Hayashi Y, Harada H. Mitochondrial Dynamics as a Pathobiological Mediator of Clonal Myeloid Disorders. Cancer Sci. 2023; 114: 2722-2728. doi: 10.1111/cas.15810.
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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.
Posttranslational modification is crucial for modulating protein functions. SUMOylation is a posttranslational modification where a small ubiquitin-related (like) modifier (SUMO) conjugates to a lysine residue in the substrate proteins. SUMOylation has been shown to affect the alteration of substrate proteins' functions, subcellular localization, or stability. Furthermore, it has been reported that SUMOylation is involved in regulating angiogenesis, cellular migration, and epithelial–mesenchymal transition (EMT). Moreover, a link between SUMO proteins and multidrug resistance in hepatocellular carcinoma and multiple myeloma has been reported. Classified as a set of transcription factors belonging to the basic region leucine zipper (bZIP) family, musculoaponeurotic fibrosarcoma (MAF) proteins are divided into two groups: large MAF (c-MAF, MAFA, and MAFB) and small MAF (MAFF, MAFG, and MAFK). We previously demonstrated that MAFK confers tumorigenic ability to nontumorigenic mammary gland epithelial cells, NMuMG cells, through induction of EMT. Furthermore, the knockdown of MAFK significantly suppressed the tumorigenic and metastatic growth of breast cancer cells. Among MAF family proteins, the SUMOylation consensus sequence, ψKxE, is highly conserved, and SUMOylation has been shown in MAF family proteins, MAFB and MAFG, respectively. In this study, we focused on SUMOylation and investigated the importance of the SUMOylation consensus sequence in MAFK for MAFK-induced EMT, cellular migration and invasion, tumor and sphere formation, acquisition of stem-like properties, and drug resistance against doxorubicin by using the non-SUMOylation mimic mutant. Additionally, our results suggest that these findings depend on the expression of ATP-binding cassette (ABC) transporter 2 (ABCG2).
Malignant transformation involves the acquisition of proliferative advantages by cells, often through the dysregulation of key signaling pathways. The Hippo pathway effectors YAP and TAZ are well-established regulators of cell proliferation, and their aberrant activation is linked to tumorigenesis in various cancers. However, the molecular mechanisms by which YAP and TAZ sustain malignant transformation remain unclear. In this study, we employed an in vitro transformation model using immortalized mouse embryonic fibroblasts (iMEFs) constitutively expressing active YAP or TAZ. We demonstrated that YAP or TAZ hyperactivation is sufficient to induce malignant transformation, and that the removal of these proteins reverses the transformed phenotype, indicating their necessity for both tumor initiation and maintenance. Transcriptomic profiling identified a 17-gene signature specifically upregulated by YAP, which was enriched in cell cycle–related genes. Among these, CDC6, a DNA replication licensing factor, emerged as a critical target of YAP and TAZ. Functional assays revealed that CDC6 depletion impaired YAP/TAZ-induced anchorage-independent growth. Moreover, analysis of The Cancer Genome Atlas (TCGA) datasets showed elevated CDC6 expression across multiple human tumors with high YAP and TAZ activity, and a strong positive correlation between CDC6 and YAP/TAZ expression. These findings highlight that the conserved YAP/TAZ–CDC6 axes are key drivers of malignant transformation and underscore their potential as therapeutic targets across diverse cancer types.
FLAURA2 has demonstrated that third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy brought a significant survival benefit over EGFR-TKI monotherapy. This suggests that EGFR-TKIs combined with chemotherapy may be a viable therapeutic strategy. Our study aimed to evaluate the efficacy, safety, and progression pattern of third-generation EGFR-TKIs combined with chemotherapy in advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) in the real world. This study designed as an observational, retrospective, single-center, real-world project enrolled 382 NSCLC individuals receiving third-generation EGFR-TKIs combined with platinum-based chemotherapy as first-line therapy. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). From July 2016 to May 2024, 382 patients were retrospectively included for the analysis. Of these patients, 120, 165, and 97 patients received osimertinib, aumolertinib, and furmonertinib plus chemotherapy as first-line therapy, respectively. Overall, the median follow-up duration was 34.6 months (95% CI: 32.2–35.6), the median PFS was 30.9 months (95% CI: 27.5–39.3), and the median OS was 53.9 months (95% CI: 46.2–NR). Overall, the ORR was 76.4% and the DCR was 98.2%. One hundred thirty-seven (35.9%) individuals experienced Grade 3 or higher AEs. Different third-generation EGFR-TKI groups show no statistically significant difference in PFS (HR = 0.75; 95% CI: 0.51–1.10; p = 0.25) after inverse probability of treatment weighting (IPTW), nor in AEs or severe AEs (p = 0.852; p = 0.502). First-line third-generation EGFR-TKI combined with pemetrexed-based chemotherapy demonstrated a favorable ORR and PFS benefit in advanced EGFRm NSCLC.
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