Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.

Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.

Human Endogenous RetroVirus (HERV) expression in tumours reflects epigenetic dysregulation of cancer and an oncogenic factor through promoter/enhancer action on genes. While more than 50% of colorectal cancers develop liver metastases, HERV has not been studied in this context.

We collected 400 RNA-seq samples from over 200 patients with primary and liver metastases, including public data and a novel set of 200 samples.

We observed global stability of HERV expression between liver metastases and primary colorectal cancers, suggesting an early oncogenic footprint. We identified a list of 17 HERV loci for liver metastatic colorectal cancer (lmCRC) characterization; with tumour-specificity validated in single-cell metastatic colorectal cancer data and normal tissue bulk RNA-seq. Eleven loci produced HERV-derived peptides as per tandem mass spectrometry from primary colorectal cancer. Six loci were associated with the risk of relapse after lmCRC surgery. Four, HERVH_Xp22.32a, HERVH_20p11.23b, HERVH_13q33.3, HERVH_13q31.3, had adverse prognostic value (log-rank p-value 0.028, 0.0083, 9e-4, 0.05, respectively) while two, HERVH_Xp22.2c (log-rank p-value 0.032) and HERVH_8q21.3b (in multivariable models) were associated with better prognosis. Moreover, the markers showed a cumulative effect on survival when expressed. Some were associated with decreased cytotoxic immune cells and most of them correlated with cell cycle pathways.

These findings provide insights into the lmCRC transcriptome landscape by suggesting prognostic markers and potential therapeutic targets.

This work was supported by funding from institutional grants from Inserm, EFS, University of Bourgogne Franche-Comté, national found "Agence Nationale de la Recherche - ANR-JCJC: Projet HERIC and ANR-22-CE45-0007", and "La ligue contre le cancer".

This study aimed to identify predictive factors for chemotherapy response in colorectal liver metastasis (CRLM) patients.

Eligible participants with CRLM who had undergone at least two systemic chemotherapy cycles postdiagnosis were retrospectively analyzed. They were categorized as responders and nonresponders based on tumor size reduction. DNA extracted from tumor tissues was subjected to sequencing. Additionally, a comparative analysis of oncogenic pathways was conducted. Logistic regression analysis was conducted to determine predictive factors for chemotherapy response.

A total of 230 Chinese patients were analyzed. Significant differences in mutation distribution were found, particularly in the KRAS gene and several specific rare gene mutations (EP300, PTPRK, KMT2A, and ACVR1B), as well as in the PI3K and RTK-RAS pathways between the two groups. Gender, utilization of biological targeted agents (BTAs), KRAS gene mutations, PI3K pathway alterations, and specific rare gene mutations were used to construct a specific efficacy prediction model, achieving an area under the curve (AUC) of 0.73. Approximately 75% (87/116) of patients could potentially avoid BTAs based on the model's predictions. In a subgroup of 52 patients not using BTAs, simulation indicated that 10 patients could benefit by including BTAs, representing 32% (10 of 31) of initially nonresponsive patients.

Gender, utilization of BTAs, and specific gene and pathway mutations may be significant predictors of chemotherapy response in CRLM patients. These findings highlight the role of genetic profiling in refining treatment strategies.

Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances in immunotherapies and targeted therapies benefit a subset of CRC patients, with sub-optimal outcomes. Hence, there is an unmet need to design and manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly in pancreatic adenocarcinoma, non-small cell lung cancer, and CRC, is an on-off switch and governs several fundamental cell signaling cascades. KRAS mutations not only propel the progression and metastasis of CRC but also critically modulate responses to targeted therapies.

We discuss the impacts of KRAS mutations on the CRC's tumor microenvironment and describe novel strategies for targeting KRAS and its associated signaling cascades and mechanisms of drug resistance.

Drug development against KRAS mutations has been challenging, mainly due to structural properties (offering no appropriate binding site for small molecules), critical functions of the wild-type KRAS in non-cancerous cells, and the complex network of its downstream effector pathways (allowing malignant cells to develop resistance). Pre-clinical and early clinical data offer promises for combining KRAS inhibitors with immunotherapies and targeted therapies.

