Molecular Oncology最新文献

Complete surgical resection is essential for oropharyngeal squamous cell carcinoma (OPSCC) therapy, underscoring the need for improved intraoperative margin assessment. To advance in vivo diagnostics for OPSCC, Nanosecond infrared laser (NIRL) tissue sampling combined with shotgun lipidomic analysis reveals lipidome differences between OPSCC tissue and adjacent healthy tissue. In this study, ablations were performed on tonsil squamous cell carcinoma in 28 samples from 11 patients using an established chamber setup, and a subset of six samples from three patients with a custom-made laser fiber-coupled applicator, designed for handheld use. Welch's t-test results (p = 0.05, two-fold change) revealed a similar OPSCC lipid profile in seven out of 11 patients. Potential tumor lipid markers were identified as consistently and significantly increased, despite the biological heterogeneity of the samples, underscoring their potential diagnostic value. Tissue ablation with fiber-coupled applicator was successful and the lipidomic analysis was consistent with the chamber setup. While limited to off-line analysis, our approach highlights the potential of fiber-based laser sampling as a rapid and minimally invasive method to obtain tissue material for advanced molecular profiling in surgical and endoscopic settings.

Single circulating tumor cell (sCTC) analysis enables the determination of predominant CTC phenotypes and genotypes. We previously demonstrated the feasibility of sCTC detection and genomic characterization in high-grade serous ovarian cancer (HGSOC) by combining immune-magnetic enrichment and image-based sorting, followed by whole-genome amplification (WGA) and next-generation sequencing-based copy number alteration analysis (CNA). Here we aimed to improve our workflow by incorporating HGSOC-specific markers, folate receptor alpha (FRα), and markers to identify epithelial (cytokeratin) and mesenchymal (vimentin) phenotypes for the phenotypic as well as genotypic analysis of sCTCs over the course of treatment in 42 HGSOC patients. We detected a significant reduction of FRα-positive cells (P = 0.0205) and an expansion of cells with a high nuclear staining and no target antigen expression (P = 0.002). Before treatment, sCTCs showed an enrichment in CNAs of Chromosomes 2, 7, and 12, while CNA dynamics of sCTCs suggested a potential selection of distinct CNAs specific to the homologous recombination pathway. sCTCs revealed persistent CNAs in the CDK4 and emerging ones in the ALK oncogene. Notably, primary tumors revealed considerable fractions of shared genomic aberrations.

Copy number variations (CNVs) play a crucial role in cancer diagnostics and prognostics, potentially impacting treatment decisions. Ultra-low-pass whole-genome sequencing (ULP-WGS) has emerged as a promising alternative to array-based methods for CNV detection, especially in formalin-fixed paraffin-embedded (FFPE) samples. However, sequencing biases and sample heterogeneity necessitate the optimization of CNV detection tools for FFPE sample-derived data. This study evaluates three open-source CNV callers (CNVpytor, ichorCNA, and WisecondorX) using ULP-WGS and compares their performance against a single nucleotide polymorphism (SNP) array. Our results demonstrate that under optimal experimental conditions, ichorCNA and WisecondorX achieved equal detection of true positive results, with reduced false positive results compared to the SNP array. The SNP array detection pattern differed somewhat from that of the CNV callers, while ichorCNA and WisecondorX had the most comparable detection pattern. We highlight the importance of (pre-)analytical parameters such as neoplastic cell content, sequencing coverage, and bin size selection on CNV detection accuracy. Our findings support the adoption of ULP-WGS-based CNV detection as a robust alternative to SNP arrays, with WisecondorX emerging as the most suitable tool for clinical implementation.

Receptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, and ERBB4 mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associated ERBB4 mutations that are located at regions important for receptor activation and/or are paralogous to known oncogenic hotspot mutations in other ERBB genes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More detailed analyses of the most potent mutations, S303F, E452K, and L798R, showed that they are activating, can co-operate with other ERBB receptors and are sensitive to clinically available second-generation pan-ERBB inhibitors neratinib, afatinib, and dacomitinib. Furthermore, the S303F mutation, together with a previously identified activating ERBB4 mutation, E715K, promoted resistance to third-generation EGFR inhibitor osimertinib in EGFR-mutant lung cancer model in vitro and in vivo. Together, these results are expected to facilitate clinical interpretation of the most recurrent cancer-associated ERBB4 mutations. The findings provide rationale for testing the efficacy of clinically used pan-ERBB inhibitors in patients harboring driver ERBB4 mutations both in the treatment-naïve setting, and upon development of resistance to targeted agents.

