Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of all cancers, and limited treatment options exist. Immunotherapy is effective in some cancer types, but the immunosuppressive tumor microenvironment (TME) of PDAC is a barrier to effective immunotherapy. CXCR2+ myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors in humans and in mouse models. MDSCs suppress effector cell function, making them attractive targets for restoring anti-tumor immunity. In this study, we show that the most abundant soluble factors released from a genetically diverse set of human and mouse PDAC cells are CXCR2 ligands, including CXCL8, CXCL5, and CXCL1. Expression of CXCR2 ligands is at least partially dependent on mutant KRAS and NFκB signaling, which are two of the most commonly dysregulated pathways in PDAC. We show that MDSCs are the most prevalent immune cells in PDAC tumors. MDSCs expressed high levels of CXCR2, and we found that myeloid cells readily migrate toward conditioned media (CM) prepared from PDAC cultures. We designed CXCR2 ligand-Fc fusion proteins to modulate the CXCR2 chemotactic signaling axis. Unexpectedly, these fusion proteins were superior to native chemokines in binding and activation of CXCR2 on myeloid cells. These "superkines" were potent inhibitors of PDAC CM-induced myeloid cell migration and were superior to CXCR2 small-molecule inhibitors and neutralizing antibodies. Our findings suggest that CXCR2 superkines may disrupt myeloid cell recruitment to PDAC tumors, ultimately improving immunotherapy outcomes in patients with PDAC.

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid malignancy, and its progression is closely associated with patient outcomes. This study investigated the role of the long non-coding RNA LINC02560 in the pathogenesis and aggressiveness of PTC through cell culture, transfection, RT-qPCR, Western blot analysis, and various functional assays, such as MTT, EdU, colony formation, wound healing, and Transwell migration assays. Our results revealed a significant upregulation of LINC02560 in PTC tissues, correlating with poor prognosis in affected patients. Functional analyses demonstrated that silencing of LINC02560 markedly inhibited the proliferation, migration, and invasion of the PTC cell lines, KTC-1, and BCPAP, whereas overexpression promoted these aggressive traits. Mechanistically, LINC02560 acted as a competitive endogenous RNA, sponging miR-505-5p and alleviating its suppression on PDE4C degradation, thereby activating the P-AKT and epithelial-mesenchymal transition (EMT) signaling pathways. Additionally, HNF4α was identified as a transcription factor capable of enhancing the expression of LINC02560. In conclusion, our findings elucidate the critical HNF4α/LINC02560/miR-505-5p/PDE4C axis in PTC pathology, presenting this regulatory network as a promising biomarker combination and potential therapeutic target to improve patient outcomes and survival rates, warranting further clinical investigation to validate these insights and support the development of targeted therapies in PTC management.

Transcribed conserved non-coding elements (TCNEs), which are non-coding genomic elements that can regulate vital gene expression, play an unclear role in the development of severe diseases mainly associated with carcinogenesis. Currently, there are no mature tools for the identification of TCNEs. To compensate for the lack of a systematic interpretation of the functional characterization and regulatory mechanisms of TCNE spatiotemporal activities, we developed a flexible pipeline, called captureTCNE, to depict the landscape of TCNEs and applied it to our breast cancer cohort (SEU-BRCA). Meanwhile, we investigated the genome-wide characteristics of TCNEs and unraveled that TCNEs harbor enhancer-like chromatin signatures as well as participate in the transcriptional machinery to regulate essential genes or architect biological regulatory networks of breast cancer. Specifically, the TCNE transcripts could recruit RBPs, such as ENOX1 and PTBP1, which are involved in gene expression regulation, to participate in the formation of regulatory networks and the association with altered splicing patterns. In particular, the presence of a non-classical secondary structure, called RNA G-quadruplex, on TCNE transcripts contributed to the recruitment of RBPs associated with subtype-specific transcriptional processes related to the estrogen response in breast cancer. Ultimately, we also analyzed the mutational signatures of variant-containing TCNEs and discerned twenty-one genes as essential components of the regulatory mechanism of TCNEs in breast cancer. Our study provides an effective TCNE identification pipeline and insights into the regulatory mechanisms of TCNEs in breast cancer, contributing to further knowledge of TCNEs and the emergence of innovative therapeutic strategies for breast cancer.

