metastases received up to six cycles of Ra-223. Effectiveness was assessed by PSA, alkaline phosphatase (ALP), time to visceral metastasis, time to cytotoxic chemotherapy, radiographic progression-free survival (PFS), and overall survival (OS). Safety was evaluated using CTCAE v5.0. Of 101 enrolled, 93 patients were analyzed. Median follow-up was 25.2 months. Early discontinuation was associated with high baseline PSA, ALP, LDH, and symptomatic disease. Subsequent therapies, including taxanes and androgen receptor signaling inhibitors (ARSIs), were administered in most patients. Maximum PSA and ALP declines of ≥ 30% were achieved in 16 (17.2%) and 39 (41.9%) patients, respectively. Median time to visceral metastasis, time to cytotoxic chemotherapy, radiographic PFS (rPFS), and OS were 32.9, 13.7, 8.8, and 23.0 months, respectively. Grade ≥ 3 adverse events occurred in 36.5%. No treatment-related deaths were reported. Ra-223 was effective and well tolerated in Japanese mCRPC patients. Early initiation in less symptomatic patients with lower disease burden may maximize benefit, and integration with subsequent therapies appears feasible. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry UMIN000040358.

Mesenchymal stromal cells (MSCs) are promising vehicles for delivering therapeutic agents to tumors, as a result of their tumor-homing ability. This study aimed to develop MSCs expressing a trimeric soluble form of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which was enhanced by incorporating an isoleucine zipper (SCZT), to improve apoptosis-inducing efficacy. Because some cancer cells are resistant to TRAIL, we also investigated the effects of combining SCZT-expressing MSCs with trichostatin A (TSA), a histone deacetylase inhibitor that enhances the expression of TRAIL death receptors (DR4/DR5) in tumor cells. TSA increased TRAIL sensitivity in resistant tumor cells in vitro by upregulating DR5, leading to enhanced caspase-8 activation and tumor cell death. MSCs accumulated at tumor sites in vivo, and the combination of SCZT-MSCs and TSA significantly suppressed tumor growth in both TRAIL-sensitive and TRAIL-resistant mouse models. Notably, this combination led to complete tumor regression in some TRAIL-resistant tumors. These in vivo findings indicate that efficient tumor targeting by MSCs is crucial for achieving therapeutic efficacy, especially in TRAIL-resistant tumors. Overall, our results demonstrate that co-treatment with TSA enhances the antitumor effect of TRAIL-expressing MSCs, offering a potential strategy to overcome TRAIL resistance and improve MSC-based cancer therapies.

Bladder cancer (BC) is a prevalent urological malignancy, with muscle-invasive subtypes exhibiting a particularly poor prognosis despite recent therapeutic advances. Established risk factors such as smoking contribute to carcinogenesis through the generation of reactive oxygen species, which trigger oxidative stress responses (OSRs). Broad-complex-Tramtrack-Bric a brac and Cap'n' collar homology 1 (BACH1), a key transcription factor regulating OSRs, has been implicated in epithelial-mesenchymal transition (EMT) and metastasis in several malignancies. This study aimed to clarify the role of BACH1 in BC progression and metastasis. Clinical analyses revealed that BACH1-positive expression was correlated with aggressive tumor features, including advanced pathological stage, high tumor grade, and poor prognosis. In vitro experiments demonstrated that BACH1 knockdown suppressed, while overexpression enhanced, the invasive, migratory, and proliferative activities. RNA sequencing indicated significant enrichment of EMT-related and cytokine-driven immune pathways following BACH1 knockdown. Furthermore, in vivo mouse allograft experiments showed that Bach1 knockout cells exhibited reduced tumor growth and fewer lung metastases, accompanied by altered expression of EMT markers and modulation of cytokine-driven immune signaling. Collectively, these findings suggest that BACH1 plays a crucial role in BC progression and metastasis, at least in part, through two complementary mechanisms, EMT activation and immune microenvironment modulation via cytokine signaling.

The current standard postoperative adjuvant therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) includes chemotherapy, including microtubule inhibitors prior to the administration of osimertinib, an EGFR-tyrosine kinase inhibitor (TKI). However, multidrug resistance following treatment with microtubule inhibitors has been reported, and the optimal sequence of drug administration for EGFR-mutated NSCLC remains undefined. In this study, we investigated whether prior treatment with microtubule inhibitors induces acquired cross-resistance to osimertinib in EGFR-mutated NSCLC cells in vitro. To model acquired resistance, PC-9 cells were exposed to vinorelbine or paclitaxel for 18 weeks-approximating the clinical duration of four adjuvant chemotherapy cycles-and subsequent drug sensitivity and signaling pathway alterations were assessed using cell viability assays, RNA sequencing, and immunoblotting. We found that two human NSCLC cell lines derived from PC-9 exhibited reduced sensitivity to osimertinib after 18 weeks of in vitro treatment with tubulin inhibitors: vinorelbine (PC-9/VNR) and paclitaxel (PC-9/PTX). Furthermore, PC-9/VNR and PC-9/PTX cells showed activation of FZD7 and calcium/calmodulin-dependent protein kinase II (CaMKII), along with increased sensitivity to the CaMKII inhibitor KN-93, which exerted additive or synergistic effects. These findings suggest that CaMKII plays a critical role in EGFR-TKI resistance. This study underscores the importance of optimizing the timing of EGFR-TKI administration in the therapeutic sequence for EGFR-mutated NSCLC.