METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma.

BACKGROUND: Ferroptosis, characterized by iron-dependent lipid peroxidation, emerges as a promising avenue for hepatocellular carcinoma (HCC) intervention due to its tumor susceptibility. RNA N6-methyladenosine (m6A) modification has been involved in several types of regulated cell death. However, the roles and molecular mechanisms of m6A-related regulators in HCC cell ferroptosis remain unclear. METHODS: By examining a series of m6A modification enzymes upon ferroptosis induction or inhibition, we identified METTL16 as a novel ferroptotic repressor in HCC cells. The roles of METTL16 on ferroptosis and HCC development were investigated in multiple cell lines, human HCC organoids, subcutaneous xenografts and MYC/Trp53-/- HCC model in hepatocyte-specific Mettl16 knockout and overexpression mice. The underlying mechanism was elucidated with MeRIP/RIP-qPCR, luciferase assay, Co-IP assay and Mass Spectrometry. The clinical significance and relevance were evaluated in human samples. RESULTS: High METTL16 expression confers ferroptosis resistance in HCC cells and mouse models, and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner, and the latter impedes the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates the chelation of free iron and reduces liable iron pool level. SENP3 and LTF are implicated in METTL16-mediated HCC progression and anti-ferroptotic effects both in vivo and in vitro. Clinically, METTL16 and SENP3 expression were positively correlated, and high METTL16 and SENP3 expression predicts poor prognosis in human HCC samples. CONCLUSIONS: Our study reveals a new METTL16-SENP3-LTF signaling axis regulating ferroptosis and driving HCC development. Targeting this axis is a promising strategy for sensitizing ferroptosis and against HCC.

Epithelial­derived head and neck squamous tumourigenesis (Review).

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein­Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5­year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Mechanisms that clear mutations drive field cancerization in mammary tissue.

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1-3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1-/-;Trp53-/- cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.

Biological function and potential application of PANoptosis-related genes in colorectal carcinogenesis.

PANoptosis induces programmed cell death (PCD) through extensive crosstalk and is associated with development of cancer. However, the functional mechanisms, clinical significance, and potential applications of PANoptosis-related genes (PRGs) in colorectal cancer (CRC) have not been fully elucidated. Functional enrichment of key PRGs was analyzed based on databases, and relationships between key PRGs and the immune microenvironment, immune cell infiltration, chemotherapy drug sensitivity, tumor progression genes, single-cell cellular subgroups, signal transduction pathways, transcription factor regulation, and miRNA regulatory networks were systematically explored. This study identified 5 key PRGs associated with CRC: BCL10, CDKN2A, DAPK1, PYGM and TIMP1. Then, RT-PCR was used to verify expression of these genes in CRC cells and tissues. Clinical significance and prognostic value of key genes were further verified by multiple datasets. Analyses of the immune microenvironment, immune cell infiltration, chemotherapy drug sensitivity, tumor progression genes, single-cell cellular subgroups, and signal transduction pathways suggest a close relationship between these key genes and development of CRC. In addition, a novel prognostic nomogram model for CRC was successfully constructed by combining important clinical indicators and the key genes. In conclusion, our findings offer new insights for understanding the pathogenesis of CRC, predicting CRC prognosis, and identifying multiple therapeutic targets for future CRC therapy.

Single-cell RNA sequencing highlights the immunosuppression of IDO1+ macrophages in the malignant transformation of oral leukoplakia.

