Animals can provide meaningful context for human single-cell data. To transfer information between species, we propose a deep learning approach that pre-trains a conditional variational autoencoder on animal data and transfers its final encoder layers to a human network architecture. Our approach then aligns latent spaces by leveraging data-level and model-learned similarities. We utilize this for label transfer and differential gene expression analysis in cross-species pairs of liver, adipose tissue, and glioblastoma datasets. Our results are robust even when gene sets differ, or datasets are small. Thus, we reliably exploit similarities between species to provide context for human single-cell data.

Cell death is a fundamental process essential to all living organisms, with apoptosis serving as one of the most crucial pathways across various stages of life. Dysregulation of apoptosis is closely associated with numerous diseases, particularly cancer. PUMA (p53 upregulated modulator of apoptosis) is a key mediator of apoptotic cell death. It is activated in response to a wide range of internal and external signals. Beyond its established role in apoptosis, PUMA also regulates other forms of cell death, including necroptosis, autophagy, and ferroptosis, underscoring its critical role in cancer cell death, especially during chemotherapy. However, PUMA activation is frequently impaired in many cancers, leading to resistance to cell death and treatment failure. This review highlights recent advancements in understanding the regulation of PUMA expression at multiple levels, including epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms. It also examines the influence of diverse cellular regulators, such as epigenetic modifiers, transcription factors, non-coding RNAs, kinases, and ubiquitin ligases in modulating PUMA activity. Additionally, we discuss PUMA's role in cancer progression, its impact on the effectiveness of anti-cancer therapies, and its potential as a prognostic biomarker for therapeutic resistance. Finally, we propose critical questions to inspire future research, aiming to deepen the understanding of PUMA regulation and its significance in cancer therapy.

Mitochondrial unfolded protein response (UPRmt) is implicated in lung adenocarcinoma (LUAD), and our study accordingly aims to establish a model incorporating UPRmt-related genes (MRGs) for predicting the therapeutic response and prognosis in LUAD.

The complex invasiveness and heterogeneity of glioblastoma multiforme (GBM) hinder the complete eradication of the tumor. The invasion of the basement membrane (BM) occurs before the spread to the meninges and the metastasis of glioma cells, increasing the recurrence rate of the disease, leading to poor patient prognosis.

Immune checkpoint inhibitors targeting PD-1 show limited efficacy in non-small cell lung cancer (NSCLC) due to primary resistance. KIF20A, a cell cycle regulator implicated in chemotherapy resistance, may influence tumor immunity, but its role in anti-PD-1 resistance remains unclear.

Theileria annulata-infected host leukocytes exhibit cancer-like phenotypes, driven by mechanisms that remain incompletely understood. This study explores the genomic alterations underlying these transformations using whole-genome sequencing and bioinformatic analyses of six clinically relevant T. annulata-infected cell lines. Here we identify 7867 exon-linked somatic mutations shared across all cell lines, with significant enrichment in oncogenes (e.g., FLT4, NOTCH2, MAP3K1, DAXX, FCGR2B, ROS1) and tumor suppressor genes (e.g., BARD1, KMT2C, GRIN2A, BAP1). These mutations are associated with critical cancer-related pathways. Functional studies revealed that inhibition of the mutated oncogene ROS1 using crizotinib induces death in infected leukocytes, confirming its role in transformation. Additionally, we observe mutations in genes linked to genomic instability and the DNA damage response (DDR) pathways, highlighting potential parallels with cancer biology. Suppression of TP53, a key tumor suppressor, is implicated in the immortalization of infected cells, while upregulation of the DNA mutator enzyme APOBEC3H suggests a parasite-driven, mutation-inducing mechanism. Our findings provide new insights into how T. annulata reprograms host cells through genomic instability and mutations, identifying ROS1 and TP53 as critical targets for therapeutic intervention. This work advances understanding of parasite-induced oncogenic transformation and offers pathways for future research.