The occurrence and death rates of colorectal cancer (CRC) have been consistently increasing, demanding the immediate requirement for the creation of dependable and effective medicinal treatments. This study investigates bardoxolone methyl (CDDO-Me), a synthetic triterpenoid, as a potential therapeutic agent for CRC. Integrating network pharmacology, bioinformatic analyses, and in vitro assays, we evaluated the effects of CDDO-Me on CRC cells. In vitro studies indicate that CDDO-Me significantly inhibits the growth of CRC cells, specifically HCT116 and RKO, with IC50 values of 3.17 µM and 7.64 µM, respectively. Additionally, CDDO-Me effectively suppresses the PI3K signaling pathway and increases reactive oxygen species (ROS) levels in CRC cells. Consequently, this leads to G2/M phase arrest, an increase in apoptosis (over 30%), and a decrease in adhesion and invasion capabilities. Importantly, these effects were reversible upon the administration of N-acetylcysteine. Collectively, our findings provide compelling evidence for the potential of CDDO-Me as a promising candidate for the treatment of CRC.

The genes NBN and MLH1 are critical for DNA repair, and this study aimed to detect and predict the effects of pathogenic single nucleotide polymorphisms (SNPs) in their mRNA and protein sequences. An in silico analysis assessed the impact of SNPs on the physicochemical properties, structure, stability, and function of MLH1 and NBN proteins. Results revealed that some SNPs significantly alter protein stability, structure, and binding interactions, potentially impairing DNA repair. Molecular docking studies further indicated disruptions in protein-protein interactions due to specific SNPs. These findings underscore the importance of using in silico methods to predict the functional effects of genetic variations, providing insights that could guide personalized treatments and improve cancer detection.

We propose HERGAST, a system for spatial structure identification and signal amplification in ultra-large-scale and ultra-high-resolution spatial transcriptomics data. To handle ultra-large spatial transcriptomics (ST) data, we consider the divide and conquer strategy and devise a Divide-Iterate-Conquer framework especially for spatial transcriptomics data analysis, which can also be adopted by other computational methods for extending to ultra-large-scale ST data analysis. To tackle the potential over-smoothing problem arising from data splitting, we construct a heterogeneous graph network to incorporate both local and global spatial relationships. In simulations, HERGAST consistently outperforms other methods across all settings with more than a 10% increase in average adjusted rand index (ARI). In real-world datasets, HERGAST's high-precision spatial clustering identifies SPP1+ macrophages intermingled within colorectal tumors, while the enhanced gene expression signals reveal unique spatial expression patterns of key genes in breast cancer.

Tricellulin belongs to the TAMP family of proteins and is primarily localized at the tricellular tight junctions. While its role in the progression of cancer has been reported, its importance in the progression of colorectal cancer (CRC) remains unclear.

This study aimed to determine the function and mechanism of tricellulin in CRC progression.

The proteins expression in cells and/or tissues was determined by Western blot, immunohistochemistry staining, and/or RT-qPCR analyses. The biological functions of tricellulin were investigated through in vitro assays (CCK-8, Transwell migration, and colony formation assays) and in vivo xenograft models. Tricellulin was significantly upregulated in CRC tissues compared to adjacent normal tissues. The expression of tricellulin was correlated with poor prognosis in patients with CRC.

In vitro assays showed that tricellulin enhanced CRC cell proliferation, migration, and invasion. Mechanistically, tricellulin activated the TGFb1/SMAD2/3 pathway, while TGFb1 reciprocally controlled the expression of tricellulin. Also, tricellulin promotes CRC cell migration/invasion through EMT. In vivo models confirmed that the overexpression of tricellulin facilitated tumor growth and activated the TGFb1/ SMAD2/3 pathway in CRC.

Our findings demonstrate thatTricellulin promotes the metastasis of colorectal cancer by activating the TGF-β/SMAD2/3 signaling pathway, and TGF-β1 can reciprocally regulate the expression of tricellulin.We have revealed a novel mechanism by which tricellulin forms a positive feedback loop to promote the growth and metastasis of CRC. This mechanism provides novel insights into CRC progression and suggests potential therapeutic targets.

Colon cancer is a prevalent malignancy that significantly threatens human health. In recent years, mRNA cancer vaccines have demonstrated considerable potential and distinct advantages in colon cancer treatment. Thus, This study identifies CUL7, ENO2, and MPP2 as potential antigens for colon cancer mRNA vaccines. Through multi-omics analysis, we classify COAD into three immune subtypes (C1-C3) with distinct molecular and clinical features.

Data from TCGA and GEO databases were analyzed using bioinformatics tools. Prognostic indices were calculated with GEPIA2, and TIMER assessed antigen-presenting cell infiltration. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards models. Immune subtypes were classified via non-negative matrix factorization (NMF) clustering, with k=3 determined by cophenetic correlation (0.92) and silhouette width (average = 0.85). Drug sensitivity, immune cell infiltration, and gene set variation were analyzed using R packages such as "pRRophetic," CIBERSORT, and GSVA. Functional enrichment analysis was performed with GO, KEGG, and GSEA. Experimental validation included immunohistochemistry and RT-PCR to confirm gene expression.

