Cancer Science最新文献

Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related mortality, with early detection being challenging. Although endoscopic screening can aid in diagnosis, its invasiveness and cost limit widespread compliance. To address this, we developed and validated a non-invasive diagnostic panel based on urinary exosomal microRNAs (miRNAs) for early ESCC detection. Urine samples were prospectively collected from ESCC patients and healthy controls across five institutions, and exosomal miRNA profiles were obtained using small RNA sequencing. A diagnostic panel was constructed using machine learning with recursive feature elimination in a proof-of-concept (POC) cohort comprising 99 ESCC and 93 control samples, and its performance was evaluated by five-fold cross-validation. This panel was subsequently tested in a blinded validation cohort of 50 ESCC and 61 control samples. In the POC cohort, the multi-miRNA panel achieved an area under the curve (AUC) of 0.90. In the validation cohort, the AUC was 0.85 (95% CI: 0.77-0.92), with 84% sensitivity and 66% specificity. The panel showed high sensitivity across disease stages-100% for Stage 0, 91% for Stage I, and 73% for Stages II-IV-and its performance was not significantly affected by sex, body mass index, alcohol use, or smoking. Furthermore, in early-stage cases, the diagnostic score significantly declined after treatment (p = 0.026). These findings suggest that the urinary exosomal miRNA panel may offer a practical screening approach for the early detection of ESCC.

Advanced-stage and metastatic endometrial cancer (EC) are characterized by markedly poor survival outcomes, necessitating a deeper understanding of the mechanisms driving disease advancement. Tumor-associated macrophages (TAMs), particularly the M2 subtype, are instrumental in remodeling the tumor microenvironment and promoting EC proliferation, migration, and metastasis. However, the specific mediators responsible for TAM-driven EC progression remain inadequately elucidated. In this study, we investigated the role of the C-X-C motif chemokine ligand 1 (CXCL1) and its receptor, chemokine receptor 2 (CXCR2), in TAM-induced EC progression. CXCR2, as the primary receptor for CXCL1, activates the NF-κB signaling pathway upon binding, thereby mediating the epithelial-mesenchymal transition process in EC cells and enhancing metastatic potential. This mechanism can be effectively inhibited by silencing CXCR2 or by employing the NF-κB inhibitor BAY 11-7082. Neutralizing CXCL1 markedly diminished the proliferative and migratory burdens imposed by TAMs on EC in subcutaneous xenograft EC models. Additionally, in EC tissue samples, CXCL1 and CXCR2 expression, as well as the extent of macrophage infiltration, exhibited a significant positive relationship with disease progression, suggesting an unfavorable prognosis. In conclusion, targeting the CXCL1/CXCR2 axis is a potential therapeutic approach for EC treatment.

Antibody-drug conjugates (ADCs) are emerging as a promising class of targeted cancer therapy. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed ADC, has demonstrated clinical efficacy in HER2-positive gastric and breast cancers, as well as in HER2-mutant non-small cell lung cancer. However, the development of acquired resistance limits their long-term efficacy. To elucidate the resistance mechanism, we established T-DXd-resistant cell lines derived from HER2-amplified gastric xenografts (N87 acquired resistance [AR]) and leptomeningeal carcinomatosis (Calu-3 AR) lung cancer cells. N87 AR cells exhibited cross-resistance to T-DXd, payload DXd, and topoisomerase I inhibitor SN-38 despite preserved HER2 expression and intact drug internalization. As payload resistance-related molecules, ATP-binding cassette (ABC) transporter ABCG2 and ABCB1 were markedly upregulated in N87 AR and Calu-3 cells, respectively. Inhibition of ABCG2 and ABCB1 in N87 AR and Calu-3 cells, respectively, through siRNA-mediated knockdown restored T-DXd sensitivity in both models. As a strategy to overcome resistance, pharmacological inhibitors of ABCG2 and ABCB1 restored the T-DXd sensitivity of N87 AR and Calu-3 cells, respectively. Moreover, BB-1701, a novel HER2-ADC containing eribulin as a payload, to which N87 AR cells are sensitive, exhibited antitumor effects in N87 AR cells in vitro and in vivo. These findings indicate that ABC transporter-mediated drug efflux is an important mechanism underlying T-DXd resistance in HER2-positive gastric and lung cancer models. Furthermore, our study suggests that both targeting drug efflux pathways and utilizing alternative payloads may be effective strategies for overcoming T-DXd resistance in HER2-positive gastric and lung cancers.