Crotonoside (CTS) is a primary bioactive component found in Croton. current research has mainly focused on leukemia, with few reports in other cancers. Considering the traditional use of Croton, this study aims to evaluate the anti-colorectal cancer (CRC) activity of CTS and reveal its potential mechanisms. First, results in vitro show that CTS can markedly suppress CRC cell proliferation, invasion and migration, and EMT pathway (P < 0.01). Then, RNA-seq analysis was employed to identify the core target and potential mechanism of CTS against CRC, and the results suggested KIF20A is a core target. Bioinformatic analysis showed that KIF20A is overexpressed in CRC and associated with a worse prognosis (P < 0.01). KEGG and GO enrichment analyses indicated that anti-CRC activity of CTS is linked to the cell cycle. Next, Results confirmed that CTS can promote the expression of CDK1 and Cyclin B1 (P < 0.01), and induces G2/M phase arrest to exert anti-CRC effects (P < 0.01). Then, a subcutaneous tumor model was established in vivo to evaluate the anti-CRC activity of CTS; the results showed that CTS significantly inhibited CRC tumor growth and reduced both tumor weight and volume (P < 0.01). CTS can suppress the expression of Ki67, E-cadherin, vimentin, and KIF20A (P < 0.05), and promote the expression of Cyclin B1 and CDK1 (P < 0.01). In addition, molecular docking analysis revealed that the binding energy of CTS to KIF20A was - 7.9 kcal/mol, and CETSA assay showed that CTS treatment attenuated the thermal degradation of KIF20A protein. These results showed CTS can bind KIF20A tightly. Finally, overexpression of KIF20A reverses the anti-CRC effect of CTS. In summary, this study confirms that CTS can target and inhibit KIF20A, thereby inducing cell G2/M phase arrest and exerting anti-CRC effects.

Colorectal cancer (CRC) is a serious threat to human health, with an approximate 14% mutation rate in the ataxia telangiectasia-mutated (ATM) gene, which is involved in homologous recombination repair. BMN673 (talazoparib), a next-generation poly(ADP-ribose) polymerase (PARP) inhibitor, is the most potent PARP inhibitor (PARPi) reported to date, demonstrating robust anticancer activity. However, the precise mechanism underlying its action in ATM-deficient CRC remains unknown. This study demonstrated that BMN673 stimulated ATM-deficient CRC cell death via a synthetic lethal effect. RNA sequencing analysis revealed significant enrichment of the PERK-ATF4 pathway, mitophagy, and ferroptosis. Functional assays confirmed that BMN673 induced a multifaceted cell death program comprising autophagy-associated death, ferroptosis, and mitophagy, in addition to synthetic lethal. Mechanistically, BMN673 was shown to enhance activating transcription factor 4 (ATF4) transcriptional activity by suppressing poly-ADP-ribosylation (PARylation), facilitating ATF4 binding to the growth differentiation factor 15 (GDF15) promoter region and thereby inducing GDF15 transcriptional expression. Notably, GDF15 overexpression modulated the sensitivity of ATM-deficient CRC cells to BMN673 by promoting autophagy-associated cell death, ferroptosis, and mitophagy, contributing to the anticancer effect of BMN673. Additionally, combining BMN673 with radiotherapy exerted a synergistic anticancer effect on ATM-deficient CRC cells, which was prevented by autophagy inhibition. The findings identified the ATF4-GDF15 pathway as a crucial mediator of BMN673 sensitivity in ATM-deficient CRC cells, revealing therapeutic vulnerability beyond canonical DNA damage repair pathways and providing new insight for combination therapy strategies.

The Kv11.1 potassium channels and the transcription factor c-Myc both play fundamental roles in controlling cellular homeostasis. Cancers take advantage of dysregulated c-Myc and Kv11.1, however, little is known about the possible link between these proteins. In this work we found that an inverse relationship between c-MYC and Kv11.1 exists in some lung adenocarcinoma. Importantly, patients expressing an elevated level of the Kv11.1 channel present a better overall survival when compared with patients with low expression. Therefore, we evaluated the hypothesis that pharmacologic activation of the Kv11.1 channel in lung cancer may impair tumor growth. We discovered that Kv11.1 activation inhibits lung cancer growth by inducing a senescent phenotype. Moreover, we found that pharmaceutical Kv11.1 opening produced a rapid proteasomal degradation of c-Myc and that this could be antagonized by the OTUD6B deubiquitinase. We concluded that use of Kv11.1 agonists should be considered as anticancer pharmacological strategy against lung adenocarcinomas.