Analysis of TCGA-COAD data revealed copy number variants in 16,354 genes, with CUL7, ENO2, and MPP2 showing significant antigen-presenting cell infiltration and associations with overall survival (OS) and relapse-free survival (RFS). Based on molecular mechanisms, cellular features, and clinical characteristics, colon cancer was categorized into three immune subtypes (C1, C2, and C3) distinct from Thorsson's pan-cancer subtypes (C1-C6) in pathway enrichment, with the C2 subtype exhibited significantly longer overall survival (OS) than C1 and C3 (median OS: C2 = 68 months vs. C1 = 42 months, C3 = 37 months; log-rank P < 0.001). The distribution of these immune subtypes showed disparities in immune patterns, and a correlation between key components and immune cells was observed. Prognostic correlation analysis indicated that the gray and turquoise modules were closely linked to colorectal cancer prognosis. Additionally, RT-PCR confirmed the association of CUL7, ENO2, and MPP2 expression levels with colon cancer.

CUL7, ENO2, and MPP2 were identified as potential antigens for colon cancer mRNA vaccines, with MPP2 showing particular immunological relevance. This study provides a foundation for mRNA vaccine development and patient stratification for vaccination in colon cancer.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

Colorectal cancer (CRC) imposes a substantial burden on global health., but research trends and hotspots in this field are still not clear. The purpose of this research is to create a visual knowledge map based on bibliometric analysis, identify research hotspots and predict future research trends.

Utilizing the Web of Science Core Collection (WoSCC) as data source and integrating the visualization capabilities of the Bibliometrix R software package, CiteSpace, and VOSviewer, analyze the authors, research institutions, countries, cited documents, publishing journals, abstracts, and keyword information of literature pertaining to neoadjuvant therapy for colorectal cancer spanning from January 2015 to December 2024.

The analysis included 1,587 articles from 1,464 institutions, 385 journals, and 61 countries or regions. China has the largest number of publications (449) and the largest number of citations (5,035). The United States occupies the leading position with an average of 21.6. "Annals of Surgical Oncology" is the most published journal with 51 articles, and "Journal of Clinical Oncology" is the journal with the most references (4,465 references). Highly cited references focus on clinical trials and guidelines for neoadjuvant therapy for colorectal cancer. In recent years, the most important keywords in the research on colorectal cancer and neoadjuvant therapy have been "artificial intelligence", "total neoadjuvant therapy" and "immunotherapy".

This article provided a review of the research on neoadjuvant therapy for colorectal cancer, can provide reference for subsequent research on neoadjuvant therapy for colorectal cancer. The results offered valuable insights and data that informed the direction of future advancements.

Increased evidence reveals that glycolysis is one of the key metabolic hallmarks of cancer cells. However, the roles of lncRNA FTX in energy metabolism and cancer progression remain unclear. In this study we aim to show that lncRNA FTX was significantly upregulated in cancer tissues and serum of CRC patients and CRC cell lines. Function study indicated that it could promote aerobic glycolysis, cell proliferation, migration and invasion in colorectal cancer cells. Further mechanistic studies showed, lncRNA FTX was found to function as a sponge for miR-215-3p, which reduced the ability of miR-215-3p to repress the YAP1 oncoprotein. Additionally, a negative correlation was observed between lncRNA FTX and miR-215-3p expression, and the knockdown of lncRNA FTX or miR-215-3p overexpression yielded opposite effects. In conclusion, this study demonstrates that FTX could directly combine with miR-215-3p as a competitive endogenous RNA, thus promoting the aerobic glycolysis and progression of CRC in vitro and in vivo.

Colorectal cancer (CRC) is a highly heterogeneous tumor, with significant variation in malignant cells, posing challenges for treatment and prognosis. However, this heterogeneity offers opportunities for personalized therapy.

The consensus non-negative matrix factorization algorithm was employed to analyze single-cell transcriptomic data from CRC, which helped identify malignant cell expression programs (MCEPs). Subsequently, a crosstalk network linking MCEPs with immune/stromal cell trajectory development was constructed using Monocle3 and NicheNet. Additionally, bulk RNA-seq data were utilized to systematically explore the relationships between MCEPs, clinical features, and genetic mutations. A prognostic model was then established through Lasso and Cox regression analyses, integrating clinical data into a nomogram for personalized risk prediction. Furthermore, key genes associated with MCEPs and their potential therapeutic targets were identified using protein-protein interaction networks, followed by molecular docking to predict drug-binding affinity.

