Cancer Science最新文献

The BCR::ABL1 oncogene plays a crucial role in the development of chronic myeloid leukemia (CML). Previous studies have investigated the involvement of mitochondrial dynamics in various cancers, revealing potential therapeutic strategies. However, the impact of BCR::ABL1 on mitochondrial dynamics remains unclear. In this study, we demonstrated that BCR::ABL1 is sufficient to induce excessive mitochondrial fragmentation by activating dynamin-related protein (DRP)1 through the mitogen-activated protein kinase (MAPK) pathway. Leukocytes obtained from patients with CML and the BCR::ABL1-positive cell lines exhibited increased mitochondrial fragmentation compared to leukocytes obtained from healthy donors and BCR::ABL1-negative cells. Furthermore, the analysis of BCR::ABL1-transduced cells showed increased phosphorylation of DRP1 at serine 616 and extracellular signal-regulated kinase (ERK) 1/2. Moreover, the inhibition of DRP1 and upstream mitogen-activated extracellular signal-regulated kinase (MEK) 1/2 suppressed mitochondrial fragmentation. Strikingly, DRP1 inhibition effectively reduced the viability of BCR::ABL1-positive cells and induced necrotic cell death. Additionally, a label-free artificial intelligence-driven flow cytometry successfully identified not only the BCR::ABL1-transduced cells but also peripheral leukocytes from CML patients by assessing mitochondrial morphological alterations. These findings suggested the crucial role of BCR::ABL1-induced mitochondrial fragmentation in driving BCR::ABL1-positive cell proliferation, and the potential use of mitochondrial morphological alterations as a clinical biomarker for the label-free detection of CML cells.

Matrix metalloproteinase 11 (MMP11), a zinc-dependent endopeptidase involved in extracellular matrix degradation and remodeling, has been identified as a tumor promoter in multiple cancer types. However, its expression pattern and role in pancreatic ductal adenocarcinoma (PDAC) remain unclear. In this study, elevated MMP11 expression was identified in PDAC tissues and was associated with diminished survival. Integrated single-cell RNA sequencing and co-immunofluorescence staining revealed that MMP11 was predominantly expressed in cancer-associated fibroblasts (CAFs). Mechanistically, cancer cell-derived TGF-β1 mediated CAF activation via the pSmad2/3 pathway and accompanied by MMP11 production. Additionally, MMP11 knockdown in CAFs impaired the proliferative and invasive abilities of AsPC-1 and BxPC-3 cells in vitro; which could be rescued by adding recombinant MMP11. Similarly, co-injection of AsPC-1 cells with MMP11-knockdown CAFs into nude mice significantly suppressed tumor growth and liver metastasis compared with tumors bearing unmodified CAFs. Furthermore, we confirmed that CAF-derived MMP11 may drive the epithelial-mesenchymal transition process of PDAC cells to promote tumor invasion via the PI3K/AKT pathway rather than extracellular matrix remodeling. Collectively, we uncovered a crosstalk between cancer cells and CAFs mediated by TGF-β1 and MMP11 that drives the progression of PDAC.

This study explores the molecular role of the BTK gene in lung adenocarcinoma (LUAD) progression and patient prognosis. Using a radiomics model based on BTK expression and PET-CT data analyzed through DeeplabV3, alongside transcriptomic and clinical data from TCGA, we established a strong predictive relationship between BTK levels and LUAD outcomes. Our findings demonstrate that low BTK expression is linked to poorer prognoses. Experimental models, including cell lines and in vivo mouse studies, revealed that BTK deficiency leads to increased LUAD cell proliferation, invasion, and metastasis. Furthermore, in vivo models indicated that BTK knockdown results in enhanced tumor growth and diminished CD8+ T cell activity. These results suggest that BTK plays a crucial role in modulating LUAD progression and the tumor immune environment, highlighting its potential as a therapeutic target.

Pancreatic cancer is among the deadliest cancers, with a grim prognosis despite advances in treatment. We conducted a population-based case-control study from Taiwan, linking Health and Welfare Data Science Center data to the Taiwan Cancer Registry, which offers a promising strategy for its treatment through drug repurposing. The study aims to identify the association of anti-parkinsonian drugs with pancreatic cancer risk across different age groups. The analysis encompassed 18,921 pancreatic cancer cases and 75,684 matched controls, employing conditional logistic regression to assess the impact of anti-parkinsonian drugs on the risk of pancreatic cancer. Key findings revealed a statistically significant association of the administration with specific anti-parkinsonian medications, including anticholinergic agents, tertiary amines, dopa derivatives, and dopamine receptor agonists, with a reduction in pancreatic cancer risk. These associations were represented as adjusted odds ratios (aORs), ranging from 0.620 (95% CI 0.470-0.810) to 0.764 (95% CI 0.655-0.891). Further, age-stratified analysis revealed variations in efficacy across different age groups. Anticholinergic agents and tertiary amines exhibited greater effectiveness in the 40-64-year age group (aOR, 0.653; 95% CI, 0.489-0.872), whereas dopa derivatives and dopamine receptor agonists were particularly efficacious in the cohort aged ≥65 years (aOR, 0.728; 95% CI, 0.624-0.850 and aOR, 0.665; 95% CI, 0.494-0.894, respectively). Notably, specific drugs such as trihexyphenidyl, levodopa/dopa decarboxylase inhibitor (DDCI), and pramipexole demonstrated a significant decrease in cancer risk, especially in the elderly population. These preliminary findings can contribute to the possible therapeutic role of anti-parkinsonian drugs in the treatment of pancreatic cancer.

Smoking-associated epigenetic changes have been linked to lung cancer (LC) risk; however, the role of epigenetic alterations independent of smoking is yet to be fully understood. This study aimed to validate 16 previously reported CpG sites that are independent of smoking yet associated with LC risk within a population-based prospective cohort. Using the Infinium Methylation EPIC BeadChip kit or the Infinium HumanMethylation450K BeadChip Assay, DNA methylation (DNAm) in whole blood was assessed in four subsets (n = 736, 1027, 997, and 312) of a population-based cohort from Germany. The DNAm levels of the 16 smoking-independent CpG sites were analyzed. Hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated to assess associations of DNAm at the 16 CpG sites with LC risk, adjusting for multiple covariates, including smoking habits and a smoking-associated DNAm score. Over 17 years of follow-up, a total of 199 LCs were observed. Among the 16 CpGs, cg02211449 showed a negative association with LC risk (HR [95% CI] per SD increase, = 0.70 [0.63-0.78]), while cg11385536 (1.04 [1.01-1.07]), cg09736286 (1.64 [1.10-2.44]), cg19907023 (1.64 [1.01-2.66]), and cg22032485 (1.52 [1.04-2.21]) displayed positive associations with LC risk. Five of the 16 suggested smoking-independent CpGs could be externally validated as predictors of LC risk. Further research should address their potential contribution to enhanced LC risk stratification.

Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.