Gastric cancer (GC) is a common malignancy of the digestive system, characterized by high invasiveness and metastasis, making it a leading cause of cancer-related deaths. Long non-coding RNAs (lncRNAs) play a crucial role in various types of cancer. This study aimed to elucidate the function of LINC01615 and its potential regulatory mechanisms in GC. In tissue and serum samples from GC patients, LINC01615 expression was significantly elevated and was associated with recurrence, distant metastasis, and TNM stage. LINC01615 promoted the proliferation, migration, and invasion of GC cells, and accelerated the growth of subcutaneous tumors in nude mice. Mechanistically, LINC01615 activated the WNT2/β-Catenin pathway by preventing WNT2 mRNA degradation and enhancing the nuclear translocation of β-Catenin. Furthermore, we identified the transcription factor YY1 as a key regulator of LINC01615 expression, which directly binds to its promoter region. Analysis of clinical samples revealed a positive correlation between the YY1/LINC01615/WNT2 signaling axis and poor prognosis in GC patients. Taken together, this study uncovers that the YY1/LINC01615/WNT2 signaling axis plays a crucial role in GC progression and may serve as a novel diagnostic marker and therapeutic target.

Cancer's staggering molecular heterogeneity demands innovative approaches beyond traditional single-omics methods. The integration of multi-omics data, spanning genomics, transcriptomics, proteomics, metabolomics and radiomics, can improve diagnostic and prognostic accuracy when accompanied by rigorous preprocessing and external validation; for example, recent integrated classifiers report AUCs around 0.81-0.87 for difficult early-detection tasks. This review synthesizes how artificial intelligence (AI), particularly deep learning and machine learning, bridges this gap by enabling scalable, non-linear integration of disparate omics layers into clinically actionable insights. We explore cutting-edge AI methodologies, including graph neural networks for biological network modeling, transformers for cross-modal fusion, and explainable AI (XAI) for transparent clinical decision support. Critical applications are highlighted, such as AI-driven therapy selection (e.g., predicting targeted therapy resistance), proteogenomic early detection, and radiogenomic non-invasive diagnostics. We further address translational challenges: data harmonization, batch correction, missing data imputation, and computational scalability. Emerging trends, federated learning for privacy-preserving collaboration, spatial/single-cell omics for microenvironment decoding, quantum computing, and patient-centric "N-of-1" models, signal a paradigm shift toward dynamic, personalized cancer management. Despite persistent hurdles in model generalizability, ethical equity, and regulatory alignment, AI-powered multi-omics integration promises to transform precision oncology from reactive population-based approaches to proactive, individualized care.

The bone marrow (BM) is a complex and compartmentalized tissue where spatial context plays a critical role in regulating cell behavior, signaling, and disease progression. To capture these dynamics, we apply spatial transcriptomics using the Visium Spatial Gene Expression platform on formalin-fixed paraffin-embedded (FFPE) BM sections from both healthy and Multiple Myeloma (MM) mouse models, as well as MM patient samples. Overcoming the technical challenges of working with mineralized long bone tissue, we develop a custom analytical framework integrating spatial and single-cell transcriptomic data to map cellular composition and interactions in situ. This approach enables the spatial characterization of transcriptionally heterogeneous malignant plasma cells (MM-PC) and their surrounding microenvironments. We identify spatially distinct gene programs linked to MM pathogenesis, including signatures of NETosis and IL-17 signalling, which are reduced in MM-PC-rich regions. Additionally, a transition gradient from effector to exhausted T cell phenotype is associated with increased remoteness from MM-PC. These spatial patterns are identified in FFPE BM biopsies from MM patients with varying tumor burdens. In summary, our study demonstrates both the capabilities and limitations of Visium technology in characterizing spatially regulated mechanisms underlying MM pathogenesis.

