Cancer letters最新文献

Metastasis is the main cause of mortality in colorectal cancer (CRC) patients. Exploring the mechanisms of metastasis is of great importance in both clinical and fundamental CRC research. CRC is a highly heterogeneous disease with variable therapeutic outcomes of treatment. In this study, we applied spatial transcriptomics (ST) to generate a tissue-wide transcriptome from two primary colorectal cancer tissues and their matched liver metastatic tissues. Spatial RNA information showed intratumoral heterogeneity (ITH) of both primary and metastatic tissues. The comparison of gene expressions across tissues revealed an apparent enrichment of cancer stem cells (CSCs) in metastatic tissues and identified FOXD1 as a novel metastatic CSC marker. Trajectory and pseudo-time analyses revealed distinct evolutionary trajectories and a dedifferentiation-differentiation process during metastasis. CellphoneDB analysis suggested a dominant interaction of CD74-MIF with tumor cells in metastatic tissues. Further analysis confirmed FOXD1 as a maker of CSCs and the predictor of patient survival, especially in metastatic diseases. Our study found ITH of primary and metastatic tissues and provides novel insights into the cellular mechanisms underlying liver metastasis of CRC and foundations for therapeutic strategies for CRC metastasis.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.

Dysregulation of epigenetics is a hallmark of cancer development, and YTHDF1 stands out as a crucial epigenetic regulator with the highest DNA copy number variation among all N6-methyladenosine (m6A) regulators in colorectal cancer (CRC) patients. Here, we aimed to investigate the specific contribution of YTHDF1 overexpression to CRC progression and its consequences. Through multiple bioinformatic analyses of human cancer databases and clinical CRC samples, we identified GID8/Twa1 as a crucial downstream target of YTHDF1. YTHDF1 manipulates GID8 translation efficiency in an m6A-dependent manner, and high expression of GID8 is associated with more aggressive tumor progression and poor overall survival. Mechanistically, GID8 is intimately associated with glutamine metabolic demands by maintaining active glutamine uptake and metabolism through the regulation of excitatory amino acid transporter 1 (SLC1A3) and glutaminase (GLS), thereby facilitating the malignant progression of CRC. Inhibition of GID8 attenuated CRC proliferation and metastasis both in vitro and in vivo. In summary, we identified a previously unknown target pertaining to glutamine uptake and metabolism in tumor cells, underscoring the potential of GID8 in the treatment of CRC.

RNA modifications play a crucial role in cancer development, profoundly influencing various stages of the RNA lifecycle. These stages encompass nuclear processing, nuclear export, splicing, and translation in the cytoplasm. Among RNA modifications, RNA ac⁴C modification, also known as N4-acetylcytidine, stands out for its unique role in acetylation processes. Specific proteins regulate RNA ac⁴C modification, maintaining the dynamic and reversible nature of these changes. This review explores the molecular mechanisms and biological functions of RNA ac⁴C modification. It examines the intricate ways in which RNA ac⁴C modification influences the pathogenesis and progression of cancer. Additionally, the review provides an integrated overview of the current methodologies for detecting RNA ac⁴C modification. Exploring the potential applications of manipulating this modification suggests avenues for novel therapeutic strategies, potentially leading to more effective cancer treatments in the future.

Prostate cancer (PCa) is the second most prevalent cancer in men worldwide, presenting a significant global public health challenge that necessitates early detection and personalized treatment. Recently, non-invasive liquid biopsy methods have emerged as promising tools to provide insights into the genetic landscape of PCa and monitor disease progression, aiding decision-making at all stages. Research efforts have concentrated on identifying liquid biopsy biomarkers to improve PCa diagnosis, prognosis, and treatment prediction. This article reviews recent research advances over the last five years utilizing extracellular vesicles (EVs) as a natural biomarker library for PCa, and discusses the clinical translation of EV biomarkers, including ongoing trials and key implementation challenges. The findings underscore the transformative role of liquid biopsy, particularly EV-based biomarkers, in revolutionizing PCa diagnosis, prediction, and treatment.

Tertiary lymphoid structures (TLSs) were associated with survival in esophageal squamous cell carcinoma (ESCC) undergoing surgery alone (SA). However, their clinical relevance in neoadjuvant therapies remains less known. Here, we firstly investigated the presence, maturation and spatial distribution of TLSs in 359 ESCC patients receiving neoadjuvant chemotherapy (NCT), neoadjuvant immunotherapy (NCI), neoadjuvant chemoradiotherapy (NCRT) or SA. We found mature TLS (MTLS) was an independent prognostic factor in ESCC. NCI group had the lowest immature TLS cases. NCRT group had the lowest MTLSs. MTLSs mostly located in stromal and normal compartments; these MTLSs were positively correlated with neoadjuvant therapy outcomes. NCI group displayed the highest T cells within 150 μm proximity of TLSs among the four groups. Most T cells were dispersed up to more than 150 μm from TLSs, while B cells remained concentrated within TLSs. Innate lymphoid cells and follicular dendritic cells infiltrated and connected with survival differently in NCRT and NCI groups compared with SA group. The novel PD-L1 combined positive score, NCPS, was positively connected with MTLSs and neoadjuvant therapy efficacy. ScRNA-seq analysis revealed TLS+ tumors had increased plasma cells, B cells, Th17, Tfh and Th1, and elevated exhausted CD8⁺ T cells that highly expressed checkpoint molecules and granzymes. Conclusively, MTLSs favored treatment outcome in ESCC patients receiving multiple neoadjuvant therapies. The spatial distribution of MTLSs was associated with multiregional immune status modified by the neoadjuvant therapies.

Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy.

Glioblastoma, previously known as glioblastoma multiform (GBM), is a type of glioma with a high degree of malignancy and rapid growth rate. It is highly dependent on glutamine (Gln) metabolism during proliferation and lags in neoangiogenesis, leading to extensive Gln depletion in the core region of GBM. Gln-derived glutamate is used to synthesize the antioxidant Glutathione (GSH). We demonstrated that GSH levels are also reduced in Gln deficiency, leading to increased reactive oxygen species (ROS) levels. The ROS production induces endoplasmic reticulum (ER) stress, and the proteins in the ER are secreted into the extracellular medium. We collected GBM cell supernatants cultured with or without Gln medium; the core and peripheral regions of human GBM tumor tissues. Proteomic analysis was used to screen out the target-secreted protein CypB. We demonstrated that the extracellular CypB expression is associated with Gln deprivation. Then, we verified that GBM can promote the glycolytic pathway by activating HIF-1α to upregulate the expression of GLUT1 and LDHA. Meanwhile, the DRP1 was activated, increasing mitochondrial fission, thus inhibiting mitochondrial function. To explore the specific mechanism of its regulation, we constructed a si-CD147 knockout model and added human recombinant CypB protein to verify that extracellular CypB influenced the expression of downstream p-AKT through its cell membrane receptor CD147 binding. Moreover, we confirmed that p-AKT could upregulate HIF-1α and DRP1. Finally, we observed that extracellular CypB can bind to the CD147 receptor, activate p-AKT, upregulate HIF-1α and DRP1 in order to promote glycolysis while inhibiting mitochondrial function to adapt to the Gln-deprived microenvironment.