Rationale: Immunosuppressive tumor microenvironment (iTME) plays an important role in carcinogenesis, and some macrophage subsets are associated with iTME generation. However, the sub-population characterization of macrophages in oral carcinogenesis remains largely unclear. Here, we investigated the immunosuppressive status with focus on function of a macrophage subset that expressed indoleamine 2,3 dioxygenase 1 (Macro-IDO1) in oral carcinogenesis. Methods: We built a single cell transcriptome atlas from 3 patients simultaneously containing oral squamous cell carcinoma (OSCC), precancerous oral leukoplakia (preca-OLK) and paracancerous tissue (PCA). Through single-cell RNA sequencing and further validation using multicolor immunofluorescence staining and the in vitro/in vivo experiments, the immunosuppressive cell profiles were built and the role of a macrophage subset that expressed indoleamine 2,3 dioxygenase 1 (Macro-IDO1) in the malignant transformation of oral leukoplakia was evaluated. Results: The iTME formed at preca-OLK stage, as evidenced by increased exhausted T cells, Tregs and some special subsets of macrophages and fibroblasts. Macro-IDO1 was predominantly enriched in preca-OLK and OSCC, distributed near exhausted T cells and possessed tumor associated macrophage transformation potentials. Functional analysis revealed the established immunosuppressive role of Macro-IDO1 in preca-OLK and OSCC: enriching the immunosuppression related genes; having an established level of immune checkpoint score; exerting strong immunosuppressive interaction with T cells; positively correlating with the CD8-exhausted. The immunosuppression related gene expression of macrophages also increased in preca-OLK/OSCC compared to PCA. The use of the IDO1 inhibitor reduced 4NQO induced oral carcinogenesis in mice. Mechanistically, IFN-γ-JAK-STAT pathway was associated with IDO1 upregulation in OLK and OSCC. Conclusions: These results highlight that Macro-IDO1-enriched in preca-OLK possesses a strong immunosuppressive role and contributes to oral carcinogenesis, providing a potential target for preventing precancerous legions from transformation into OSCC.

Highly expressed B3GALT5-AS1 contributes to gastric cancer progression by recruiting WDR5 to mediate B3GALT5 and regulating ß-catenin/ZEB1 axis.

Long non-coding RNAs (lncRNAs) play an important role in the progression of gastric cancer (GC), but its specific regulatory mechanism remains to be further studied. We previously identified that lncRNA B3GALT5-AS1 was upregulated in GC serum. Here, we investigated the functions and molecular mechanisms of B3GALT5-AS1 in GC tumorigenesis. qRT-PCR was used to detect B3GALT5-AS1 expression in GC. EdU, CCK-8, and colony assays were utilized to assess the proliferation ability of B3GAL5-AS1, and transwell, tube formation assay were used to assess the invasion and metastasis ability. Mechanically, FISH and nuclear plasmolysis PCR identified the subcellular localization of B3GALT5-AS1. RIP and CHIP assays were used to analyse the regulation of B3GALT5-AS1 and B3GALT5. We observed that B3GALT5-AS1 was highly expressed in GC, and silencing B3GALT5-AS1 could inhibit the proliferation, invasion, and migratory capacities of GC. Additionally, B3GALT5-AS1 was bound to WDR5 and modulated the expression of B3GALT5 via regulating the ZEB1/ß-catenin pathway. High-expressed B3AGLT5-AS1 promoted GC tumorigenesis and regulated B3GALT5 expression via recruiting WDR5. Our study is expected to provide a new idea for clinical diagnosis and treatment.

PILRB potentiates the PI3K/AKT signaling pathway and reprograms cholesterol metabolism to drive gastric tumorigenesis and metastasis.

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.

FOSL1 promotes stem cell­like characteristics and anoikis resistance to facilitate tumorigenesis and metastasis in osteosarcoma by targeting SOX2.