Plasticity, or the ability to rapidly and reversibly change phenotypes, may help explain how a single progenitor cell eventually generates a tumor with many different cell phenotypes. Normal colon plasticity is characterized by a conserved and broadly permissive epigenome, where expression and phenotype are determined by the microenvironment instead of epigenetic remodeling. To determine whether this stem-like plasticity is retained during progression, gene expression was measured with spatial transcriptomics and compared with gene-level DNA methylation in two colorectal cancers (CRCs). Like normal colon, genes that were differentially expressed between regions, subclones, and phenotypes (superficial, invasive, and metastatic) tended to have lower DNA methylation variability. We propose a quantitative signal of plasticity that correlates gene epigenetic variability with gene expression variability. In this framework, negative correlation implies phenotypic plasticity, as more variably expressed genes tend to have less epigenetic variability. We verify the presence of this signal in multiple external single-cell RNA-Seq datasets, in both normal colon and CRC samples. Therefore, the plasticity of normal colon appears to be retained during progression. A CRC progenitor with a preconfigured plastic phenotype is poised for rapid growth because it expresses, as needed, transcripts required for progression with minimal epigenetic remodeling.

Bruton's Tyrosine Kinase (BTK) is an anchor in B-cell receptor signaling and plays an important role in chronic lymphocytic leukemia (CLL). The use of covalent inhibitors of BTK, such as ibrutinib, enhances the survival of patients with CLL. However, mutations at the C481 residue cause resistance to ibrutinib and diminish its clinical efficacy. Recently, super-resistant mutants, i.e., T474M-C481S and T474I-C481S, were reported to cause manifold resistance to the BTK-targeting drug, ibrutinib; however, the mechanism of this resistance is still elusive. Structure-based approaches proved to be effective in deciphering drug resistance mechanisms (s) that could guide the development of novel, effective therapeutics. Therefore, we used molecular modeling combined with biophysical simulation approaches to determine the impact of T474M-C481S and T474I-C481S mutations on the binding of ibrutinib. Our results revealed that essential hydrogen bonds and a covalent interaction with C481 are lost due to these mutations. Using µs simulations, our results revealed that the regions 432-439 and 545-559 demonstrated dynamically unstable behavior with the transition of secondary structure, where a helix to loop and loop to helix transition could be observed. Structural compactness, residue flexibility, and average hydrogen bonds in each trajectory reported significant variations. The binding free energy calculation using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) and MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approaches revealed that both the vdW and electrostatic energies are reduced in mutants. Using the MM-PBSA approach, the wild type demonstrated a total binding free energy (TBE) of -42.65 ± 0.08 kcal/mol, while T474M-C481S and T474I-C481S had TBE values of -38.81 ± 0.18 kcal/mol, and - 33.04 ± 0.13 kcal/mol, respectively. The MM-GBSA results revealed that the wild type had a TBE of -60.33 ± 0.06 kcal/mol, while the TBE values for T474M-C481S and T474M-C481S mutants were - 53.18 ± 0.12 kcal/mol and - 49.12 ± 0.10 kcal/mol, respectively. PCA and FEL results further revealed the dynamic variations caused by these mutations. These findings underline the significant impact of mutations T474M and C481S on the binding free energy, highlighting the importance of these residues in ibrutinib-BTK interactions.

