Cancer Science最新文献

Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high-grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia-related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient-derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two-dimensional cultures, it significantly suppressed cell proliferation in three-dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA-sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial-related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear-encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti-tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.

Watanabe, T., Kidoguchi, K. and Kimura, S. (2025), Treating Hematological Malignancies With OR-2100, an Orally Bioavailable Prodrug of Decitabine. Cancer Sci, 116: 853–861. https://doi.org/10.1111/cas.16452

In Table 1, the reference citations were incorrect. The correct table is shown below:

Figure 3 legend was incorrect. The correct legend is shown below:

FIGURE 3 OR-2100 prevents leukemogenesis associated with aberrant DNA methylation in AKR mice. Tumor cells isolated from AKR mice have hypermethylated proximal promoter regions compared with normal T cells (left panel). Kaplan–Meier survival curves of AKR mice treated with vehicle, OR-2100, or DAC (right panel) [48]. Part of material from: Yuta Yamamoto et al., DNA demethylating agents for chemoprevention of oncovirus-associated leukemogenesis, Leukemia, 2024, Springer Nature.

In the third paragraph of the section “2.3 OR21 Monotherapy in ATL,” the text “Several genes that negatively regulate T-cell receptor signaling, including THEMIS, LAIR1, and RNF130, were down-regulated through promoter hypermethylation in ATL cells [16].” was incorrect.

This should have read: “Several genes that negatively regulate T-cell receptor signaling, including THEMIS, LAIR1, and RNF130, were down-regulated through promoter hypermethylation in ATL cells [30].”

We apologize for these errors.

Clear cell renal cell carcinoma (ccRCC) with sarcomatoid differentiation is a rare histological type of ccRCC, characterized by aggressive clinical behavior and poor prognosis. However, the malignant characteristics of this disease have yet to be fully elucidated. Here, we performed single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), and WES analysis on a single patient with sarcomatoid ccRCC. By integrating scRNA-seq and scATAC-seq data from 19 previous classical ccRCC samples (19,819 tumor cells and 21,684 nuclei), we firstly identified the transcriptional regulatory features of sarcomatoid differentiated tumor cells by scATAC-seq, primarily evidenced by active binding with FOS/JUND, FOSL1/JUN, and FOSL2. In addition, we identified DST, FRMD4A, and PREX2 as tumor markers for ccRCC with sarcomatoid differentiation, which were validated in a cohort study. Moreover, we determined that PREX2 played a malignant role in ccRCC with sarcomatoid differentiation in vitro and in vivo, facilitating tumor progression by inhibiting PTEN and activating the PI3K/AKT pathway. This study demonstrated the comprehensive gene expression and DNA regulation information of ccRCC with sarcomatoid differentiation, highlighting its malignant characteristics, thereby offering novel insights for the diagnosis and treatment of sarcomatoid ccRCC.

Microbiomes within the tumor microenvironment (TME) are intricately linked to the modulation of cancer cell properties and the prognoses of various types of cancer, including esophageal squamous cell carcinoma (ESCC). However, their contribution to the onset and advancement of ESCC is still not fully elucidated. We adopted single-cell RNA sequencing to investigate the effects of esophageal commensal bacteria during the development of mice's spontaneous ESCCs. By analyzing the single-cell transcriptomes of 54,562 cells across different ESCC pathological stages, commensal bacteria were observed to display a cellular heterogeneous distribution in the ESCC TME. These bacteria were associated with the malignant transformation of epithelial cells and the formation of inflammatory fibroblasts, contributing to a chronic inflammatory microenvironment. However, after depriving commensal bacteria with an antibiotic cocktail (ABX), infiltrations of inflammatory fibroblasts and anti-bacteria macrophages were lower than those in the control H₂O group, while the infiltration of regulatory Cd4⁺ T (Treg) cells was higher. Interactions between inflammatory fibroblasts and Treg cells were intensified in the ABX group, which exacerbated the immunosuppressive state in the TME and developed more invasive carcinomas. This study demonstrates the significant role of commensal bacteria in ESCC tumorigenesis and sheds light on the potential clinical applications of adjusting commensal bacteria for the prevention and treatment of ESCC.

Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age-related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context-dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro-tumorigenic and pro-aging effects.

Glioblastoma (GBM) is an aggressive malignant brain tumor, characterized by a poor prognosis and a limited response to chemoradiotherapy and immunotherapy. Increasing evidence indicates that the extracellular matrix (ECM), particularly collagen proteins, contributes to tumor progression and immune evasion. In this study, we identified COL1A2, COL6A2, COL8A1, and COL8A2 as survival-related genes that were overexpressed in GBM and significantly upregulated in short-term survivors. Subsequently, COL6A2 was verified to be associated with chemotherapy and immunosuppression. Functional assays demonstrated that COL6A2 promotes GBM cell proliferation, invasion, and chemoresistance. Cytometry by time-of-flight (CyTOF) and Tumor Immune Estimation Resource (TIMER) analysis revealed that high COL6A2 expression correlates with immunosuppressive features in the tumor microenvironment, particularly the accumulation of immature dendritic cells (DCs) and impaired cytotoxic T-cell activity. Mechanistically, COL6A2 silencing restored DCs' activation and enhanced the infiltration and function of effector immune cells. Our findings highlight COL6A2 as a key oncogenic and immunomodulatory ECM component in GBM and suggest that targeting collagen-mediated immune suppression may improve therapeutic outcomes in GBM patients.

Actinin-4 (gene name: ACTN4) is an actin-bundling protein implicated in cancer invasion and metastasis. This study evaluated whether ACTN4 amplification and actinin-4 protein expression were associated with osimertinib efficacy in epidermal growth factor receptor-mutant non-small cell lung cancer. We retrospectively analyzed 63 patients with epidermal growth factor receptor-mutant non-small cell lung cancer treated with osimertinib as first-line treatment. Immunohistochemistry was performed for pretreatment tumor tissues. Actinin-4 immunohistochemistry positivity was defined as positive staining of ≥ 30% tumor cells. In positive cases, ACTN4 amplification was assessed via fluorescence in situ hybridization. Progression-free survival and overall survival were compared across groups. Among 63 patients (median age: 73 years, 52 with Eastern Cooperative Oncology Group performance status 0–1, 63 with adenocarcinoma; epidermal growth factor receptor mutations: 19del/L858R/uncommon = 32/24/7), there were 33 and 30 actinin-4 immunohistochemistry-positive and actinin-4 immunohistochemistry-negative cases, respectively. The propensity score-weighted overall survival and progression-free survival were significantly shorter for actinin-4 immunohistochemistry-positive patients than for actinin-4 immunohistochemistry-negative patients (overall survival: hazard ratio, 2.76; 95% confidence interval, 1.02–7.45; progression-free survival: hazard ratio, 1.91; 95% confidence interval, 1.03–3.54). Among the 33 actinin-4 immunohistochemistry-positive cases, four showed positivity in ACTN4 fluorescence in situ hybridization. Overall survival and progression-free survival were numerically shorter for patients with ACTN4 positivity than for those with ACTN4 negativity in fluorescence in situ hybridization. The findings suggest that ACTN4 amplification and actinin-4 protein expression are prognostic markers for poor osimertinib efficacy in epidermal growth factor receptor-mutant non-small cell lung cancer.