Monomethyl auristatin E (MMAE) is used as the cytotoxic payload for enfortumab vedotin (EV) in the treatment of locally advanced and metastatic bladder cancer (BC). However, the development of resistance to MMAE in BC is a therapeutic problem. To explore the mechanism of resistance to MMAE in BC, we established MMAE-resistant BC cells (MR-BCs). RNA sequencing analysis showed that the expression of dipeptidyl peptidase 4 (DPP4, also called CD26) increased significantly in MR-BCs compared with parental BC cells. Knock down of DPP4 expression using small interfering RNA inhibited the viability of MR-BCs. In addition, the DPP4 inhibitor sitagliptin suppressed the proliferation, migration, and invasion of BC cells, and cotreatment with MMAE effectively induced cell apoptosis, arrested cells in the G₂M phase of the cell cycle, increased reactive oxygen species production by inhibiting the AKT pathway, and significantly inhibited the in vivo growth of MMAE-resistant cells. This study provides insights into the use of DPP4 inhibitors as a treatment strategy for MMAE-resistant BC.

Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a major driver of hepatocellular carcinoma (HCC). Crouchet et al. identify PRDX2 as a key regulator linking oxidative stress, metabolic imbalance, and oncogenic signaling. Across multiple in vivo and in vitro models, PRDX2 inhibition restores metabolic homeostasis, reduces tumor initiation, and selectively impairs HCC cell survival. These findings highlight PRDX2 as a promising biomarker and hepatocyte-directed target for chemoprevention, emphasizing the importance of the interplay between metabolism and liver cancer development.

A hypoxic microenvironment promotes the aggressiveness of lung adenocarcinoma (LUAD) through treatment resistance and generation of new lymphatic vessels (i.e., lymphangiogenesis) favoring metastatic dissemination. Transcriptomic analysis of cohorts of LUAD patients highlighted LINC01116, a long noncoding RNA, associated with a bad prognosis, a high rate of recurrence, and induced by hypoxia in tumors. Gain- (overexpression) and loss-of-function (CRISPRi (Clustered Regularly Interspaced Short Palindromic Repeats interference, RNA interference)) approaches performed in LUAD cancer cell lines did not reveal a clear regulatory role for LINC01116 in tumor cells. Analyses of LUAD single-cell RNA sequencing data sets and RNA Fluorescent In Situ Hybridization (RNA-FISH) showed high expression of LINC01116 in lymphatic endothelial cells (LEC) pointing to this transcript as a specific biomarker of tumoral lymphangiogenesis. Efficient knockdown of LINC01116 in LEC in normoxic or hypoxic conditions impacted the proliferation rate under hypoxic stimulation and revealed a gene signature associated with proliferation and hypoxia sensing. Together, our data suggest a role for LINC01116 in pathological lymphangiogenesis of lung tumors.

Hepatoblastoma (HB), the most frequent pediatric liver cancer (2.16 cases/million), has surgery and perioperative chemotherapy as primary treatment, with severe lifelong side effects. This study evaluates the efficacy of the Wnt/CTNNB1 inhibitor WNTinib as a potential HB treatment, since CTNNB1 mutations occur in 70-90% of HBs. WNTinib's efficacy was assessed in three animal models (n = 48): (a) patient-derived xenograft (PDX) HB tumors (n = 5 CTNNB1-mutant, n = 1 CTNNB1 wild-type) implanted in NSG mice; (b) PDX-derived TT001- and (c) HepG2-HB cells subcutaneously implanted in Fox1^nu mice; and in two patient-derived organoids from CTNNB1-mutant HBs. WNTinib delayed tumor growth in n = 4/5 CTNNB1-mutant PDX models and significantly improved survival versus controls (P = 0.03), with no effect in the wild-type model. Further, in the TT001 and HepG2 models, WNTinib reduced tumor growth (P < 0.05 and P = 0.002) and extended survival (P = 0.03 and P = 0.008), respectively. In HB organoids, WNTinib demonstrated greater efficacy than standard-of-care cisplatin (P = 0.009, org-1), and its antitumor effect was further enhanced when combined with chemotherapy (P = 0.01, org-1; P = 0.007, org-22). WNTinib delays tumor progression and increases survival in CTNNB1-mutated HB models, providing rationale to explore its use in human HB.

Potassium channels in brain tissue orchestrate essential cellular processes, including the regulation of membrane potential and neuronal excitability. Among them, large-conductance calcium-activated potassium (BK_Ca) channels play a pivotal role in both normal brain physiology and the pathogenesis of glioblastoma multiforme, a highly aggressive primary brain tumor. Within the central nervous system, BK_Ca channels are widely expressed in neurons, astrocytes, and oligodendrocytes, contributing to ion homeostasis and synaptic transmission. In glioblastoma cells, overexpression of BK_Ca channels, particularly the glioma-specific gBK_Ca variant, facilitates tumor progression by enhancing cell migration, invasion, and therapeutic resistance. Recent evidence highlights the significance of the mitochondrial isoform of the BK_Ca channel (mitoBK_Ca) in modulating oxidative phosphorylation and reactive oxygen species generation, thereby promoting tumor cell survival under hypoxic and cytotoxic stress. This review summarizes current insights into the role of BK_Ca and mitoBK_Ca channels in glioblastoma biology, their potential classification as oncochannels, and the emerging pharmacological strategies targeting these channels, emphasizing the translational challenges in developing BK_Ca-directed therapies for glioblastoma treatment.