Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging).

This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs.

Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended.

Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.

Raman spectroscopy is a promising non-invasive technique not only for the rapid and accurate detection of colorectal cancer (CRC) but also for the identification of positive surgical margins. In this study, micro-Raman spectroscopy was used to explore biochemical differences in surgically resected intestinal segments, with a focus on boundary tumor zone. Spectral and statistical analyses, including Partial least squares discriminant analysis (PLS-DA), were performed to identify significant molecular signatures and distinguish different tissue types. Our findings suggest that boundary tumor zone contain a mix of cancerous and normal cells, complicating the discrimination of these regions. Despite this challenge, we achieved a classification accuracy of 82 % for tumor margin differentiation from normal tissue along with identifying several biochemically significant spectroscopic differences. Rapid Raman measurements using a portable system, taken from resected tissues immediately after surgery, further demonstrated the technique's ability to differentiate cancerous from healthy tissues with 97 % accuracy, 98 % sensitivity, and 96 % specificity, underscoring the potential of Raman spectroscopy for real-time clinical applications in CRC surgery.

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.

Fibronectin extra domain B (FN‑EDB) is a unique domain of FN), whose expression is significantly upregulated in the tumor microenvironment (TME). FN‑EDB plays a key role in tumor cell adhesion, angiogenesis and invasion, and is closely related to tumor malignancy and poor prognosis. Moreover, the high expression of FN‑EDB in multiple cancer types makes it a potential therapeutic target. However, comprehensive studies of the mechanism of FN‑EDB in different cancer types and its potential as therapeutic targets are lacking. The present study aimed to explore the general role of FN‑EDB in multiple types of cancer and to integrate the knowledge of cell biology, molecular biology and immunology, so as to give a comprehensive understanding of the role of FN‑EDB in TME. Furthermore, by focusing on the use of FN‑EDB in clinical diagnosis and treatment, the potential of targeting FN‑EDB as a diagnostic and therapeutic target was evaluated and the progress in clinical trials of these drugs was discussed. By searching web sites such as PubMed and web of science, various high‑quality studies including RNA sequencing, drug experiments, cell experiments, animal models, clinical randomized controlled experiments and large‑scale cohort studies were collected, with sufficient evidence to support a comprehensive evaluation of the function and potential application of FN‑EDB. The present study revealed the general role of FN‑EDB in multiple types of cancer and evaluated its potential as a diagnostic and therapeutic target. It also provided a basis for future development of more effective and precise cancer therapies.

The lung tumour microenvironment (TME) or stroma is a dynamic space of numerous cells and their released molecules. This complicated web regulates tumour progression and resistance to different modalities. Lung cancer cells in conjunction with their stroma liberate a wide range of factors that dampen antitumor attacks by innate immunity cells like natural killer (NK) cells and also adaptive responses by effector T cells. These factors include numerous growth factors, exosomes and epigenetic regulators, and also anti-inflammatory cytokines. Understanding the intricate interactions between tumour cells and various elements within the lung TME, such as immune and stromal cells can help provide novel strategies for better management and treatment of lung malignancies. The current article discusses the complex network of cells and signalling molecules, which mediate communications in lung TME. By elucidating these multifaceted interactions, we aim to provide insights into potential therapeutic targets and strategies for lung cancer treatment.

Identifying genetic mutations contributing to solid tumors by altering the biological pathways related to tumor formation and development is essential for the development of targeted therapies. This study aimed to identify commonly mutated genes and altered pathways in canine solid tumors. Four dogs with different types of naturally occurring neoplasias (urothelial carcinoma, adenocarcinoma, rhabdomyosarcoma, and chondrosarcoma) were randomly selected and classified into carcinoma and sarcoma groups based on histopathological findings. Tumor tissues were analyzed using whole-genome sequencing, and significant variants shared within each tumor group were identified. Gene set enrichment analyses were conducted to compare the biological and functional pathways altered by the mutations in each carcinoma and sarcoma group. Forty-three and fifty-eight genes were identified in the carcinoma and sarcoma groups, respectively. Distinctions between the two tumor groups were noted for mutations related to tumor metastatic function. Mutations were identified in genes encoding cell adhesion molecules in the carcinoma group, whereas significant variations in extracellular matrix-related molecules were evident in the sarcoma group. This study revealed mutations and modified pathways associated with immune and tumor metastatic functions in canine carcinoma and sarcoma, indicating their significant relevance to the development and progression of each tumor group. Additionally, the distinctions indicated that different therapeutic approaches were required for each tumor group.

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

The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.

The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin β1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.