Metastasis is the leading cause of cancer­related death in osteosarcoma (OS). OS stem cells (OSCs) and anoikis resistance are considered to be essential for tumor metastasis formation. However, the underlying mechanisms involved in the maintenance of a stem­cell phenotype and anoikis resistance in OS are mostly unknown. Fos­like antigen 1 (FOSL1) is important in maintaining a stem­like phenotype in various cancers; however, its role in OSCs and anoikis resistance remains unclear. In the present study, the dynamic expression patterns of FOSL1 were investigated during the acquisition of cancer stem­like properties using RNA sequencing, PCR, western blotting and immunofluorescence. Flow cytometry, tumor­sphere formation, clone formation assays, anoikis assays, western blotting and in vivo xenograft and metastasis models were used to further investigate the responses of the stem­cell phenotype and anoikis resistance to FOSL1 overexpression or silencing in OS cell lines. The underlying molecular mechanisms were evaluated, focusing on whether SOX2 is crucially involved in FOSL1­mediated stemness and anoikis in OS. FOSL1 expression was observed to be upregulated in OSCs and promoted tumor­sphere formation, clone formation and tumorigenesis in OS cells. FOSL1 expression correlated positively with the expression of stemness­related factors (SOX2, NANOG, CD117 and Stro1). Moreover, FOSL1 facilitated OS cell anoikis resistance and promoted metastases by regulating the expression of apoptosis related proteins BCL2 and BAX. Mechanistically, FOSL1 upregulated SOX2 expression by interacting with the SOX2 promoter and activating its transcription. The results also showed that SOX2 is critical for FOSL1­mediated stem­like properties and anoikis resistance. The current findings indicated that FOSL1 is an important regulator that promotes a stem cell­like phenotype and anoikis resistance to facilitate tumorigenesis and metastasis in OS by regulating the transcription of SOX2. Thus, FOSL1 might represent an attractive target for therapeutic interventions in OS.

Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing's sarcoma.

Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing's sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing's sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing's sarcoma.

CRISPR-Cas9 Mediated AGO2 Knockout inhibits tumorigenesis in human colorectal cancer cells.

AGO2 plays a vital role in small RNA-guided gene silencing, which has been implied in the tumorigenesis of different types of tumors. Fundamentally, increased expression of AGO2 protein is associated with cancer progression and metastasis. This study aims to investigate the molecular mechanism by which AGO2 promotes tumorigenesis in colorectal cancer (CRC). Databases were used to analyze the expression levels of AGO2 in CRC and confirmed by a quantitative reverse transcriptase-PCR (qRT-PCR) assay in CRC tissues and normal adjacent tissues collected from 25 CRC patients. CRISPR/Cas9-mediated genome editing was used to knockout the AGO2 in HCT116 cells as a model system for colorectal cancers. The cell proliferation, migration and invasion ability of HCT116 cells were detected by CCK-8 assay, Wound scratch assay and Transwell assay. Moreover, the quantities of miRNA binding with AGO2 were detected by RNA-Binding Protein Immunoprecipitation (RIP-Assay). We demonstrated that AGO2 was aberrantly high-expressed in 25 matched-tissue pairs of colorectal cancer and para-carcinoma tissue. The following functional experiments verified that knockout of AGO2 suppressed cell proliferation, migration and tumorigenesis to hamper the aggressiveness of CRC. Our study also suggests a possible link between AGO2 and miRNA in RISC. AGO2 was elevated in CRC and knockout of AGO2 suppressed proliferation and tumorigenicity of CRC cells. Moreover, RISC formation and the function of miRNAs are also subject to AGO2. AGO2 may be a meaningful target for CRC therapy.

Genome composition-based deep learning predicts oncogenic potential of HPVs.

Human papillomaviruses (HPVs) account for more than 30% of cancer cases, with definite identification of the oncogenic role of viral E6 and E7 genes. However, the identification of high-risk HPV genotypes has largely relied on lagged biological exploration and clinical observation, with types unclassified and oncogenicity unknown for many HPVs. In the present study, we retrieved and cleaned HPV sequence records with high quality and analyzed their genomic compositional traits of dinucleotide (DNT) and DNT representation (DCR) to overview the distribution difference among various types of HPVs. Then, a deep learning model was built to predict the oncogenic potential of all HPVs based on E6 and E7 genes. Our results showed that the main three groups of Alpha, Beta, and Gamma HPVs were clearly separated between/among types in the DCR trait for either E6 or E7 coding sequence (CDS) and were clustered within the same group. Moreover, the DCR data of either E6 or E7 were learnable with a convolutional neural network (CNN) model. Either CNN classifier predicted accurately the oncogenicity label of high and low oncogenic HPVs. In summary, the compositional traits of HPV oncogenicity-related genes E6 and E7 were much different between the high and low oncogenic HPVs, and the compositional trait of the DCR-based deep learning classifier predicted the oncogenic phenotype accurately of HPVs. The trained predictor in this study will facilitate the identification of HPV oncogenicity, particularly for those HPVs without clear genotype or phenotype.

