Cancer Science最新文献

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.

This case study describes the clinical course of a 39-year-old woman with metastatic breast cancer harboring a germline PALB2 mutation who was treated with a PARP inhibitor. She initially demonstrated a clinical benefit with reduced tumor markers and favorable imaging findings. However, disease progression occurred after eight months. Liquid biopsy-based genomic profiling identified three PALB2 reversion mutations that restored homologous recombination, leading to treatment resistance. The case illustrates both the therapeutic potential of PARP inhibitors in PALB2-mutated cancers and the emergence of resistance. It emphasizes the importance of liquid biopsy-based genomic profiling for understanding tumor evolution and guiding treatment strategies.

Guanosine triphosphate (GTP) is increasingly recognized as a critical actor in cancer cell proliferation, yet its regulatory mechanism remains incompletely defined. A key contributor to elevated GTP levels in tumors is inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in the de novo guanine nucleotide biosynthetic pathway. Although IMPDH inhibitors, mycophenolic acid (MPA) and mycophenolate mofetil (MMF), have shown potential in cancer therapies, their success has been limited due to their immunosuppressive side effects and several unresolved regulatory mechanisms, including paradoxical control of IMPDH activity by GTP. This review provides a systematic summary of the current understanding of IMPDH biology, emphasizing its complex regulation and therapeutic relevance in cancer. We will outline key unresolved questions, including isozyme-specific roles and mechanisms for escaping regulation, and propose mechanistic and translational strategies to design IMPDH-targeted cancer therapies.

CENP-C, an essential component of the kinetochore, connects centromeric chromatin to the outer kinetochore, and thereby ensures accurate chromosome segregation. Although deletion of the Mis12-binding domain (M12BD) of CENP-C does not cause developmental disorders in mice, it promotes malignant tumor progression in the two-stage DMBA/TPA-induced skin carcinogenesis model. In this study, we have demonstrated that M12BD deletion of CENP-C enhances proliferation and then promotes abnormal differentiation in DMBA/TPA-induced carcinomas in mice. To elucidate the underlying molecular mechanisms, we performed RNA sequencing and found the dysregulated expression of keratinization-related genes. Intriguingly, elevated chromosomal aneuploidy was detectable in mice with the M12BD deletion of CENP-C. Among the aneuploidies, trisomies of chromosomes 6 and 10 took place at the highest frequency. These specific chromosomal gains were accompanied by upregulation of genes involved in immune and inflammatory responses. Together, our present findings strongly suggest that M12BD of CENP-C plays a critical role in the regulation of epithelial differentiation during tumor development in mice.

Reprimo (encoded by RPRM) was initially identified as a p53 target gene in 2000 and functions as a tumor suppressor. Promoter hypermethylation of RPRM is frequently observed in various cancers, suggesting that it is transcriptionally silenced during tumorigenesis. Previous studies have reported that overexpression of RPRM induces G2/M cell cycle arrest, inhibits cell proliferation, promotes apoptosis, and increases cellular sensitivity to DNA damage. However, the molecular function of Reprimo is not completely understood. In particular, our recent studies revealed that Reprimo has a novel extracellular function, being secreted outside the cells where it functions to induce apoptosis in its target cells. Furthermore, we found that this apoptosis pathway is novel, mediated by a signaling pathway composed of p53-Reprimo-protocadherin family-Hippo-YAP/TAZ-p73. Reprimo is the first example of an extracellular ligand that induces cell death by modulating YAP activity and is a unique upstream regulator of Hippo signaling. This review summarizes current knowledge of the tumor-suppressive mechanisms of Reprimo, with an emphasis on its unique extracellular function and discusses potential future research directions and clinical applications in cancer therapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a tumor-specific treatment using monoclonal antibody (mAb) photosensitizer conjugates, followed by near-infrared light irradiation. This study aimed to identify the optimum target for treating esophagogastric junction (EGJ) adenocarcinoma and to evaluate the efficacy of NIR-PIT using mAbs in preclinical models. Tumor samples from 46 consecutive patients who had undergone surgery without any prior treatment for EGJ adenocarcinoma were assessed for expression and homogeneity of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and epithelial cell adhesion molecule (EpCAM) through immunohistochemistry. Results showed positive rates of 22%, 13%, and 98% for EGFR, HER2, and EpCAM, respectively, with EpCAM also demonstrating the highest homogeneity (93%). Therefore, EpCAM was selected as the optimal target for NIR-PIT. The fully human monoclonal antibody targeting EpCAM, adecatumumab, was conjugated with the photosensitizer IR700 at different dye-antibody ratios (DAR2, DAR4, DAR7) and tested on OE19 cells and xenograft mouse models under near-infrared light irradiation. NIR-PIT with adecatumumab-IR700 significantly reduced tumor size and improved prognoses compared to controls, with DAR2 showing the best balance of efficacy and minimal side effects. Notable EpCAM expression and homogeneity underpin EpCAM as a promising target for NIR-PIT in EGJ adenocarcinoma. The fully human anti-EpCAM antibody may be suitable for NIR-PIT in EGJ adenocarcinoma.

