Tumor Types Research Articles

Multiplexed Glycan Immunofluorescence Identification of Pancreatic Cancer Cell Subpopulations in Both Tumor and Blood Samples.

Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays suitable for early disease detection that would improve patient outcomes. The CA19-9 glycan is currently used as a standalone biomarker for PDAC. Furthermore, previous studies have shown that cancer cells may display aberrant membrane-associated glycans. We therefore hypothesized that PDAC cancer cell subpopulations could be distinguished by aberrant glycan signatures. We used multiplexed glycan immunofluorescence combined with pathologist annotation and automated image processing to distinguish between PDAC cancer cell subpopulations within tumor tissue. Using a training-set/test-set approach, we found that PDAC cancer cells may be identified by signatures comprising 4 aberrant glycans (VVL, CA19-9, sTRA, and GM2) and that there are three glycan-defined PDAC tumor types: sTRA type, CA19-9 type, and intermixed. To determine whether the aberrant glycan signatures could be detected in blood samples, we developed hybrid glycan sandwich assays for membrane-associated glycans. In both patient-matched tumor and blood samples, the proportion of aberrant glycans detected was consistent. Furthermore, our multiplexed glycan immunofluorescent approach proved to be more sensitive and more specific than CA19-9 alone. Our results provide proof of concept for a novel methodology to improve early PDAC detection and patient outcomes.

CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient’s age, and tumor types

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient’s age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR’s hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

Expression and clinical significance of CLDN7 and its immune-related cells in breast cancer

BackgroundCLDN is a core component of tight junctions (TJs). Abnormal expressions of CLDNs are commonly detected in various types of tumors. CLDNs are of interest as a potential therapeutic target. CLDNs are closely associated with most cancers of epithelial origin, especially when CLDN7 promotes cancer cell metastasis, such as in gastric, cervical, and ovarian cancers.Its expression and prognosis in breast cancer (BC) remain unknown.The purpose of this study was to investigate the expression pattern of CLDN7 and related immune factors in BC and shed light on a better therapeutic avenue for BC patients.MethodThe cBioPortal, GEPIA, and TCGA databases were used to comprehensively assess the expression of CLDN7 in BC. The Kaplan-Meier Plotter (KMP) database was applied to examine the relationship among the CLDN7 overexpression (OE), prognosis, and overall survival (OS) of BC patients. Immunohistochemical staining was performed on 92 BC tissue samples and 20 benign breast tumors to verify the expression level of CLDN-7 protein and its correlation with clinicopathological features and prognosis. TIMER2.0 was used to analyze the correlation between the CLDN7 OE and immune gene activation using BC-related transcriptomic data. Enrichment analyses of CLDN7-related immune pathways were conducted using online databases. The risk of expression of CLDN7-related immune genes was assessed and differentially expressed (DE) genes were included in the construction of the risk prognosis nomogram.ResultsBoth database analysis and clinical sample validation results showed that CLDN7 was significantly overexpressed (OE) in BC, and the OE was correlated with poor DFS in BC patients (p < 0.05). TIMER2.0 analysis indicated that CLDN7 OE was negatively associated with the activation of B-cells, CD4+ T-cells, and CD8+ T-cells but positively with the M0 macrophages. Pathway enrichment analysis suggested that CLDN7-related immune factors were mostly involved in the NF-κB and T-cell receptor (TCR) signaling pathways. Univariate Cox regression was used to analyze the correlation between 52 CLDN7 related genes and OS, and 22 genes that are related to prognosis were identified. Prognostic genes were included in the prognostic nomogram of BC with a C-index of 0.76 to predict the 3-year and 5-year OS probabilities of BC individuals.ConclusionsThese findings provide evidence for the role of CLDN7-linked tumor immunity, suggesting that CLDN7 might be a potential immunotherapeutic target for BC, and its association with immune markers could shed light on the better prognosis of BC.

CAR-T Cells in the Treatment of Nervous System Tumors.

Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies.