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly becomes treatment-resistant. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations, such as BRCA2 or ATM defects, that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging-particularly prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography-to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies. Multi-omics innovations, including liquid biopsy technologies, enable the real-time tracking of emergent AR splice variants or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies, such as pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors, to inhibit tumor plasticity. Immuno-oncological approaches remain challenging for unselected patients; however, subsets with mismatch repair deficiency or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances, and discuss how biomarker-guided integrative treatments can improve mPCa management.

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) are key regulators of sphingolipid signaling, a pathway essential for maintaining cell structure and function but frequently deregulated in tumors, making them promising targets for cancer therapy. Preliminary work from our laboratory showed that FAM46C expression synergizes with administration of SKI-I, a pan-inhibitor of sphingosine kinases. In this study, we focused specifically on SphK1, the sphingosine kinase predominantly implicated in cancer and investigated the combinatorial effect of forced FAM46C expression and treatment with PF-543, a selective SphK1 inhibitor. We found that FAM46C overexpression enhances, whereas its downregulation reduces, the cytotoxic efficacy of PF-543 in MM cell lines. Using an in vivo xenograft model, we further validated these findings, showing that FAM46C-expressing MM tumors are indeed sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C are not. Overall, our results uncover a novel synergistic interaction between FAM46C expression and SphK1 inhibition, highlighting a promising therapeutic strategy for MM treatment.

Resistance to tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of hepatocellular carcinoma (HCC). Although dysregulation of mitochondrial dynamics has been implicated in the aggressive behaviors of various tumors, the specific role and underlying mechanisms by which this dysregulation contributes to cabozantinib resistance in HCC cells remains insufficiently characterized. By investigating mitochondrial dynamics as central regulators of cabozantinib resistance, this work specifically aims to discover actionable targets for restoring drug sensitivity in treatment-refractory HCC cells. We employed transmission electron microscopy (TEM) and confocal microscopy to analyze mitochondrial morphology in HCC cells resistant to TKIs. Additionally, we utilized an oncogene hydrodynamic injection-induced primary liver cancer mouse model to assess the therapeutic efficacy of combining cabozantinib with other pharmacological agents. Our results demonstrated significant increases in mitochondrial fragmentation, p62 aggregation, and mitophagy in cabozantinib-resistant HCC cells, which correlated with overexpression of c-Myc. Notably, inhibiting mitochondrial fission, p62 aggregation, or autophagy effectively reversed the resistance of HCC cells to cabozantinib. Mechanistically, cabozantinib treatment was shown to induce c-Myc expression, which significantly enhanced mitochondrial fragmentation and p62 aggregation, thereby promoting mitophagy. This mitophagic process selectively eliminated damaged mitochondria, reducing cytochrome C-induced apoptosis in cabozantinib-resistant cells. Ultimately, combining cabozantinib with either the autophagy inhibitor chloroquine or the p62 aggregation inhibitor XRK3F2 resulted in improved anticancer efficacy. In conclusion, c-Myc overexpression facilitates p62 aggregation-mediated mitophagy, leading to cabozantinib resistance in HCC cells. Inhibition of autophagy effectively restores cabozantinib sensitivity in HCC.