We classified CRC malignant cell transcriptional states into eight distinct MCEPs and successfully constructed crosstalk networks between these MCEPs and immune or stromal cells. A prognostic model containing 15 genes was developed, demonstrating an AUC greater than 0.8 for prognostic evaluation over 1 to 10 years when combined with clinical features. A key drug target gene TIMP1 was identified, and several potential targeted drugs were discovered.

This study demonstrated that characterization of the malignant cell transcriptional programs could effectively reveal the biological features of highly heterogeneous tumors like CRC and exhibit significant potential in tumor prognosis assessment. Our research provides new theoretical and practical directions for CRC prognosis and targeted therapy.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by a complex interplay of genetic, environmental, and immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, the Notch signaling pathway is instrumental in governing cell fate decisions, tissue renewal, homeostasis, and immune cell development. As a highly conserved mechanism, Notch signaling not only modulates tumor cell behavior but also shapes the immune landscape within the tumor microenvironment (TME). Aberrant Notch signaling in CRC fosters immune evasion and tumor progression through its effects on the balance and functionality of immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Elevated Notch pathway activation correlates with advanced clinicopathological features and poorer clinical outcomes, highlighting its relevance as both a prognostic biomarker and a therapeutic target. Therapeutic approaches aimed at inhibiting the Notch pathway, such as γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) in combination with other therapies, have demonstrated promising efficacy in preclinical and clinical settings. This review examines the impact of Notch signaling on CRC immunity, elucidating its regulatory mechanisms within immune cells and its role in promoting tumor progression. Additionally, this review discusses therapeutic strategies targeting Notch signaling, including GSIs, mAbs, and potential combination therapies designed to overcome resistance and improve patient outcomes. By elucidating the multifaceted role of Notch within the CRC TME, this review underscores its potential as a target for innovative therapeutic strategies.

Despite remarkable advances in cancer treatment, most solid cancers remain difficult to cure. We recently developed an antibody-drug conjugate (ADC; 84-EBET) for pancreatic cancer by using the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) antibody #84.7 and the bromodomain and extra-terminal (BET) protein degrader EBET. In this study, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of colorectal, lung, and breast cancers revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of colorectal-, lung-, and breast cancer patient-derived xenograft tumors and cell line-derived xenograft tumors. Moreover, in mouse syngeneic colorectal cancer, lung cancer, and breast cancer models resistant to PD-1 antibody, the combination of 84-EBET and PD-1 antibody induced complete regression of most tumors. Mechanistically, 84-EBET degraded bromodomain-containing protein 4 in both cancer and stromal cells via bystander efficacy. It decreased stromal inflammatory phenotypes and increased activated T-cell numbers in tumors. These results demonstrate that delivering BET protein degraders to tumors and their microenvironments via a CEACAM6-targeted ADC may be effective against a wide range of solid cancers.

Colorectal cancer (CRC) is one of the most common cancers worldwide. With the growing understanding of immune regulation in tumors, the complement system has been recognized as a key regulator of tumor immunity. Traditionally, the complement cascade, considered an evolutionarily conserved defense mechanism against invading pathogens, has been viewed as a crucial inhibitor of tumor progression. Complement components or activation products produced via cascade‑dependent or ‑independent processes are associated with the regulation of tumor‑associated inflammation. Various forms of complement activation products present in body fluids or inside cells, along with complement regulatory proteins and complement receptors, are involved in tumor cell growth and modulating the tumor microenvironment. In the present review, the role of the complement system in the tumor immunity of CRC is discussed. In addition, the contribution of the unconventional cascade‑independent pathway of complement activation in CRC progression is highlighted. A deeper understanding of the mechanism underlying the complement system in colitis‑associated colorectal cancer (CAC) may provide novel insights to assist the development of methods to prevent tumor progression and identify potential targets for the treatment of CAC.

The role of cancer-associated fibroblasts (CAFs) in modulating the tumor microenvironment (TME) is gaining attention, yet their impact on prognosis and therapeutic response in colon cancer remains unclear. Here, we identified genes associated with CAF infiltration via weighted gene co-expression network analysis (WGCNA) utilizing data from The Cancer Genome Atlas (TCGA) and GSE39582 cohorts. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct CAF molecular signatures (CAFscore). Patients were categorized into high and low CAFscore groups to analyze clinicopathological traits, somatic mutations, immune evasion, and treatment responses. In this study, a total of 244 genes were correlated with CAF infiltration, with 11 linked to overall survival. Notably, FSTL3, CRIP2, and SLC2A3 were selected for the CAFscore. A higher CAFscore was associated with poorer prognoses, increased malignancy, and therapeutic resistance, particularly among patients with high tumor mutation burden and microsatellite instability. Furthermore, elevated FSTL3 expression was associated with reduced CD8+ T cell infiltration, indicating a suppressive TME. Mechanistically, CAFs may promote immune evasion via NAMPT ligand-receptor interactions based on single-cell RNA sequencing data. Thus, the CAFscore is crucial for personalizing treatment strategies and identifying patients who require more aggressive management.

Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis.

In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples.

Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR.

These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.

Colorectal cancer (CRC), characterized by its complex genetic heterogeneity and varied responses to treatment, is a leading cause of cancer-related mortality worldwide. The role of N1-methyladenosine (m1A)-related genes in tumor biology remains underexplored. This study aimed to investigate the prognostic value of m1A-related genes in CRC, characterize their role in tumor molecular subtyping, and explore their influence on the tumor microenvironment (TME) and immune infiltration.

To identify prognostic markers, univariate Cox analysis was performed using multiple datasets, including TCGA and GEO, identifying 43 m1A-related genes. Four distinct molecular subtypes of CRC were defined based on the expression of these genes using non-negative matrix factorization (NMF). Immune infiltration analysis was conducted, and the TIDE algorithm was used to predict response to immune checkpoint inhibitors (ICIs). Furthermore, a prognostic model based on m1A-related genes was constructed and validated across multiple datasets.

The results demonstrated that the four CRC molecular subtypes exhibited significant differences in survival outcomes and clinical characteristics. Stromal cells showed higher m1A scores, suggesting a regulatory role in the TME. There was a positive correlation between m1A-related gene expression and immune checkpoint genes. Moreover, the constructed prognostic model showed robust predictive performance and outperformed other recently published models.

The findings suggest that m1A-related genes are not only valuable biomarkers for CRC prognosis but also have significant implications for the immune landscape and could serve as potential targets for therapeutic intervention, particularly in the context of immunotherapy. For instance, SLC12A2 was found to enhance invasion, proliferation, and migration of colorectal cancer cells while inhibiting apoptosis. Further studies are needed to understand the functional roles of m1A modifications across different cell types within the TME.

Our study's aim was to evaluate the clinicopathological profile of colorectal cancer (CRC) patients from North-East Romania in relation to the Kirsten rat sarcoma viral oncogene homolog (KRAS). We designed a retrospective study on 108 CRC patients using the fully automated real-time PCR-based molecular testing system, IdyllaTMKRAS Mutation Test (Biocartis, Mechelen, Belgium). Of the patients, 64 (59.3%) were men and 62 (57.4%) were older than the group average, with left bowel location in 38 cases (35.2%), adenocarcinoma NOS in 102 cases (94.4%), mixed histological pattern in 65 cases (60.2%), T3 in 60 patients (55.6%), N2 in 46 patients (42.6%), and 7-12 tumour buds registered in 58 tumours (53.7%). A total of 54 tumour samples (50%) showed KRAS mutation. Statistical comparative analyses associated KRAS mutations with the histopathological pattern (p = 0.018), tumour grade (p = 0.030), depth of invasion (pT) (p < 0.001), lymph node involvement (pN) (p < 0.001), venous vascular invasion (p = 0.048), and tumour buds' number (p = 0.007). Our results demonstrate the relationship between KRAS mutation and clinicopathological features, with possible impact in clinical tumour stratification and therapeutic management.

Eukaryotic Initiation Factor 5A1 (EIF5A1) is a translation factor, and its pro-tumorigenic role has been extensively documented across various cancer types. However, its specific function in bladder cancer (BLCA) remains unclear.

We integrated proteomics and transcriptomics data with clinical data from BLCA patients to investigate the correlation between EIF5A1 expression and BLCA, as well as its potential clinical applications. Transcriptomic data were employed to explore the downstream signaling pathways regulated by EIF5A1. Furthermore, ChIP analysis and luciferase reporter assays were conducted to identify the upstream transcription factors regulating EIF5A1.

EIF5A1 expression is significantly upregulated in cancer tissues and cells and is strongly associated with poor prognosis. Silencing EIF5A1 in BLCA cells significantly reduced invasiveness, and proliferative capacity. Mechanistic studies identified YAP/TEAD4 as a transcription factor that regulates EIF5A1, influencing mitochondrial-mediated apoptosis by activating the JAK2/STAT3 signaling pathway, thereby promoting BLCA progression.

Our research demonstrates that EIF5A1 is upregulated in BLCA and associated with poor prognosis. We identified TEAD4 as a potential transcriptional regulator of EIF5A1 and showed that EIF5A1 expression is associated with changes in JAK2/STAT3 signaling and mitochondrial apoptosis in BLCA.

Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.