Retrospective analysis of data on the prevalence of malignant neoplasms in dogs and cats

The article presents the results of a study on the primary incidence of malignant tumors in dogs and cats in Moscow over the period from January 1, 2023, to July 1, 2024. The study was conducted on the basis of the Department of Diseases of Small Domestic, Laboratory and Exotic Animals and the Research Laboratory of Oncology, Ophthalmology and Animal Biochemistry of the Russian Biotechnological University “ROSBIOTECH”. The study included 208 cats and 325 dogs with primary, spontaneous malignant tumors of various origins. To confirm the diagnosis, a comprehensive approach was used, including clinical examination, hematological tests, and special diagnostic techniques such as ultrasonography, radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Verification of the tumor process was based on cytological and histological methods.The purpose of this work is to analyze the structure of the incidence of small domestic animals with malignant tumors. As a result, we identified the most common types of tumors in cats and dogs. In cats, breast carcinoma was the most common type (44.23%), followed by lymphoma (18.27%), sarcomas (13.46%) and carcinomas (13.94%), as well as squamous cell carcinoma (6.25%). In dogs, breast carcinoma also accounted for the majority of cases (37.23%), along with sarcomas (23.38%), mastocytomas (16.31%), and carcinomas (14.15%).

Health disparities among cancer patients who received molecular testing for biomarker-directed therapy.

Health disparities present a barrier to successful oncology treatment. The potential for precision oncology to reduce health disparities has not previously been analyzed. We performed a retrospective analysis of 12,627 patients from six major cancer centers whose tumors underwent genomic testing at Caris Life Sciences between 2010-2020. Kaplan-Meier and Cox regression were used to describe and analyze overall survival (OS). Molecular and demographic features of the cohort were analyzed by Chi-square and analysis of variance (ANOVA) tests. Black patients composed 25% of the cohort and White patients 63%. Among this molecularly-tested cohort, there were minimal outcome differences based on race, geographic location, or poverty level. When analyzing the interaction of age, race, and sex, racial-based disparities were noted primarily for young non-White women in the study cohort, but were more pronounced for men and women of all ages in the broader patient population within the SEER database. Mutations in five genes-APC, EGFR, STK11, TP53, and KRAS-were found to affect OS among our cohort and their prevalence varied by race in specific tumor types. Real-world outcomes data in mutation-defined cohorts also provided additional context to previously reported therapeutic response trends. Our study shows that patients who undergo molecular testing display reduced racial health disparities compared to the general population, while persistent racial disparities are influenced by age and sex. Genomic-driven racial disparities should be examined at a tumor lineage-specific level. Increased access to molecular testing for all eligible patients may play a role in improving health equity.

Gene and Protein Expression of MAGE and Associated Immune Landscape Elements in Non-Small-Cell Lung Carcinoma and Urothelial Carcinomas.

Melanoma-associated antigen-A (MAGE-A) is expressed in multiple cancers with restricted expression in normal tissue. We sought to assess the MAGE-A3/A6 expression profile as well as immune landscape in urothelial (UC) and non-small cell lung carcinoma (NSCLC). We also assessed co-expression of immune-associated markers, including programmed cell death ligand 1 (PD-L1) in tumor and/or immune cells, and assessed the effect of checkpoint inhibitor treatment on these markers in the context of urothelial carcinoma. We used formalin-fixed paraffin-embedded (FFPE) tissue sections from a variety of tumor types were screened by IHC for MAGE-A and PD-L1 expression. Gene expression analyses by RNA sequencing were performed on RNA extracted from serial tissue sections. UC tumor samples from patients treated with checkpoint inhibitors were assessed by IHC and NanoString gene expression analysis for MAGE-A and immune marker expression before and after treatment. Overall, 84 samples (57%) had any detectable MAGE-A expression. Detectable MAGE-A expression was present at similar frequencies in both tumor tissue types, with 41 (50%) NSCLC and 43 (64%) UC. MAGE-A expression was not significantly changed before and after checkpoint inhibitor therapy by both IHC and NanoString mRNA sequencing. Other immune markers were similarly unchanged post immune checkpoint inhibitor therapy. Stable expression of MAGE-A3/A6 pre and post checkpoint inhibitor treatment indicates that archival specimens harvested after checkpoint therapy are applicable to screening potential candidates for MAGE therapies.

