Cancer Communications最新文献

Background: Increased Galectin 3-binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.

Methods: The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis (MASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis. The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.

Results: In patients with MASH and HCC, the levels of LGALS3BP and TGFB1 exhibited positive correlations. Stimulation of LGALS3BP by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice, with increased TGFB1 levels. LGALS3BP directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl₄ induced fibrosis. Moreover, LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.

Conclusion: LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.

Dendritic cells (DCs) comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body. However, several factors impair the immune function of DCs and may promote immune evasion in cancer. Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumor microenvironment (TME) is critical for designing effective strategies for cancer immunotherapy. Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system. Herein, factors in the TME that induce DC dysfunction, such as cytokines, hypoxic environment, tumor exosomes and metabolites, and co-inhibitory molecules, have been described. Furthermore, several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified. Finally, this review provides an overview of current clinical immunotherapies targeting DCs, especially therapies with proven clinical outcomes, and explores future developments in DC immunotherapies.

Background: N4-acetylcytidine (ac4C) represents a novel messenger RNA (mRNA) modification, and its associated acetyltransferase N-acetyltransferase 10 (NAT10) plays a crucial role in the initiation and progression of tumors by regulating mRNA functionality. However, its role in hepatocellular carcinoma (HCC) development and prognosis is largely unknown. This study aimed to elucidate the role of NAT10-mediated ac4C in HCC progression and provide a promising therapeutic approach.

Methods: The ac4C levels were evaluated by dot blot and ultra-performance liquid chromatography-tandem mass spectrometry with harvested HCC tissues. The expression of NAT10 was investigated using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemical staining across 91 cohorts of HCC patients. To explore the underlying mechanisms of NAT10-ac4C in HCC, we employed a comprehensive approach integrating acetylated RNA immunoprecipitation and sequencing, RNA sequencing and ribosome profiling analyses, along with RNA immunoprecipitation, RNA pull-down, mass spectrometry, and site-specific mutation analyses. The drug affinity responsive targets stability, cellular thermal shift assay, and surface plasmon resonance assays were performed to assess the specific binding of NAT10 and Panobinostat. Furthermore, the efficacy of targeting NAT10-ac4C for HCC treatment was elucidated through in vitro experiments using HCC cells and in vivo HCC mouse models.

Results: Our investigation revealed a significant increase in both the ac4C RNA level and NAT10 expression in HCC. Notably, elevated NAT10 expression was associated with poor outcomes in HCC patients. Functionally, silencing NAT10 suppressed HCC proliferation and metastasis in vitro and in vivo. Mechanistically, NAT10 stimulates the ac4C modification within the coding sequence (CDS) of high mobility group protein B2 (HMGB2), which subsequently enhances HMGB2 translation by facilitating eukaryotic elongation factor 2 (eEF2) binding to the ac4C sites on HMGB2 mRNA's CDS. Additionally, high-throughput compound library screening revealed Panobinostat as a potent inhibitor of NAT10-mediated ac4C modification. This inhibition significantly attenuated HCC growth and metastasis in both in vitro experiments using HCC cells and in vivo HCC mouse models.

Conclusions: Our study identified a novel oncogenic epi-transcriptome axis involving NAT10-ac4C/eEF2-HMGB2, which plays a pivotal role in regulating HCC growth and metastasis. The drug Panobinostat validates the therapeutic potential of targeting this axis for HCC treatment.

Background: Anaplastic lymphoma kinase (ALK) test in advanced non-small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement. This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC.

Methods: In this real-world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)-VENTANA-D5F3. The positive ALK gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well.

Results: The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC-VENTANA-D5F3 revealed an intra-hospital consistency rate of 98.2% (879/895) and an inter-hospital consistency rate of 99.2% (646/651). IHC-VENTANA-D5F3 was used in 53.6%, real-time polymerase chain reaction (RT-PCR) in 25.4%, next-generation sequencing (NGS) in 18.3%, and fluorescence in-situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT-PCR. The overall ALK gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of > 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all P < 0.05).

Conclusions: This study highlights the real-world variability and challenges of ALK test in advanced NSCLC, demonstrating a predominant use of IHC-VENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.

Background: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.

Methods: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS).

Results: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed.

Conclusions: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.

Trial registration: ClinicalTrials.gov number, NCT03849768.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Patient-derived xenograft (PDX) models have been used to explore therapeutic opportunities for pancreatic ductal adenocarcinoma (PDAC) [1]. Although original tumor characteristics are altered by cancer-stromal interactions in a PDX-specific manner [2], the implications of clonal evolution from PDAC tumors to PDX are largely unknown.