"Viral mimicry" refers to the induction of an innate immune response and interferon signaling by endogenous stimuli such as double-stranded RNA (dsRNA). This response has been shown to have strong cancer therapeutic potential, including by enhancing the effectiveness of immune checkpoint inhibition (ICI) therapies, and may represent a tumor suppression mechanism that needs to be overcome for malignant transformation to proceed. In a recent study, Zhou and colleagues identify KRAS, a frequently mutated oncogene, as a negative regulator of dsRNA and viral mimicry in an ICI-resistant colorectal cancer model. Oncogenic KRASG12D mutations downregulate the RNA-binding protein DDX60 by activating the AKT signaling pathway, which inhibits STAT3, a critical transcription factor regulating DDX60 and other interferon-stimulated genes. Overexpression of DDX60, which competitively binds to dsRNA to prevent RISC-mediated degradation, or targeting of KRASG12D elevated dsRNA levels, resulting in viral mimicry activation and potentiation of ICI treatment. These results establish KRAS as a promising target to sensitize immune "cold" tumors to ICI therapy and demonstrate the potential role of oncogenic mutations in viral mimicry evasion during tumorigenesis.

Colorectal cancer (CRC) patients with microsatellite-stable (MSS) tumors are mostly treated with chemotherapy. Clinical benefits of targeted therapies depend on mutational states and tumor location. Many tumors carry mutations in KRAS proto-oncogene, GTPase (KRAS) or B-Raf proto-oncogene, serine/threonine kinase (BRAF), rendering them more resistant to therapies. We performed whole-exome sequencing and RNA-Sequencing of 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized CRC patients based on their microsatellite instability (MSI) status, single-nucleotide variations (SNVs)/copy number alterations (CNAs), and pathway/transcription factor activities at the individual patient level. Variants were classified using a computational score for integrative cancer variant annotation and prioritization. Complementing this with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be more strongly activated in MSS patients, whereas Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) molecular cascades were activated specifically in MSI tumors. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified Runt-related transcription factors (RUNX transcription factors) as putative biomarkers in CRC, given their role in the regulation of pathways involved in tumor progression and immune evasion. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impact that KRAS mutations have on immunogenicity, particularly in the MSS patient subgroup, with implications for diagnosis and treatment.

Patients affected by metastatic carcinoma of the colon/rectum (mCRC) harboring mutations in the BRAF gene (MBRAF) respond poorly to conventional therapy and have a prognosis worse than that of patients without mutations. Despite the promising outcomes of targeted therapy utilizing multi-targeted inhibition of the mitogen-activated protein kinase (MAPK) signaling system, the therapeutic efficacy, especially for the microsatellite stable/DNA proficient mismatch repair (MSS/PMMR) subtype, remains inadequate. Patients with MBRAF/mCRC and high microsatellite instability or DNA deficient mismatch repair (MSI-H/DMMR) exhibit a substantial tumor mutation burden, suggesting a high probability of response to immunotherapy. It is widely acknowledged that MSS/pMMR/mCRC is an immunologically "cold" malignancy that exhibits resistance to immunotherapy. The integration of targeted therapy and immunotherapy may enhance clinical outcomes in patients with MBRAF/mCRC. Efforts to enhance outcomes are exclusively focused on MSS/DMMR-BRAF mutant cancers, which constitute the largest proportion. This review evaluates the clinical efficacy and advancement of novel immune checkpoint blockade therapies for MSI-H/DMMR and MSS/PMMR BRAF mutant mCRC. We examine potential indicators in the tumor immune milieu for forecasting immunotherapeutic response in BRAF mutant mCRC.

Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.

IntroductionCopy number variation is a significant characteristic of colorectal cancer progression. RBFOX1 (A2BP1) is the gene with the highest frequency of copy number loss in colorectal cancer, but current research related to it and colorectal cancer is relatively scarce.MethodsData from TCGA and other sources were used to analyze the copy number variation and mRNA expression levels of RBFOX1, as well as their correlation with clinical pathological data. Immunohistochemistry and immunofluorescence experiments were used to analyze the expression of RBFOX1 protein in colorectal cancer cells and tissues.ResultsRBFOX1 has a high frequency (22.4%) of copy number loss and diverse copy number variations in colorectal cancer tissues. High-level RBFOX1 deletion is prone to occur in the right-sided colon and tissues with high microsatellite instability. The copy number variation of RBFOX1 and mRNA expression are not correlated. In tumor tissues, RBFOX1 mRNA shows a characteristic of reduced expression, which is significantly related to BRAF mutation (P = 4.7e-05, P = 0.03). Low expression of RBFOX1 is prone to occur in the right-sided colon and tissues with high microsatellite instability. The protein encoded by RBFOX1 is expressed in normal intestinal tissues, but shows a characteristic of absence in some colorectal cancer tissues.ConclusionIn the right-sided colon and tissues with high microsatellite instability, RBFOX1 shows copy number loss and low mRNA expression. This characteristic is closely related to BRAF gene mutation, and the protein of RBFOX1 is absent in some colorectal cancer tissues.