Saliva, a non-invasive, self-collected liquid biopsy, holds promise for early gastric cancer (GC) screening. This study aims to assess the potential of saliva as a proxy for malignant gastric transformation and its diagnostic value through transcriptomic profiling. Leveraging transcriptomic data from the Gene Expression Omnibus (GEO), we constructed and validated predictive models through machine learning algorithms within the tidymodels framework. Tissue-based models were validated on independent tissue datasets, and subsequently applied to saliva. Additionally, an independent saliva-derived model was created and evaluated using sensitivity, specificity, accuracy, area under the curve (AUC), and likelihood ratio (LR) metrics. Tissue-derived models demonstrated excellent performance, with AUC values exceeding 0.9, but did not translate effectively to saliva, suggesting distinct molecular landscapes between tissue and saliva in GC. The saliva-specific model using support vector machine (SVM) achieved the highest performance, with an AUC of 0.87 (95% CI 0.72-0.97), a sensitivity of 0.79 (95% CI 0.58-0.95) and a specificity of 0.70 (95% CI 0.40-0.90). While saliva may not mirror tissue gene expression profile, it represents a promising non-invasive predictive tool for the early detection of GC. Further research is warranted to optimize saliva-derived molecular signatures, increasing their sensitivity and specificity for early cancer detection and advance the use of liquid biopsies in personalized medicine for improved screening, diagnostic and prognostic capabilities.

Like-Smith protein 12 (LSM12), an RNA-binding protein, is highly expressed in tumor tissues of patients with lung squamous cell carcinoma (LUSC). However, the role of LSM12 in LUSC is unclear. In this study, overexpression of LSM12 promotes the proliferation, migration, and invasion and prevents the apoptosis of LUSC cells. In vivo, LSM12 accelerates the tumor growth and metastasis of LUSC cells using male BALB/c nude mice. Furthermore, we find that the Sterile alpha motif domain containing 4A (SAMD4A) is directly bound to the mRNA of LSM12 and accelerates the mRNA degradation. High-throughput omics analysis is performed to identify the potential target genes of LSM12 in LUSC cells. LSM12 regulates alternative splicing events and increases exon 13 skipped splicing of ARRB1 and mRNA expression. Our findings may provide fundamental research for the investigation of the development of LUSC and the potential role of LSM12 in LUSC cells.

Scutellarin, a natural compound extracted from Scutellaria barbata, has demonstrated antitumor activity in various cancers. However, its role in ovarian cancer has not been fully explored. This study aims to evaluate the therapeutic potential and underlying mechanisms of Scutellarin in ovarian cancer. The effects of Scutellarin on cell proliferation and migration were assessed in ovarian cancer cell lines including SKOV3, A2780, OVCAR3, and OVCAR8. Patient-derived ovarian cancer organoids were used to further validate the in vitro findings. Calcein-AM and PI staining were used to analyze cell viability, and ATP assays were performed to assess organoid activity. Western blot was used to evaluate the regulation of METTL5 protein by Scutellarin. The gene and protein expression levels of METTL5 and their association with ovarian cancer prognosis were assessed using the databases The Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), TNMplot, KM-plotter and The Cancer Genome Atlas (TCGA). The functional role of METTL5 was assessed by transwell migration and colony formation assays, and its involvement in Scutellarin's mechanism of action was confirmed by rescue experiments using wound healing and transwell assays. Scutellarin significantly inhibited the proliferation and migration of ovarian cancer cells. In organoid models, Scutellarin markedly reduced organoid growth, induced cell damage, and decreased ATP levels. Compared to normal ovarian tissue, ovarian cancer tissue exhibited elevated RNA and protein expression levels of METTL5. High METTL5 expression was associated with poorer prognosis in ovarian cancer patients and promoted the migration and clonogenicity of ovarian cancer cells. Scutellarin downregulated METTL5 expression, and rescue experiments demonstrated that Scutellarin inhibited ovarian cancer migration by targeting METTL5. Scutellarin demonstrates potent, broad-spectrum anti-tumor activity in ovarian cancer cell lines, potentially mediated through targeting METTL5. These findings suggest a novel and promising therapeutic strategy for ovarian cancer treatment.