Identification and Validation of STC1 Act as a Biomarker for High-Altitude Diseases and Its Pan-Cancer Analysis.

High-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), are closely related to an individual's ability to adapt to hypoxic environments. However, specific research in this field is relatively limited, and further biomarker research and clinical trials are needed to clarify the exact role and potential therapeutic applications of key genes in high-altitude diseases. This study focuses on the role of the STC1 gene in high-altitude diseases and explores its expression patterns in different types of cancer. By using gene expression data analysis and functional experiments, we identified STC1 as a key gene affecting the development of altitude sickness. In addition, we also conducted expression and mutation analysis on STC1 in various cancer samples and found significant differences in the expression of this gene in 13 types of malignant tumors, which is associated with the hypoxic state in the tumor microenvironment. In addition, STC1 is significantly associated with patient prognosis and influences tumor immunity by mediating six types of immune cells (CD8+T cells, CD4+T cells, neutrophils, macrophages, monocytes, and B cells) in the tumor microenvironment. The expression and diagnostic value of STC1 were confirmed through GEO datasets and qPCR testing, indicating consistency with the results of bioinformatics analysis. These results indicate that STC1 is not only an important factor in the adaptive response to high-altitude diseases but may also play a role in the adaptation of cancer to low-oxygen environments. Our research provides a new perspective and potential targets for the discovery of biomarkers for high-altitude diseases and cancer treatment.

Transcriptome profiling of pediatric extracranial solid tumors and lymphomas enables rapid low-cost diagnostic classification

Approximately 80% of pediatric tumors occur in low- and middle-income countries (LMIC), where diagnostic tools essential for treatment decisions are often unavailable or incomplete. Development of cost-effective molecular diagnostics will help bridge the cancer diagnostic gap and ultimately improve pediatric cancer outcomes in LMIC settings. We investigated the feasibility of using nanopore whole transcriptome sequencing on formalin-fixed paraffin embedded (FFPE)-derived RNA and a composite machine learning model for pediatric solid tumor diagnosis. Transcriptome cDNA sequencing was performed on a heterogenous set of 221 FFPE and 32 fresh frozen pediatric solid tumor and lymphoma specimens on Oxford Nanopore Technologies’ sequencing platforms. A composite machine learning model was then used to classify transcriptional profiles into clinically actionable tumor types and subtypes. In total, 95.6% and 89.7% of pediatric solid tumors and lymphoma specimens were correctly classified, respectively. 71.5% of pediatric solid tumors had prediction probabilities > 0.8 and were classified with 100% accuracy. Similarly, for lymphomas, 72.4% of samples that had prediction probabilities > 0.6 were classified with 97.6% accuracy. Additionally, FOXO1 fusion status was predicted accurately for 97.4% of rhabdomyosarcomas and MYCN amplification was predicted with 88% accuracy in neuroblastoma. Whole transcriptome sequencing from FFPE-derived pediatric solid tumor and lymphoma samples has the potential to provide clinical classification of both tissue lineage and core genomic classification. Further expansion, refinement, and validation of this approach is necessary to explore whether this technology could be part of the solution of addressing the diagnostic limitations in LMIC.

STK11 (LKB1) immunohistochemistry is a sensitive and specific marker for STK11 adnexal tumours.

ST11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz-Jeghers syndrome. It predominantly originates from the para-adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non-specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics. IHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli-Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra-ovarian sex cord-stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo-ovarian high-grade serous carcinomas, five ovarian mesonephric-like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high-grade serous carcinoma with subclonal loss. STK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context.