Cellular differentiation is controlled by intricate layers of gene regulation, involving the modulation of gene expression by various transcriptional regulators. Due to the complexity of gene regulation, identifying master regulators across the differentiation trajectory has been a longstanding challenge. To tackle this problem, a computational framework, single-cell Boolean network inference and control (BENEIN), is presented. Applying BENEIN to human large intestinal single-cell transcriptome data, MYB, HDAC2, and FOXA2 are identified as the master regulators whose inhibition induces enterocyte differentiation. It is found that simultaneous knockdown of these master regulators can revert colorectal cancer cells into normal-like enterocytes by synergistically inducing differentiation and suppressing malignancy, which is validated by in vitro and in vivo experiments.

The conventional one-drug-one-disease theory has lost its sheen in multigenic diseases such as Alzheimer's disease (AD). Propolis, a honeybee-derived product has ethnopharmacological evidence of antioxidant, anti-inflammatory, antimicrobial and neuroprotective properties. However, the chemical composition is complex and highly variable geographically. So, to leverage the potential of propolis as an effective treatment modality, it is essential to understand the role of each phytochemical in the AD pathophysiology. Therefore, the present study was aimed at investigating the anti-Alzheimer effect of bioactive in Indian propolis (IP) by combining LC-MS/MS fingerprinting, with network-based analysis and experimental validation. First, phytoconstituents in IP extract were identified using an in-house LC-MS/MS method. The drug likeness and toxicity were assessed, followed by identification of AD targets. The constituent-target-gene network was then constructed along with protein-protein interactions, gene pathway, ontology, and enrichment analysis. LC-MS/MS analysis identified 16 known metabolites with druggable properties except for luteolin-5-methyl ether. The network pharmacology-based analysis revealed that the hit propolis constituents were majorly flavonoids, whereas the main AD-associated targets were MAOB, ESR1, BACE1, AChE, CDK5, GSK3β, and PTGS2. A total of 18 gene pathways were identified to be associated, with the pathways related to AD among the topmost enriched. Molecular docking analysis against top AD targets resulted in suitable binding interactions at the active site of target proteins. Further, the protective role of IP in AD was confirmed with cell-line studies on PC-12, in situ AChE inhibition, and antioxidant assays.

Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.

Metastatic colorectal cancer is a leading cause of cancer-related death across the world. The treatment paradigm has shifted away from systemic chemotherapy alone to include targeted therapy and immunotherapy. The past two decades have been characterized by increased investigation into molecular profiling of colorectal cancer. These molecular profiles help physicians to better understand colorectal cancer biology among patients with metastatic disease. Additionally, improved data on genetic pathways allow for specific therapies to be targeted at the underlying molecular profile. Investigation of the EGFR, VEGF, HER2, and other pathways, as well as deficient mismatch repair, has led to the development of multiple targeted therapies that are now utilized in the National Comprehensive Cancer Network guidelines for colon and rectal cancer. While these new therapies have contributed to improved survival for metastatic colorectal cancer, long-term survival remains poor. Additional investigation to understand resistance to targeted therapy and development of new targeted therapy is necessary. New therapies are under development and are being tested in the preclinical and clinical settings. The aim of this review is to provide a comprehensive evaluation of molecular profiling, currently available therapies, and ongoing obstacles in the field of colorectal cancer.

PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.

Somatic tumors have a high-dimensional, sparse, and small sample size nature, making cancer subtype stratification based on somatic genomic data a challenge. Current methods for improving cancer clustering performance focus on dimension reduction, integrating multi-omics data, or generating realistic samples, yet ignore the associations between mutated genes within the patient-gene matrix. We refer to these associations as gene mutation structural information, which implicitly includes cancer subtype information and can enhance subtype clustering. We introduce a novel method for cancer subtype clustering called SIG(Structural Information within Graph). As cancer is driven by a combination of genes, we establish associations between mutated genes within the same patient sample, pair by pair, and use a graph to represent them. An association between two mutated genes corresponds to an edge in the graph. We then merge these associations among all mutated genes to obtain a structural information graph, which enriches the gene network and improves its relevance to cancer clustering. We integrate the somatic tumor genome with the enriched gene network and propagate it to cluster patients with mutations in similar network regions. Our method achieves superior clustering performance compared to SOTA methods, as demonstrated by clustering experiments on ovarian and LUAD datasets.