Atorvastatin lowers breast cancer risk by reversing an early tumorigenic signature.

Breast cancer remains a significant health challenge with complex molecular mechanisms. While many studies have explored genetic markers in breast carcinogenesis, few have studied the potential impact of pharmacological interventions such as Atorvastatin on its genetic landscape. This study aimed to elucidate the molecular distinctions between normal and tumor-adjacent tissues in breast cancer and to investigate the potential protective role of atorvastatin, primarily known for its lipid-lowering effects, against breast cancer. Searching the Gene Expression Omnibus database identified two datasets, GSE9574 and GSE20437, comparing normal breast tissues with tumor-adjacent samples, which were merged, and one dataset, GSE63427, comparing paired pre- and post-treated patients with atorvastatin. Post-ComBat application showed merged datasets' consistency, revealing 116 DEGs between normal and tumor-adjacent tissues. Although initial GSE63427 data analysis suggested a minimal impact of atorvastatin, 105 DEGs post-treatment were discovered. Thirteen genes emerged as key players, both affected by Atorvastatin and dysregulated in tumor-adjacent tissues. Pathway analysis spotlighted the significance of these genes in processes like inflammation, oxidative stress, apoptosis, and cell cycle control. Moreover, there was a noticeable interaction between these genes and the immunological microenvironment in tumor-adjacent tissues, with Atorvastatin potentially altering the suppressive immune landscape to favor anti-tumor immunity. Survival analysis further highlighted the prognostic potential of the 13-gene panel, with 12 genes associated with improved survival outcomes. The 13-gene signature offers promising insights into breast cancer's molecular mechanisms and atorvastatin's potential therapeutic role. The preliminary findings advocate for an in-depth exploration of atorvastatin's impact on.

SNORD88B-mediated WRN nucleolar trafficking drives self-renewal in liver cancer initiating cells and hepatocarcinogenesis.

Whether small nucleolar RNAs (snoRNAs) are involved in the regulation of liver cancer stem cells (CSCs) self-renewal and serve as therapeutic targets remains largely unclear. Here we show that a functional snoRNA (SNORD88B) is robustly expressed in Hepatocellular carcinoma (HCC) tumors and liver CSCs. SNORD88B deficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically, SNORD88B anchors WRN in the nucleolus, promoting XRCC5 interacts with STK4 promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression of STK4 and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally, snord88b knockout suppresses mouse liver tumorigenesis. Notably, co-administration of SNORD88B antisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate that SNORD88B drives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.

Hypermethylated RASAL1's promotive role in chemoresistance and tumorigenesis of choriocarcinoma was regulated by TET2 but not DNMTs.