Glioblastoma (GBM) is a highly aggressive brain tumor with poor outcomes and limited treatment options. The telomerase reverse transcriptase (TERT) promoter mutation, one of the key biomarkers in GBM, is linked to tumor progression and prognosis. This study employed terahertz time-domain spectroscopy (THz-TDS) to analyze frozen GBM tissue sections, extracting six spectral features: absorption coefficient, dielectric loss factor, dielectric constant, extinction coefficient, refractive index, and dielectric loss tangent. LASSO regression was employed for feature selection, and then principal component analysis (PCA) was applied to minimize inter-feature correlations. A Random Forest classifier built on these features successfully predicted TERT mutation status, achieving an area under the receiver operating characteristic curve (AUC) of 0.908 in the validation set. Our findings demonstrate that THz spectroscopy, coupled with machine learning, can identify molecular differences associated with TERT mutations, supporting its potential as a rapid, intraoperative diagnostic tool for personalized GBM treatment. This approach could enhance surgical decision-making and optimize patient outcomes through precise, real-time molecular diagnostics.

Head and neck cancer is the sixth most common cancer worldwide. Among them, oral squamous cell carcinoma (OSCC) has remarkable local invasiveness and lymph node metastasis and is frequently found at an advanced stage. The 5-year survival rate of OSCC has remained at approximately 50% for several decades, and there is an urgent need to identify molecular markers that are effective for early diagnosis and treatment. Multiple C2 transmembrane proteins (MCTPs) are C2 domain-containing proteins, with two subtypes in humans: MCTP1 and MCTP2. MCTP1 has been reported to exhibit tumor-promoting activity in several cancer types; however, the role of MCTP2 in cancer remains largely unknown. In this study, we performed a comprehensive analysis using big data from over 500 head and neck cancer cases registered in The Cancer Genome Atlas (TCGA), expression profiling of 63 OSCC samples, and in vitro functional assessment using cell lines to elucidate MCTP2 involvement in OSCC. Compared to normal oral mucosa, MCTP2 expression was elevated in OSCC, and its expression rate was significantly increased at both protein and mRNA levels in cases with lymph node metastasis. In vitro experiments using two OSCC cell lines demonstrated that MCTP2 may be involved in cancer cell migration, invasive capacity acquisition, and epithelial-mesenchymal transition (EMT) phenotype. Furthermore, MCTP2 expression levels were upregulated by TGF-β1 in a concentration-dependent manner. These findings suggest that MCTP2 may serve as a novel marker of invasion and EMT in OSCC, with promising implications for developing new MCTP2-targeted diagnostic and therapeutic approaches for OSCC.

Systematic inference of enzyme activity in human tumors is key to understanding cancer progression and resistance to therapy. However, standard protein or transcript abundances are blind to the activity status of the measured enzymes, regulated, for example, by active-site amino acid mutations or post-translational protein modifications. Current methods for activity-based proteome profiling (ABPP), which combine mass spectrometry (MS) with chemical probes, quantify the fraction of enzymes that are catalytically active. Here, we describe depletion-dependent ABPP (dd-ABPP) combined with automated SWATH/DIA-MS, which simultaneously determines three molecular layers of studied enzymes: i) catalytically active enzyme fractions, ii) enzyme and background protein abundances, and iii) context-dependent enzyme-protein interactions. We demonstrate the utility of the method in advanced lung adenocarcinoma (LUAD) by monitoring nearly 4000 protein groups and 200 serine hydrolases (SHs) in tumor and adjacent tissue sections routinely collected for patient histopathology. The activity profiles of 23 SHs and the abundance of 59 proteins associated with these enzymes retrospectively classified aggressive LUAD. The molecular signature revealed accelerated lipoprotein depalmitoylation via palmitoyl(protein)hydrolase activities, further confirmed by excess palmitate and its metabolites. The approach is universal and applicable to other enzyme families with available chemical probes, providing clinicians with a biochemical rationale for tumor sample classification.