This study was designed to illustrate the mechanism underlying the up-regulation of LINC00857 expression and to identify novel molecular targets for the treatment of ovarian cancer (OC). The LINC00857 and methyltransferase-like 3 (METTL3) expression levels were observed in clinical OC tissues and cells, and their correlation within tissues was analyzed. To further explore the relationship between LINC00857 and METTL3, a combined transfection of pcDNA3.1-LINC00857 and METTL3 siRNA was performed. Subsequently, cell invasion, viability, migration, and sphere-forming capabilities were assessed using Transwell, Cell Counting Kit-8, scratch and sphere-formation assays. Furthermore, western blot analysis was conducted to determine the expression of proteins related to cancer cell stemness and the yes-associated protein (YAP) pathway. The relationship between LINC00857 and METTL3 was verified using the MeRIP-qPCR kit, RNA pull-down assay and RNA stability assay. Both LINC00857 and METTL3 demonstrated high expression levels in OC cells and tissues, with a positive correlation observed in clinical tissues. When knocking down the LINC00857 expression level, the invasion, migration, proliferation, and sphere-forming capabilities of cells were all notably reduced. Knocking down LINC00857 expression also markedly decreased the activity of the YAP pathway and the expression of proteins related to cancer cell stemness. Overexpression of LINC00857 yielded opposite effects. When knocking down METTL3, the stability of LINC00857 and the modification level of N6-methyladenosine were remarkably decreased. Moreover, there was interaction between METTL3 and LINC00857. METTL3-mediated N6-methyladenosine modification of LINC00857 enhanced metastasis and stemness of OC cells via activating the YAP-TEA domain transcription factor pathway.

Oxidative phosphorylation (OXPHOS) is a key player in mitochondrial bioenergetic functions. In hepatocellular carcinoma (HCC), OXPHOS slows down or switches to glycolysis via what is known as the Warburg effect. The altered respiration in cancer was reported to affect mitochondrial temperature. We investigated the impact of the metabolic switch on the mitochondrial temperature in HepG2 HCC cell line. Metformin (N, N-dimethylbiguanide) treatment was used to suppress glycolysis to emulate lower metabolically active cells (Met-HepG2). The mitochondrial temperature was assessed using mito-thermo yellow (MTY) absorbing mitochondrial radiant heat. Mito-tracker green (MTG) fluorescent dye was used to confirm mitochondrial localization. Our data showed lower MTY dye intensity in the Met-HepG2 treated group, indicating a significant increase in mitochondrial temperature compared to untreated HepG2 cells (NT-HepG2). Genotypic analysis of the metabolic respiration gene expression showed significant down-regulation in glycolytic genes (ERR-gamma, HK2, PGK, ALDOC, TPI1, IDH1, and PKM2) in the Met-HepG2 cells compared to the NT-HepG2 cells. OXPHOS as evidenced by ATP, ROS, and NADPH production was significantly up-regulated in the Met-HepG2 group compared to the NT-HepG2 group. Transmission electron microscopy showed fewer mitochondria with swollen elongated appearance, as a marker for activated OXPHOS in the Met-HepG2 group. These data show a correlation between HepG2 altered metabolism and mitochondrial temperature and suggest that less metabolically active HepG2 cells are correlated with higher mitochondrial temperature, providing evidence for a possible role of mitochondrial temperature in diagnosis of HCC.

Colorectal cancer (CRC), a highly heterogeneous disease, is the second leading cause of cancer related deaths. Mounting evidence has indicated that the zinc finger of the cerebellum 5 (ZIC5) is involved in the pathological processes of cancer. At present, there are few and conflicting studies on ZIC5 in CRC. The aim of this study was to elucidate the clinical value, function and molecular mechanism of ZIC5 in colon cancer. ZIC5 expression analysis in pan-cancer was performed using the TCGA database. The correlation of ZIC5 expression with clinicopathologic parameters of colon cancer was assessed in public and external datasets, respectively. The influence of ZIC5 expression on survival was analyzed by Kaplan-Meier (KM) curve and Cox regression models. In addition, a series of in vitro experiments on cell proliferation, invasion, migration and stemness were performed to further explore the function and potential mechanisms of ZIC5 in colon cancer. ZIC5 mRNA expression is significantly elevated in the vast majority of cancers. We found that ZIC5 is elevated in colon cancer tissues, and high ZIC5 expression was associated with poorer survival of colon cancer patients. ZIC5 expression was positively correlated with the malignant pathological phenotype, and it's an independent risk marker for the overall survival (OS) of colon cancer patients. We demonstrated that ZIC5 promoted proliferation, invasion, migration and EMT of colon cancer cells. Additionally, ZIC5 enhances colon cancer stem cell (CSC) properties. Mechanistically, ZIC5 functions in colon cancer cells by upregulating Wnt signaling. ZIC5 could enhance Wnt/β-catenin signaling by interacting with β-catenin. Interestingly, in HCT116 cells, ZIC5 doesn't affect the protein level of β-catenin and its nuclear translocation likely due to the deletion mutation of β-catenin at Ser45. We identified ZIC5 as a survival marker for colon cancer patients. Our study shows that inhibition of ZIC5 might be a potential therapeutic strategy for colon cancer.