Repurposed AT9283 triggers anti-tumoral effects by targeting MKK3 oncogenic functions in Colorectal Cancer

BackgroundColorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related deaths worldwide, with a survival rate near to 10% when diagnosed at an advanced stage. Hence, the identification of new molecular targets to design more selective and efficient therapies is urgently required. The Mitogen activated protein kinase kinase 3 (MKK3) is a dual-specificity threonine/tyrosine protein kinase that, activated in response to cellular stress and inflammatory stimuli, regulates a plethora of biological processes. Previous studies revealed novel MKK3 roles in supporting tumor malignancy, as its depletion induces autophagy and cell death in cancer lines of different tumor types, including CRC. Therefore, MKK3 may represent an interesting new therapeutic target in advanced CRC, however selective MKK3 inhibitors are currently not available.MethodsThe study involved transcriptomic based drug repurposing approach and confirmatory assays with CRC lines, primary colonocytes and a subset of CRC patient-derived organoids (PDO). Investigations in vitro and in vivo were addressed.ResultsThe repurposing approach identified the multitargeted kinase inhibitor AT9283 as a putative compound with MKK3 depletion-mimicking activities. Indeed, AT9283 drops phospho- and total-MKK3 protein levels in tested CRC models. Likely the MKK3 silencing, AT9283 treatment: i) inhibited cell proliferation promoting autophagy and cell death in tested CRC lines and PDOs; ii) resulted well-tolerated by CCD-18Co colonocytes; iii) reduced cancer cell motility inhibiting CRC cell migration and invasion; iv) inhibited COLO205 xenograft tumor growth. Mechanistically, AT9283 abrogated MKK3 protein levels mainly through the inhibition of aurora kinase A (AURKA), impacting on MKK3/AURKA protein–protein interaction and protein stability therefore uncovering the relevance of MKK3/AURKA crosstalk in sustaining CRC malignancy in vitro and in vivo.ConclusionOverall, we demonstrated that the anti-tumoral effects triggered by AT9283 treatment recapitulated the MKK3 depletion effects in all tested CRC models in vitro and in vivo, suggesting that AT9283 is a repurposed drug. According to its good tolerance when tested with primary colonocytes (CCD-18CO), AT9283 is a promising drug for the development of novel therapeutic strategies to target MKK3 oncogenic functions in late-stage and metastatic CRC patients.

Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established. Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and insitu hybridization were employed to analyse gene and protein expression. Four invivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway. Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non-canonical NF-κB signalling pathway. Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target.

Multiomics and machine learning-based analysis of pancancer pseudouridine modifications

Pseudouridine widely affects the stability and function of RNA. However, our knowledge of pseudouridine properties in tumors is incomplete. We systematically analyzed pseudouridine synthases (PUSs) expression, genomic aberrations, and prognostic features in 10907 samples from 33 tumors. We found that the pseudouridine-associated pathway was abnormal in tumors and affected patient prognosis. Dysregulation of the PUSs expression pattern may arise from copy number variation (CNV) mutations and aberrant DNA methylation. Functional enrichment analyses determined that the PUSs expression was closely associated with the MYC, E2F, and MTORC1 signaling pathways. In addition, PUSs are involved in the remodeling of the tumor microenvironment (TME) in solid tumors, such as kidney and lung cancers. Particularly in lung cancer, increased expression of PUSs is accompanied by increased immune checkpoint expression and Treg infiltration. The best signature model based on more than 112 machine learning combinations had good prognostic ability in ACC, DLBC, GBM, KICH, MESO, THYM, TGCT, and PRAD tumors, and is expected to guide immunotherapy for 19 tumor types. The model was also effective in identifying patients with tumors amenable to etoposide, camptothecin, cisplatin, or bexarotene treatment. In conclusion, our work highlights the dysregulated features of PUSs and their role in the TME and patient prognosis, providing an initial molecular basis for future exploration of pseudouridine. Studies targeting pseudouridine are expected to lead to the development of potential diagnostic strategies and the evaluation and improvement of antitumor therapies.

First independent validation of the proton-boron capture therapy concept

Boron has been suggested to enhance the biological effectiveness of proton beams in the Bragg peak region via the p + 11B → 3α nuclear capture reaction. However, a number of groups have observed no such enhancement in vitro or questioned its proposed mechanism recently. To help elucidate this phenomenon, we irradiated DU145 prostate cancer or U-87 MG glioblastoma cells by clinical 190 MeV proton beams in plateau or Bragg peak regions with or without 10B or 11B isotopes added as sodium mercaptododecaborate (BSH). The results demonstrate that 11B but not 10B or other components of the BSH molecule enhance cell killing by proton beams. The enhancement occurs selectively in the Bragg peak region, is present for boron concentrations as low as 40 ppm, and is not due to secondary neutrons. The enhancement is likely initiated by proton-boron capture reactions producing three alpha particles, which are rare events occurring in a few cells only, and their effects are amplified by intercellular communication to a population-level response. The observed up to 2–3-fold reductions in survival levels upon the presence of boron for the studied prostate cancer or glioblastoma cells suggest promising clinical applications for these tumour types.