Precision oncology tailors treatment strategies to a patient's molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling analysis of complex tumor ecosystems; thereby it has the potential to advance our understanding of cancer biology and supports drug development, biomarker discovery, and patient stratification. We describe available highly multiplexed imaging modalities, discuss their advantages and disadvantages for clinical use, and potential paths to implement these into clinical practice. Significance: This review provides guidance on how high-resolution, multiplexed tissue imaging of patient samples can be integrated into clinical workflows. It systematically compares existing and emerging technologies and outlines potential applications in the field of precision oncology, thereby bridging the ever-evolving landscape of cancer research with practical implementation possibilities of highly multiplexed tissue imaging into routine clinical practice.

Colorectal cancer (CRC) represents the second leading cause of cancer-related mortality worldwide, with a significant portion of patients presenting with metastatic disease at diagnosis. Resistance to initial anti-EGFR therapy, a key treatment for RAS wild-type metastatic CRC, remains a major challenge. This study aimed to assess the efficacy and safety of rechallenge with anti-EGFR therapy in patients with metastatic CRC who have progressed after prior treatments.

A systematic search was conducted across PubMed, Web of Science, Cochrane, and Scopus. Studies were included if they were randomized controlled trials (RCTs) or observational studies involving patients with EGFR-mutated metastatic CRC who received anti-EGFR therapy as a rechallenge. Endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events. Statistical analyses were performed using the DerSimonian/Laird random effect model, with heterogeneity assessed via I2 statistics. R, version 4.2.3, was used for statistical analyses.

Fourteen studies were included with 520 patients; 50.3% were male, and the median age was 63 years old. The median progression-free survival (mPFS) ranged between 2.4 and 4.9 months, while the median overall survival (mOS) ranged from 5 to 17.8 months. Our pooled analysis demonstrated an objective response rate (ORR) of 17.70% (95% CI, 8.58-26.82%) and a disease control rate (DCR) of 61.72% (95% CI, 53.32-70.11%), both with significant heterogeneity (I2, 84% and 80%, respectively; p < 0.01). In the subgroup analysis, cetuximab showed an ORR of 18.31% (95% CI, 4.67-31.94%), and panitumumab an ORR of 10.9% (95% CI, 0.00-26.82%), while the combination of both resulted in an ORR of 29.24% (95% CI, 0.00-65.84%). For DCR, cetuximab resulted in 62.1% (95% CI, 49.32-74.87%), panitumumab in 63.05% (95% CI, 52.13-73.97%), and the combination in 60.34% (95% CI, 31.92-88.77%), all with significant heterogeneity. Adverse events included anemia (15.39%), diarrhea (4.20%), hypomagnesemia (6.40%), neutropenia (22.57%), and skin rash (13.22%).

Rechallenge with anti-EGFR therapy in metastatic CRC patients shows moderate efficacy with manageable safety profiles. These findings highlight the need for careful patient selection and monitoring to optimize outcomes. Further studies are warranted to refine strategies for maximizing the therapeutic benefits of anti-EGFR rechallenge.

The emergence of 16S rRNA and metagenomic sequencing has gradually revealed the close relationship between dysbiosis and colorectal cancer (CRC). Recent studies have confirmed that intestinal dysbiosis plays various roles in the occurrence, development, and therapeutic response of CRC. Perturbation of host immunity is one of the key mechanisms involved. The intestinal microbiota, or specific bacteria and their metabolites, can modulate the progression of CRC through pathogen recognition receptor signaling or via the recruitment, polarization, and activation of both innate and adaptive immune cells to reshape the protumor/antitumor microenvironment. Therefore, the administration of gut bacteria to enhance immune homeostasis represents a new strategy for the treatment of CRC. In this review, we cover recent studies that illuminate the role of gut bacteria in the progression and treatment of CRC through orchestrating the immune response, which potentially offers insights for subsequent transformative research.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

Patient-derived organoids (PDOs) established from tissues from various tumor types gave the foundation of ex vivo models to screen and/or validate the activity of many cancer drug candidates. Due to their phenotypic and genotypic similarity to the tumor of which they were derived, PDOs offer results that effectively complement those obtained from more complex models. Yet, their potential for predicting sensitivity to combination therapy remains underexplored. In this review, we discuss the use of PDOs in both validation and optimization of multi-drug combinations for personalized treatment strategies in CRC. Moreover, we present recent advancements in enriching PDOs with diverse cell types, enhancing their ability to mimic the complexity of in vivo environments. Finally, we debate how such sophisticated models are narrowing the gap in personalized medicine, particularly through immunotherapy strategies and discuss the challenges and future direction in this promising field.