Breast cancer (BC) is the most common malignancy among women, with its progression and prognosis significantly influenced by the tumor microenvironment (TME). Age-related differences in TME composition lead to distinct tumor behaviors: young patients (≤ 40 years) exhibit aggressive tumors, while elderly patients (> 70 years) experience immunosenescence and reduced therapy responses. We performed single-cell RNA sequencing (scRNA-seq) analysis on tumors from 10 breast cancer patients (5 ≤ 40 years, 5 ≥ 70 years), encompassing 33,664 high-quality cells. After cell annotation and batch correction, malignant epithelial cells were identified using inferCNV. We applied pseudotime trajectory analysis, pathway enrichment, and cell-cell communication profiling to investigate age-specific TME dynamics. Survival relevance was assessed using a GEO cohort (GSE20685) of young breast cancer patients, and immunohistochemical staining was performed on clinical tumor and fibroadenoma tissues to validate protein-level expression of key ISGs. In young patients, malignant epithelial cells showed gradual upregulation of interferon-stimulated genes (ISGs) such as IFI44, IFI44L, IFIT1, and IFIT3 along the pseudotime trajectory, suggesting their involvement in early tumorigenesis. High expression of these ISGs was significantly associated with poor overall survival in a young BC cohort (GSE20685). Immunohistochemical validation further confirmed elevated IFIT3 protein levels in young tumor tissues. In contrast, elderly patients had a TME enriched in macrophages and fibroblasts, with activation of immunosuppressive pathways (e.g., SPP1, COMPLEMENT). Our integrative analysis identifies ISGs as key transcriptional drivers of tumorigenesis in young breast cancer, with potential prognostic and therapeutic value. Despite limited sample size, the combination of single-cell transcriptomics, clinical survival data, and protein-level validation provides robust evidence of age-specific TME remodeling. These findings support the development of age-tailored immunotherapy strategies targeting interferon signaling in young patients and immune checkpoint pathways (e.g., LAG3, CTLA4) in elderly individuals.

This study introduces a unique magnetic resonance imaging dataset focusing on metastatic breast cancer to the brain, a significant clinical challenge in cancer treatment. Comprising 297 T1-weighted post-contrast images from 165 patients, this dataset from the University of Minnesota Medical Center is the first dedicated to breast cancer brain metastases. This collection includes expert-reviewed lesion segmentations with original image files, genetic markers, and an extensive array of tumor-derived radiomic features. The dataset's uniqueness lies in its detailed focus on metastatic breast cancer to the brain-offering a rich resource for advanced image-based tumor phenotyping and the vast potential for radiogenomic-based predictions based on machine learning model development. The inclusion of clinician-reviewed tumor segmentations and radiomic features, encompassing shape and texture characteristics, enhances the dataset's utility. This dataset aims to facilitate a deeper understanding of breast cancer metastasis to the brain, promote advancements in precision medicine, and improve patient care.

Head and neck squamous cell carcinoma (HNSCC) exhibits a poor prognosis, with 5-year survival rates below 50%. This study employed network pharmacology to investigate the anti-HNSCC mechanism of silibinin, a plant-derived compound with established anticancer activity. We obtained potential silibinin targets from pharmacological databases and HNSCC-associated targets from TCGA. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to identify critical pathways and biological processes. Through protein-protein interaction (PPI) network screening, we selected hub genes for molecular docking validation. We evaluated silibinin's effects on HNSCC proliferation and invasion using CCK-8 assays, colony formation tests, and cell invasion experiments. Our data suggested that silibinin may inhibit HNSCC progression through modulation of the interleukin-17 signaling pathway. Molecular docking confirmed strong binding affinity between silibinin and key targets, supporting its potential as an HNSCC therapeutic agent.