BACKGROUND: Patients with choriocarcinoma (CC) accompanying chemoresistance conventionally present a poor prognosis. Whether ras protein activator like-1 (RASAL1) functions as a tumor promoter or suppressor depends on tumor types. However, the role of RASAL1 in process of chemoresistance of CC and underlying molecular mechanism remain elusive. METHODS: The expression pattern of RASAL1 in CC cells and tissues was measured using Western blotting, immunohistochemistry and qRT-PCR. Cell viability and proliferative ability were assessed by MTT assay, Tunnel assay and flow cytometric analysis. Additionally, the stemness was evaluated by the colony formation and tumor sphere formation. Methotrexate (MTX) was applied to exam the chemosensitivity of CC cells. RESULTS: The expression of RASAL1 was reduced both at the protein and mRNA levels in CC tissues and cells compared to hydatidiform mole (HM) and invasive mole (IM). Loss of RASAL1 was attributed to its promoter hypermethylation and could be restored by 5-Aza. Knock-down of RASAL1 promoted the viability, proliferative potential, stemness and EMT phenotype of JEG-3 cells. However, induced overexpression of RASAL1 by 5-Aza significantly prohibited cell proliferation and stemness potential of the JAR cell. Additionally, the xenograft model indicated that knockdown of RASAL1 led to a remarkable increase of tumor volume and weight in comparison with its counterpart. Moreover, the stimulatory activity brought by decrease of RASAL1 could be deprived by ß-catenin inhibitor XAV 939, yet the suppressive activity resulted from its promoter demethylation could be rescued by ß-catenin activator BML-284, indicating that function of RASAL1 depends on ß-catenin. Besides, the co-immunoprecipitation assay confirmed the physical binding between RASAL1 and ß-catenin. Further investigations showed hypermethylated RASAL1 was regulated by TET2 but not DNMTs. CONCLUSION: Taken together, the present data elucidated that reduced RASAL1 through its promoter hypermethylation regulated by TET2 promoted the tumorigenicity and chemoresistance of CC via modulating ß-catenin both in vitro and in vivo.

Tata-box-binding protein-associated factor 15 as a new potential marker in gastrointestinal tumors.

In this editorial, the roles of tata-box-binding protein-associated factor 15 (TAF15) in oncogenesis, tumor behavior, and as a therapeutic target in cancers in the context of gastrointestinal (GI) tumors are discussed concerning the publication by Guo et al. TAF15 is a member of the FET protein family with a comprehensive range of cellular processes. Besides, evidence has shown that TAF15 is involved in many diseases, including cancers. TAF15 contributes to carcinogenesis and tumor behavior in many tumors. Besides, its relationship with the mitogen-activated protein kinases (MAPK) signaling pathway makes TAF15 a new target for therapy. Although, the fact that there is few studies investigating the expression of TAF15 constitutes a potential limitation in GI system, the association of TAF15 expression with aggressive tumor behavior and, similar to other organ tumors, the influence of TAF15 on the MAPK signaling pathway emphasize that this protein could serve as a new molecular biomarker to predict tumor behavior and target therapeutic intervention in GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic role of TAF15 in GI tumors, especially in tumors resistant to therapy.

Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.

Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.

CHD4 R975H mutant activates tumorigenic pathways and promotes stemness and M2-like macrophage polarization in endometrial cancer.

Endometrial cancer (EC), one of the most prevalent carcinomas in females, is associated with increasing mortality. We identified the CHD4 R975H mutation as a high-frequency occurrence in EC patients through a comprehensive survey of EC databases. Computational predictions suggest that this mutation profoundly impacts the structural and functional integrity of CHD4. Functional assays revealed that the CHD4 R975H mutation enhances EC cell invasion, proliferation, and colony formation, promoting a cancer stem cell (CSC)-like phenotype. RNA-seq analysis of cells expressing CHD4 R975H mutant revealed a transcriptomic landscape marked by the activation of several cancer-promoting signaling pathways, including TNF-α signaling via NF-κB, KRAS, P53, mTOR, TGF-ß, EGFR, Myc and growth factor signaling. Validation assays confirmed the activation of these pathways, further demonstrating that CHD4 R975H mutation induces stemness in EC cells and M2-like polarization of tumor-associated macrophages (TAMs). Our study elucidated the oncogenic role of CHD4 R975H mutation, highlighting its dual impact on facilitating cancer stemness and transforming TAMs into an immunosuppressive subtype. These findings contribute valuable insights into the molecular mechanisms driving EC progression and open avenues for targeted therapeutic interventions.

Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine.