The standard treatment for muscle-invasive bladder cancer (MIBC) is cisplatin (CDDP)-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy. However, only about 40% of patients respond to NAC, and tools to predict individual responses remain limited. The zebrafish patient-derived xenograft (zPDX) model offers a rapid and cost-effective platform for functional drug testing, but its application to MIBC has not yet been established. In this study, we developed a zPDX model optimized for evaluating CDDP sensitivity using clinical bladder cancer specimens. This model was validated through three steps: (1) evaluation of CDDP response in zPDXs derived from cell lines, (2) comparison of drug responses between mouse PDX (mPDX) and zPDX models, and (3) correlation of zPDX responses with clinical outcomes. The robustness of step 1 was demonstrated through complementary assays, including temperature optimization, in vivo platinum quantification, fluorescent dye validation, Cap Analysis of Gene Expression (CAGE), and whole-mount immunofluorescence. An image-based platform for quantifying drug response by measuring fluorescent area was established and applied in steps 2 and 3. Step 2, using mPDXs, provided essential technical validation before applying the protocol to clinical samples. In step 3, patient-derived tumors were transplanted into zebrafish, allowing successful prediction of CDDP efficacy. Despite the small patient cohort, this study provides fundamental evidence supporting zPDX as a clinically relevant and experimentally validated tool for functional assessment of CDDP sensitivity in bladder cancer.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with poor prognosis and significant molecular heterogeneity. This study investigates the role of tumor-specific enhancers in metabolic reprogramming, focusing on glucose-6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Using native elongating transcript–cap analysis of gene expression and single-cell RNA sequencing, tumor-specific enhancers driving G6PD overexpression were identified in ICC tumor epithelial cells. Functional assays demonstrated that G6PD promotes tumor proliferation by enhancing PPP activity and maintaining redox homeostasis, which provides NADPH to counter oxidative stress. Enhancer knockdown disrupted G6PD expression and PPP activity, increasing reactive oxygen species levels and reducing the NADPH/NADP⁺ ratio. These metabolic changes impaired tumor cell proliferation and sensitized ICC cells to cisplatin, emphasizing the dual therapeutic potential of targeting G6PD to inhibit tumor growth and overcome chemoresistance. Survival analyses showed that high G6PD expression correlates strongly with poor overall survival in ICC patients. While previous studies have recognized the roles of G6PD and PPP in cancer metabolism, this study uniquely links enhancer-mediated regulation to these processes in ICC, offering novel insights into epigenetic mechanisms driving metabolic reprogramming. Moreover, the findings highlight tumor-specific enhancers as critical epigenetic drivers of ICC progression, with potential as therapeutic targets. Future research should explore the integration of enhancer profiling into precision medicine frameworks and the development of novel enhancer-targeting strategies. These efforts could uncover additional metabolic vulnerabilities and provide effective treatments for this highly aggressive cancer.

In Japan, neuropsychological symptoms after human papillomavirus (HPV) vaccinations were publicized as “adverse effects,” leading to vaccine hesitancy. Anti-vaccine activists claimed that adjuvants in HPV vaccines could cause an immune-mediated neurological disease. Adjuvants in the bivalent HPV vaccine (2vHPV) and quadrivalent HPV vaccine (4vHPV) are AS04 [composed of aluminum (Al) hydroxide (AH) and monophosphoryl lipid A (MPL)] and Al hydroxyphosphate sulfate (AHS), respectively. We determined whether HPV vaccinations in mice could reproduce alleged immunopathology. We injected mice intramuscularly with 2vHPV, 4vHPV, two hepatitis B virus vaccines containing AH or AHS, or a varicella-zoster virus vaccine (vVZV) containing an adjuvant AS01 (comprising MPL and QS-21). Histologically, 12 weeks after vaccinations, all four Al-containing vaccine groups had Al-laden macrophage accumulation at the injected muscle; no groups had abnormalities in any other organs, including the brain, heart, liver, and kidney. Immunologically, although the four Al-containing vaccine groups had continuously increased levels of several cytokines, including interferon (IFN)-β, cytokine profiles were not associated with muscle pathology. No groups exhibited any clinical signs, except for the vVZV group, which lost body weight temporarily following each injection. Weight loss in the vVZV group was associated with increased levels of cytokines, including interleukin (IL)-18. Experiments using IL-18 receptor-deficient mice and AS01 injection alone demonstrated that IL-18 and AS01 contributed to weight loss. Since 2vHPV containing AS04 (AH and MPL) did not induce weight loss, QS-21, but not MPL, in AS01 seemed responsible for weight loss, demonstrating the safety of MPL.