Pancreatic cancer remains a highly lethal disease, largely attributed to the rapid development of resistance against standard chemotherapy regimens. Although an acidic tumor microenvironment (TME) has been implicated in this resistance, the molecular mechanisms involved are not fully understood. In this study, we identified Family with Sequence Similarity 111 Member B (FAM111B) as significantly upregulated in pancreatic cancer cells under acidic conditions through RNA sequencing and validated. Functional analyses revealed that FAM111B regulates intracellular pH (pHi). Moreover, combining gemcitabine with α-cyano-4-hydroxycinnamic acid, a lactate transporter inhibitor known to decrease pHi, markedly suppressed pancreatic cancer cell viability compared to gemcitabine alone, thereby enhancing the sensitivity under acidic conditions in both in vitro and in mouse xenograft models. Clinically, elevated FAM111B expression correlated with significantly poorer overall survival in pancreatic cancer patients receiving gemcitabine-based chemotherapy (median OS: 2.05 vs. 3.66 years, p = 0.038). Multivariate analysis identified FAM111B expression as an independent predictor of poor prognosis (HR = 3.05, p = 0.032). These findings highlight the crucial role of FAM111B in maintaining pHi homeostasis under acidic TME conditions and contributing to gemcitabine resistance. Targeting FAM111B may represent a novel therapeutic strategy to overcome chemotherapy resistance and improve clinical outcomes in pancreatic cancer.

Breast cancer remains a leading cause of cancer mortality worldwide, underscoring the urgent need for novel and effective therapeutic strategies. Eph receptor tyrosine kinases, particularly EphB4, exhibit diverse roles in cancer biology, acting as either tumor promoters or suppressors depending on the cellular environment and ligand engagement. EphB4 is frequently overexpressed in breast cancer and contributes to dysregulated signaling and tumor progression through the abnormal interaction with its ligand Ephrin-B2. We herein developed an improved anti-EphB4 monoclonal antibody, Eb₄Mab-7-mG_2a, which can be characterized as a subclass-switched IgG_2a variant designed to enhance immune effector function, specifically antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Our findings showed that Eb₄Mab-7-mG_2a effectively blocked Ephrin-B2-induced ERK phosphorylation and proliferation in EphB4-positive MCF-7 breast cancer cells but had no effect on EphB4-knockout (KO) MCF-7 cells. Flow cytometry confirmed high-affinity binding between Eb₄Mab-7-mG_2a and EphB4-expressing cells, whereas in vitro assays demonstrated potent and selective ADCC and CDC activities against EphB4-positive tumor cells. In vivo experiments showed that Eb₄Mab-7-mG_2a significantly suppressed xenograft growth in models bearing EphB4-overexpressing CHO-K1 and EphB4-positive MCF-7, but showed no therapeutic effect in EphB4-negative CHO-K1 and EphB4-KO MCF-7 xenografts. Immunohistochemical analysis revealed reduced Ki-67 proliferation indices in treated tumors, supporting the antiproliferative effects of the developed antibody. Overall, these findings demonstrate that Eb₄Mab-7-mG_2a exerts dual-action antitumor activity through ligand blockade and immune effector engagement. Further evaluations in other EphB4-overexpressing cancers and in combination with immune checkpoint inhibitors are warranted. Humanization and tumor-selective engineering may enhance its clinical potential for precision oncology.