New clinical trial design borrowing information across patient subgroups based on fusion-penalized regression models.

In cancer research, basket trials aim to assess the efficacy of a drug using baskets, wherein patients are organized into subgroups according to their tumor type. In this context, using information borrowing strategy may increase the probability of detecting drug efficacy in active baskets, by shrinking together the estimates of the parameters characterizing the drug efficacy in baskets with similar drug activity. Here, we propose to use fusion-penalized logistic regression models to borrow information in the setting of a phase 2 single-arm basket trial with binary outcome. We describe our proposed strategy and assess its performance via a simulation study. We assessed the impact of heterogeneity in drug efficacy, prevalence of each tumor types and implementation of interim analyses on the operating characteristics of our proposed design. We compared our approach with two existing designs, relying on the specification of prior information in a Bayesian framework to borrow information across similar baskets. Notably, our approach performed well when the effect of the drug varied greatly across the baskets. Our approach offers several advantages, including limited implementation efforts and fast computation, which is essential when planning a new trial as such planning requires intensive simulation studies.

Circulating tumor DNA in management of primary liver malignancy: A review of the literature and future directions.

Primary liver malignancies are a serious and challenging global health concern. The most common primary tumors are hepatocellular carcinoma and cholangiocarcinoma. These diseases portend poor prognosis when presenting with progressive, extensive disease. There is a critical need for improved diagnosis, therapeutic intervention, and monitoring surveillance in liver-related malignancies. Liquid biopsy using ctDNA provides an opportunity for growth within these domains for liver-related malignancy. However, ctDNA is relatively understudied in this field compared with other solid tumor types, possibly due to the complex nature of the pathology. In this review, we aim to discuss ctDNA, the current literature, and future directions of this technology within primary liver malignancies.

CD47 and IFT57 Are Colinear Genes That Are Highly Coexpressed in Most Cancers and Exhibit Parallel Cancer-Specific Correlations with Survival.

An association between high CD47 expression and poor cancer survival has been attributed to its function on malignant cells to inhibit phagocytic clearance. However, CD47 mRNA expression in some cancers lacks correlation or correlates with improved survival. IFT57 encodes an essential primary cilium component and is colinear with CD47 across amniote genomes, suggesting coregulation of these genes. Analysis of The Cancer Genome Atlas datasets identified IFT57 as a top coexpressed gene with CD47 among 1156 human cancer cell lines and in most tumor types. The primary cilium also regulates cancer pathogenesis, and correlations between IFT57 mRNA and survival paralleled those for CD47 in thyroid and lung carcinomas, melanoma, and glioma. CD47 ranked first for coexpression with IFT57 mRNA in papillary thyroid carcinomas, and higher expression of both genes correlated with significantly improved overall survival. CD47 and IFT57 mRNAs were coordinately regulated in thyroid carcinoma cell lines. Transcriptome analysis following knockdown of CD47 or IFT57 in thyroid carcinoma cells identified the cytoskeletal regulator CRACD as a specific target of IFT57. CRACD mRNA expression inversely correlated with IFT57 mRNA and with survival in low-grade gliomas, lung adenocarcinomas, and papillary thyroid carcinomas, suggesting that IFT57 rather than CD47 regulates survival in these cancers.