BACKGROUND: Organoids are approved by the US FDA as an alternative to animal experiments to guide drug development and for sensitivity screening. Stable organoids models of gastric cancer are desirable for personalized medicine and drug screening. METHODS: Tumor tissues from a primary cancer of the stomach and metastatic cancer of the lymph node were collected for 3D culture. By long-term culture for over 50 generations in vitro, we obtained stably growing organoid lines. We analyzed short tandem repeats (STRs) and karyotypes of cancer cells, and tumorigenesis of the organoids in nude mice, as well as multi-omics profiles of the organoids. A CCK8 method was used to determine the drugs sensitivity to fluorouracil (5-Fu), platinum and paclitaxel. RESULTS: Paired organoid lines from primary cancer (SPDO1P) and metastatic lymph node (SPDO1LM) were established with unique STRs and karyotypes. The organoid lines resulted in tumorigenesis in vivo and had clear genetic profiles. Compared to SPDO1P from primary cancer, upregulated genes of SPDO1LM from the metastatic lymph node were enriched in pathways of epithelial-mesenchymal transition and angiogenesis with stronger abilities of cell migration, invasion, and pro-angiogenesis. Based on drug sensitivity analysis, the SOX regimen (5-Fu plus oxaliplatin) was used for chemotherapy with an optimal clinical outcome. CONCLUSIONS: The organoid lines recapitulate the drug sensitivity of the parental tissues. The paired organoid lines present a step-change toward living biobanks for further translational usage.

Tumor antigen presentation and the associated signal transduction during carcinogenesis.

Numerous developments have been achieved in the study and treatment of cancer throughout the decades that it has been common. After decades of research, about 100 different kinds of cancer have been found, each with unique subgroups within certain organs. This has significantly expanded our understanding of the illness. A mix of genetic, environmental, and behavioral variables contribute to the complicated and diverse process of cancer formation. Mutations, or changes in the DNA sequence, are crucial to the development of cancer. These mutations have the ability to downregulate the expression and function of Major Histocompatibility Complex class I (MHC I) and MHCII receptors, as well as activate oncogenes and inactivate tumor suppressor genes. Cancer cells use this tactic to avoid being recognized by cytotoxic CD8+T lymphocytes, which causes issues with antigen presentation and processing. This review goes into great length into the PI3K pathway, changes to MHC I, and positive impacts of tsMHC-II on disease-free survival and overall survival and the involvement of dendritic cells (DCs) in different tumor microenvironments. The vital functions that the PI3K pathway and its link to the mTOR pathway are highlighted and difficulties in developing effective cancer targeted therapies and feedback systems has also been mentioned, where resistance mechanisms include RAS-mediated oncogenic changes and active PI3K signalling.

Spatial profiling of non-small cell lung cancer provides insights into tumorigenesis and immunotherapy response.

Lung cancer is the second most common cancer worldwide and a leading cause of cancer-related deaths. Despite advances in targeted therapy and immunotherapy, the prognosis remains unfavorable, especially in metastatic cases. This study aims to identify molecular changes in non-small cell lung cancer (NSCLC) patients based on their response to treatment. Using tumor and matched immune cell rich peritumoral tissues, we perform a retrospective, comprehensive spatial transcriptomic analysis of a proven malignant NSCLC sample treated with immune checkpoint inhibitor (ICI). In addition to T cells, other immune cell types, such as B cells and macrophages, were also activated in responders to ICI treatment. In particular, B cells and B cell-mediated immunity pathways are consistently found to be activated. Analysis of the histologic subgroup (lung squamous cell carcinoma, LUSC; lung adenocarcinoma, LUAD) of NSCLC also confirms activation of B cell mediated immunity. Analysis of B cell subtypes shows that B cell subtypes were more activated in immune cell-rich tissues near tumor tissue. Furthermore, increased expression of B cell immunity-related genes is associated with better prognosis. These findings provide insight into predicting ICI treatment responses and identifying appropriate candidates for immunotherapy in NSCLC patients.