Pancreatic ductal adenocarcinoma (PDAC) is an age-associated malignancy closely linked to the extracellular matrix (ECM). However, the impact of age-related ECM changes in the normal pancreas on PDAC progression remains unclear. Here, we find that increased linear ECM alignment in normal pancreatic tissues from aged PDAC patients is associated with PDAC progression and worse outcomes. Furthermore, serum methylmalonic acid (MMA) levels are elevated in aged PDAC patients and associated with increased linear ECM alignment in normal pancreatic tissues of PDAC patients. Functionally, MMA promotes LOXL2 expression in pancreatic stellate cells (PSCs), increases linear ECM alignment in normal pancreatic tissues, and facilitates tumor progression. Mechanistically, MMA upregulates KLF10, which forms a transcriptional complex with SP1 to enhance LOXL2 expression in PSCs. Our study demonstrates the role of MMA-induced LOXL2+PSCs in ECM remodeling, thus serving as a potential therapeutic target to mitigate PDAC progression in aged patients. Schematic diagram showing the molecular mechanism by which MMA-induced LOXL+PSCs promote PDAC progression in the aging pancreas. In aged individuals, elevated levels of MMA in the blood induce the activation of the KLF10/SP1‒LOXL2 axis in PSCs to increase linear ECM alignment. Following the initiation of pancreatic cancer, this increased linear ECM alignment leads to increased tumor invasion into surrounding tissues, resulting in a greater proportion of stage T3/T4 tumors and a greater incidence of LVI and PNI in aged patients, ultimately leading to poorer outcomes (This schematic was created with www.figdraw.com ,export id: PRPRS4e268).

Evolutionary cancer therapy (ECT) delays or forestalls the progression of metastatic cancer by adjusting treatment based on individual patient and disease characteristics. Clinical implementation of ECT can improve patient outcomes but faces technical and cultural challenges. To address those, we propose a systems approach incorporating systems modeling, problem structuring, and stakeholder engagement. This approach identifies and addresses barriers to implementation, ensuring the feasibility of ECT in clinical practice and enabling better metastatic cancer care.

The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.

The over-activation of oncogenes is a critical genetic event in the development and progression of solid malignancies. Gene amplification and specific mutations represent the prominent mechanisms that convert proto-oncogenes into their active, oncogenic forms. C-myc oncogene (gene locus: 8q24.21) regulates crucial cell and tissue functions, whereas its deregulation is implicated in carcinogenesis. Our research aimed to investigate the impact C-myc numerical imbalances on a series of laryngeal squamous cell carcinomas (LSCCs) characterized by different clinic-pathological features.

Disruptions in the circadian rhythm are linked to various diseases. The clock gene DEC1 is related to the progression and recurrence of various types of cancer; however, its role in colorectal cancer has not been determined. Therefore, we aimed to evaluate the significance of DEC1 expression level in colorectal cancer and its relationship with prognosis.

Nasopharyngeal carcinoma (NPC) is a virally associated epithelial malignancy with a high prevalence in East Asia. While Epstein-Barr virus (EBV) infection is a well-established risk factor, the role of host immune-related genetic variants remains insufficiently understood. Interleukin-12 (IL-12), a key immunoregulatory cytokine, is essential for EBV-specific T-cell responses, however, the impact of IL-12A gene polymorphisms on NPC susceptibility remains unknown.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths, often due to liver metastases. Neoantigen-based immunotherapy has shown promise in clinical trials of solid tumors, including CRC. However, the immunogenic factors of neoantigens and their optimal selection in metastatic tumors are not well understood. Therefore, this study aimed to identify the relationship between tumor mutation burden and immunogenicity of neoantigens in CRCs and metastatic CRCs and evaluate the changes in immunogenic neoantigens between the primary and metastatic lesions in metastatic CRCs.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with few available targeted therapies. In this study, we examined the predictive power of several biomarkers, comprising the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, PD-L1 combined positive score (CPS), intra-tumoral tumor-infiltrating lymphocytes (iTILs), and stromal TILs (sTILs), in an Asian population of patients with metastatic TNBC treated with immunotherapy.