Elucidating the pan-oncologic landscape of S100A9: prognostic and therapeutic corollaries from an integrative bioinformatics and Mendelian randomization analysis

The calcium-binding protein S100A9 has emerged as a pivotal biomolecular actor in oncology, implicated in numerous malignancies. This comprehensive bioinformatics study transcends traditional boundaries, investigating the prognostic and therapeutic potential of S100A9 across diverse neoplastic entities. Leveraging a wide array of bioinformatics tools and publicly available cancer genomics databases, such as TCGA, we systematically examined the S100A9 gene. Our approach included differential expression analysis, mutational burden assessment, protein interaction networks, and survival analysis. This robust computational framework provided a high-resolution view of S100A9’s role in cancer biology. The study meticulously explored S100A9’s oncogenic facets, incorporating comprehensive analyses of its relationship with prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration across various tumor types. This study presents a panoramic view of S100A9 expression across a spectrum of human cancers, revealing a heterogeneous expression landscape. Elevated S100A9 expression was detected in malignancies such as BLCA (Bladder Urothelial Carcinoma), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), COAD (Colon adenocarcinoma), ESCA (Esophageal carcinoma), and GBM (Glioblastoma multiforme), while reduced expression was noted in BRCA (Breast invasive carcinoma), HNSC (Head and Neck squamous cell carcinoma), and KICH (Kidney Chromophobe). This disparate expression pattern suggests that S100A9’s role in cancer biology is multifaceted and context-dependent. Prognostically, S100A9 expression correlates variably with patient outcomes across different cancer types. Furthermore, its expression is intricately associated with TMB and MSI in nine cancer types. Detailed examination of six selected tumors—BRCA, CESC, KIRC (Kidney renal clear cell carcinoma), LUSC (Lung squamous cell carcinoma), SKCM (Skin Cutaneous Melanoma); STAD (Stomach adenocarcinoma)—revealed a negative correlation of S100A9 expression with the infiltration of most immune cells, but a positive correlation with neutrophils, M1 macrophages, and activated NK cells, highlighting the complex interplay between S100A9 and the tumor immune environment. This bioinformatics synthesis posits S100A9 as a significant player in cancer progression, offering valuable prognostic insights. The data underscore the utility of S100A9 as a prognostic biomarker and its potential as a therapeutic target. The therapeutic implications are profound, suggesting that modulation of S100A9 activity could significantly impact cancer management strategies.

PTBP1 knockdown impairs autophagy flux and inhibits gastric cancer progression through TXNIP-mediated oxidative stress

BackgroundGastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood.MethodsTo assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT–qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT–qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1’s regulation of autophagy in GC.ResultsOur findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo.ConclusionPTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC.Graphical

Prognostic significance of HS2ST1 expression in patients with hepatocellular carcinoma

BackgroundHeparan sulfate 2-O-sulfotransferase 1 (HS2ST1) catalyzes the sulfation of glucuronic acid residues in heparan sulfate proteoglycans, enabling these proteoglycans to interact with numerous ligands within tumor microenvironments. However, the prognostic role of HS2ST1 expression in cancer remains unclear.ObjectiveThis investigated HS2ST1 expression levels and their prognostic significance in various cancer types, demonstrated the prognostic value of HS2ST1 expression in hepatocellular carcinoma (HCC) patients, and identified molecular signatures associated with HS2ST1 expression.MethodsHS2ST1 expression and patient survival data from The Cancer Genome Atlas (TCGA) datasets were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) portal. We obtained gene expression and clinicopathological information on HCC patients from the TCGA and the Japan and France International Cancer Genome Consortium (ICGC) databases and performed survival analyses. We also examined relevant protein networks, differentially expressed genes, gene set enrichments, and tumor immune microenvironment features associated with HS2ST1 expression.ResultsHS2ST1 exhibited higher expression in eight tumor types compared with normal tissues and was associated with poor prognoses in five tumors, including HCC. HS2ST1 status correlated with poor prognosis in two ICGC HCC cohorts. Elevated HS2ST1 expression in HCC tumors was associated with signaling pathways involved in cell cycle progression, protein secretion, and mTORC1 signaling. Moreover, HS2ST1 expression levels were inversely correlated with immune cell infiltration in the tumor microenvironment.ConclusionOur study elucidates the prognostic significance of HS2ST1 expression in HCC patients and provides insights into the potential roles of HS2ST1 in signaling pathways and the tumor microenvironment.