The phase 3 KEYNOTE-522 study in high-risk early-stage triple-negative breast cancer (TNBC) showed significantly improved efficacy outcomes with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy alone. We present findings from the KEYNOTE-522 Japan subgroup. Eligible participants (aged ≥ 18 years) with untreated locally advanced TNBC (stage T1c N1-2 or T2-4 N0-2) were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo plus chemotherapy every 3 weeks for 8 cycles followed by surgery and adjuvant pembrolizumab or placebo for ≤ 9 cycles. Primary endpoints were pathologic complete response (pCR; ypT0/Tis ypN0) at the time of surgery and event-free survival (EFS). Of 76 participants enrolled in Japan, 45 were randomized to the pembrolizumab arm and 31 to the placebo arm. Median time from randomization to data cutoff (March 22, 2024) was 76.3 months. Twenty-four participants (53%) in the pembrolizumab arm and 15 (48%) in the placebo arm achieved pCR (between-treatment arm difference, 4.9%; 95% CI, -17.6% to 27.1%); findings were similar regardless of PD-L1 expression. Rates of EFS at 60 months were 84% and 73%, respectively (HR, 0.54; 95% CI, 0.20-1.50). Grade 3 or 4 treatment-related AEs occurred in 37 of 45 participants (82%) treated with pembrolizumab and 23 of 30 participants (77%) treated with placebo; there were no grade 5 AEs. In conclusion, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab showed improved efficacy outcomes and manageable safety versus neoadjuvant chemotherapy alone in Japanese participants, supporting the use of this regimen in Japanese patients with high-risk early-stage TNBC. Trial Registration: The study (ClinicalTrials.gov, NCT03036488) was conducted in compliance with local and/or national regulations and International Council for Harmonization Good Clinical Practice guidelines and in accordance with the ethical principles originating from the Declaration of Helsinki.

Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare but aggressive malignancy for which no standardized chemotherapy or effective targeted therapies currently exist. To identify therapeutic vulnerabilities in MTMCT, we performed a genome-wide CRISPR-Cas9 knockout screen using the MTMCT-derived NOSCC1 cell line. Two parallel selective pressures were applied: in vivo tumorigenicity in immunodeficient mice and cisplatin exposure in vitro. From this screen, 67 negatively selected genes were identified, among which SOD1 and NDUFB4 emerged as top candidates based on high basal expression levels and clinical relevance. Integration with spatial transcriptomic data from three independent MTMCT patient tumors further supported the prioritization of these targets. SOD1 was selected for further investigation due to the availability of known pharmacological inhibitors. Both siRNA-mediated knockdown and small-molecule inhibition of SOD1 using LCS-1 significantly suppressed MTMCT cell proliferation in vitro by inducing oxidative stress and impairing cell cycle progression. This antiproliferative effect was reversed by co-treatment with N-acetylcysteine, a reactive oxygen species scavenger. In vivo validation using patient-derived xenograft models demonstrated that oral administration of LCS-1 led to significant tumor growth suppression and increased expression of apoptotic and DNA damage markers, including cleaved caspase-3 and γH2AX. These findings establish SOD1 as a critical vulnerability in MTMCT and provide preclinical evidence supporting redox modulation as a therapeutic strategy for this highly chemoresistant and understudied ovarian cancer subtype. Our integrative approach combining functional genomics, spatial transcriptomics, and pharmacologic validation offers a framework for the discovery of novel targets in rare gynecologic malignancies.

Neoadjuvant therapy (NAT) is increasingly used for pancreatic ductal adenocarcinoma (PDAC); yet most patients only achieve partial response. Pathological treatment response grading focuses on assessing residual tumor burden, often overlooking changes in tumor microenvironment (TME). To address this gap, we compared tumor cells and TME of 13 NAT-naïve and 23 post-NAT PDACs using integrated spatial pathomics and transcriptomics, with validation in an independent single-cell spatial dataset. NAT significantly reduced tumor burden (14.7%-6.2%, p = 0.004), but systemic comparison of 13 cytomorphometric features of tumor cells alone did not reliably distinguish between naïve and NAT cases. In contrast, NAT profoundly remodeled TME by increasing cancer-associated fibroblast (CAF) and CD8⁺ T cell densities, promoting CD8⁺ T cell-tumor cell proximity and fibrosis, reducing tumor-associated neutrophils, and redistributing tertiary lymphoid structures (TLSs). Spatial transcriptomics shows NAT induced apoptosis, DNA-damage response, and AGC-kinase (S_TK_X) signaling in tumor cells, and upregulated complement pathway, p53 signaling, and cellular senescence program in TME. Cross-platform single-cell spatial analysis revealed decreased regulatory T cells (Treg) and a shift from myofibroblastic (mCAF) to inflammatory CAF (iCAF). Importantly, post-NAT patients with more fibrosis had longer overall survival (p = 0.02), and higher B-cell density showed a favorable trend (p = 0.06). Together, these results suggest that beyond tumor debulking, NAT induces a coordinated TME remodeling characterized by fibroblast reprogramming, matrix fibrosis, and immune spatial reorganization. Incorporating assessment of NAT-induced stromal and immune changes into TRG may improve prognostication and guide more precise therapy in post-NAT PDAC.