In this study, we have conducted a comprehensive genomic analysis using 36 patient-matched PDAC tumor and PDX samples (Figure 1A). The detailed methods regarding this study are described in the Supplementary Materials. The clinical information is summarized in Supplementary Table S1. To compare the somatic mutation profiles of PDAC tumors and PDX, 33 whole exome sequencing data were analyzed by using matched patient blood as a normal control. The proportion of PDX samples with Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Tumor Protein P53 (TP53), Mothers Against Decapentaplegic Homolog 4 (SMAD4), and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations increased compared to PDAC tumors, indicating that cancerous clones evolved in PDX from primary tumors (Supplementary Table S2-S5, Figure 1B) [3]. Specifically, the frequency of the KRAS G12D mutation increased during PDX establishment, suggesting that this mutation could be responsible for driving clonal evolution in PDX models (Supplementary Table S2). Next, we observed the high correlation of the variant allele frequencies (VAFs) of commonly mutated genes between matched PDAC tumors and PDX in pairwise comparison (Figure 1C), indicating that the overall mutation rate was conserved during PDX construction. When VAFs were compared at the gene level, VAFs of driver genes significantly increased in PDX compared to primary tumors (Figure 1D). Copy number variation (CNV) profiles of protein-coding genes were also similar between the matched samples (Figure 1E, Supplementary Figure S1), while the copy numbers of driver genes became more evident in PDX compared to primary tumors (Figure 1F). Clonality analysis showed that subclones of primary tumors evolved as monoclonal or polyclonal patterns in matched PDX (Supplementary Figure S2). Despite the lack of investigations into clonal evolution over passages, these results suggest that molecular subtypes of PDX could deviate from PDAC tumors via clonal evolution during PDX model construction.

To investigate whether conventional PDAC subtyping is applicable to PDX, the molecular subtypes defined by Bailey et al. [5] were assigned to PDAC tumors and PDX. PDAC tumors were clearly clustered according to the Bailey gene signatures, showing the worst prognosis of patients with the squamous subtype as previously reported (Figure 1G). However, PDX clustering based on the Bailey gene signatures exhibited 61% (22/36) conflicting subtypes between the matched PDAC tumor and PDX samples (Supplementary Table S6). In particular

Chronic myeloid leukemia (CML) is a lethal hematopoietic malignancy with a global incidence primarily attributed to the breakpoint cluster region-Abelson (BCR-ABL1) fusion oncogene in over 95% of cases. The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized CML management; however, a subset of patients encounters challenges such as resistance and relapse, hindering the achievement of complete remission. Overcoming these challenges in CML also requires addressing persistent leukemia stem cells (LSCs) with inherent resistance mechanisms. Key regulators of LSC metabolism, proliferation, and survival, as well as genetic and epigenetic alterations, provide potential targets [1].

In this study, leveraging in silico analysis (methods and descriptions of other assays are in the Supplementary file) of LSCs from CML patients at diagnosis, we demonstrated enrichment in pathways predominantly associated with proliferation, oxidative phosphorylation (OXPHOS), and metabolism, concurrently with a decrease in immune response pathways (Figure 1A). Similarly, genes negatively impacting proliferation in CML cell lines, when depleted by CRISPR, were enriched in processes related to OXPHOS, metabolism, and proliferation, mirroring the enrichment observed in LSCs (Figure 1B) [2].

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD)⁺-dependent histone deacetylases. SIRT1 and SIRT2 modulate key signaling proteins impacting metabolism, survival, and stress response [3]. Overexpression of SIRT1 and SIRT2 was observed in various cancers, including leukemia (Supplementary Figure S1A) [4, 5]. However, our analysis of CML patients revealed variability in the expression levels of SIRT1 and SIRT2 across datasets (Supplementary Figure S1B). Given the relatively small sample sizes, we recognized the limitations of relying solely on single gene expression data, as it may not fully capture the functional relevance of SIRT1/2 in CML. In response to this limitation, we expanded our analysis to identify broader gene expression patterns associated with SIRT1/2. Specifically, we identified a CML-related network comprising 180 co-regulated transcriptional targets associated with SIRT1/2 enriched in genes relevant to leukemia (Figure 1C, Supplementary Figure S1C-E). To quantify their collective impact, we consolidated the expression of all transcripts in the SIRT1/2 regulon into a unified score, referred to as the SIRT1-2 regulon score. This score effectively discriminated between healthy hematopoietic stem cells and LSCs from CML patients at diagnosis (Figure 1D), indicating the collective impact of SIRT1 and SIRT2 on the disease.

Given the complementary roles of SIRT1 and 2 in regulating metabolic and survival pathways and their potential to compensate for each other's loss of function [3], we postulated that exploiting metabolic vulnerabilities in LSCs throu