Dysregulation of YAP, the terminal effector of the Hippo pathway, contributes to cancer progression and drug resistance. Its role in glioblastoma (GBM), the most aggressive brain cancer, remains incompletely understood. Single-cell RNA sequencing data from a published GBM dataset were reanalyzed to assess YAP expression across cell populations. YAP was silenced via shRNA in GBM cell lines (U-251 MG, U-87 MG) and patient-derived GBM cells. Resveratrol (RV), a natural blood-brain barrier-permeable compound, was evaluated for growth inhibition and YAP-targeted effects. Functional assays measured proliferation, spheroid formation, migration, invasion, and drug sensitivity. YAP and its cofactor TEAD were highly upregulated in GBM cells compared with normal brain and stromal cells. YAP depletion by shRNA suppressed proliferation, spheroid formation, migration, and invasion. RV treatment similarly inhibited YAP expression, reducing proliferation and viability in monolayer and 3D spheroid cultures, and impairing migration and invasion via epithelial-mesenchymal transition (EMT) inhibition. RV-mediated YAP suppression also enhanced sensitivity to temozolomide (TMZ) and carmustine (BCNU), increasing their cytotoxicity in GBM cells. RV acts as a novel YAP inhibitor in GBM, impairing malignant phenotypes and potentiating the effects of standard chemotherapy. These findings support RV as a potential adjunct in YAP-targeted GBM therapy, warranting further in vivo validation for clinical translation.

Tumor tissues in pancreatic cancer develop with abundant cancer-associated fibroblasts (CAFs), promoting tumor progression. CAF-conditioned medium induces the expression of sushi domain-containing 2 (SUSD2) and enhances the invasive potential of pancreatic cancer cells. We showed that SUSD2 binds to integrin β1 and promotes pancreatic cancer cell motility by inducing phosphorylation of focal adhesion kinase (FAK), facilitating the formation of focal adhesion complexes in cells adhered to collagen 1 or fibronectin. Orthotopic transplantation of SUSD2-overexpressing human pancreatic cancer cell lines into the mouse pancreas enhanced liver metastasis in Panc-1 cells, whereas in KP2 cells, it increased primary tumor growth without promoting metastasis. In spheroid cultures of KP2 cells, forced SUSD2 expression elevated FAK phosphorylation independently of cell adhesion, suggesting that SUSD2 promotes cell proliferation even in non-metastatic cells. High SUSD2 expression in cancer cells contributes to tumor growth and metastasis, identifying SUSD2 as a potential therapeutic target in pancreatic cancer.

Lung adenocarcinoma (LUAD) is one of the most common cancers and a leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. Proteasome 26S Subunit, Non-ATPase 12 (PSMD12), a component of the proteasomal 19S regulatory particle, is associated with tumorigenesis; however, its role in LUAD remains poorly understood. Integrative bioinformatic analysis of The Cancer Genome Atlas (TCGA) and other publicly available LUAD datasets identified PSMD12 as a candidate driver gene on chromosome 17q, a region frequently amplified in LUAD. Clinicopathological and prognostic analyses revealed that PSMD12 was significantly upregulated in tumor tissues because of DNA copy number gain. High PSMD12 expression was associated with poor prognosis and advanced pathological stages. Gene set enrichment analysis of TCGA LUAD dataset demonstrated that samples with high PSMD12 expression were enriched for cell cycle-related pathways. Using CRISPR-Cas9-mediated PSMD12 knockout and lentivirus-mediated overexpression models, we demonstrated that PSMD12 promoted tumor cell proliferation by accelerating the G2/M cell cycle transition in vitro, and xenograft experiments confirmed its tumor-promoting effect in vivo. Mechanistically, PSMD12 overexpression reduced the ubiquitination of CDK1, a key regulator of mitotic entry. Cycloheximide chase and MG132 assays confirmed that PSMD12 stabilized CDK1 by inhibiting proteasome-mediated degradation. In conclusion, we identified PSMD12 as a novel driver gene and prognostic biomarker of LUAD. PSMD12 promoted LUAD progression by modulating CDK1 ubiquitination and enhancing cell cycle progression. These findings suggest that PSMD12 is a promising molecular target for future LUAD therapies.