Chemotherapy, which aims to eradicate tumor cells and enhance patient survival, is a prevalent approach for tumor treatment. Nevertheless, recurrence and drug resistance resulting from consecutive chemotherapy regimens have emerged as significant factors contributing to the high fatality rates among cancer patients. Numerous studies have revealed that chemicals discharged by injured and deceased cells can trigger the host repair program mediated by toll-like receptor-4 (TLR-4), enhancing tumor resistance. TLR-4 is not only expressed in immune cells but also in various malignant tumor cells, especially inflammation-associated tumor cells, and plays a crucial role in tumor formation, development, and chemoresistance. Endogenous ligands are released upon the killing of tumor cells by chemotherapy drugs, binding to and activating TLR-4, subsequently activating downstream NF-κB and other essential molecules, leading to the release of multiple factors associated with tumor proliferation and invasion, creating a microenvironment conducive to local recurrence and metastasis, and promoting tumor progression and drug resistance. This review assessed studies on the resistance of several tumor cells to commonly utilized anticancer treatments induced by TLR-4 to better comprehend the phenomena and mechanism of TLR-4-dependent resistance, as well as to put forward suggestions and insights for overcoming tumor resistance.

As one of the most prevalent primary brain tumors, glioblastoma (GBM) is characterized by its severe malignancy and extremely poor prognosis. Recent studies have demonstrated that targeting anoikis and malignancy showed impressed efficiency for treatment in a wide range of solid tumors, however, relevant research on GBM still remains unclarified.

In this study, genes related with malignancy and anoikis of GBM were identified by utilizing the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and the Molecular Signatures Database (MSigDB). Subsequently, the role of the key gene was validated via proliferation, invasion and migration experiments both in conditions with and without attachment. Moreover, RNA sequencing analysis was employed to reveal further mechanisms.

Here, Type V collagen alpha 1 (COL5A1) was identified as a critical gene associated with anoikis and poor outcomes. Additionally, COL5A1 knockdown induced significant reduction in malignancy of GBM both in vitro and in vivo. Moreover, cell anoikis was remarkable enhanced by reduced expression of COL5A1 after low-attachment cell culture. Mechanically, RNA sequencing analysis revealed that the activity of the Wnt/β-catenin signaling pathway was diminished following COL5A1 knockdown, which indicated that COL5A1 reduced anoikis via regulating Wnt/β-catenin signaling pathway thus promoted malignancies of GBM cells.

These findings demonstrated the novel evidence that COL5A1 serves as an essential regulatory factor influencing both anoikis and malignancy of GBM cells by regulating Wnt/β-catenin signaling pathway, indicating that COL5A1 could be a novel prognosis-related biomarker and potential therapeutic target for GBM.

Clinically effective treatments for peritoneal metastases (PM) remain a significant unmet need. To expedite drug development in PM, hyaluronan (HA) hydrogel-supported PM patient-derived tumor explants (PDTE) that better preserve histological features, composition, and biological pathways of the original tumor, as compared to conventional PDTE culture methods are developed. Hydrogel modulation shows that stiffness, degradation, three-dimensional embedding, and HA itself are key parameters that enhance PDTE maintenance ex vivo. Further, HA hydrogels effectively preserve PDTE viability by disrupting myosin II-mediated tissue contraction, a phenomenon that occurs in the absence of hydrogel embedding. Lastly, the addition of ascites into PM PDTE not only recapitulates changes to the tumor microenvironment as observed in patients but also ascites-dependent drug efficacy, highlighting the importance of incorporating ascites into ex vivo PM models for accurate therapeutic evaluation. The bioengineered PM PDTE models in this study serve as a valuable platform for drug development and treatment personalization.

Matrix metalloproteinase 1 plays a pivotal role in tumor biology and immune modulation through its enzymatic remodeling of the extracellular matrix, facilitating tumor progression. In this study, we utilized large-scale single-cell RNA sequencing and spatial transcriptomics to investigate MMP1 expression, its cellular localization, and its impact on tumor progression and immune modulation. Our findings reveal that MMP1 expression is elevated in various tumor types and is strongly correlated with metastatic potential. High MMP1 expression was associated with increased activity in epithelial-mesenchymal transition signaling and TNFα/NF-κB pathways, which are known to promote tumor progression. Furthermore, MMP1+ malignant cells exhibited significant interactions with immune cells, particularly macrophages and CD8+ T cells. MMP1 expression correlated with enhanced macrophage infiltration and impaired CD8+ T-cell function, contributing to an immunosuppressive tumor microenvironment. Notably, the CXCL16-CXCR6 and ANXA1-FPR3 signaling axes were identified as key mediators of these interactions. Inhibition of MMP1 in vitro demonstrated reduced cell invasion, stemness, and proliferation, while increasing reactive oxygen species levels and promoting apoptosis. Our findings position MMP1 as a key player in the "tumor-immune" vicious cycle and a promising therapeutic target to enhance anti-tumor responses and improve patient outcomes.

One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.

The family with the sequence similarity 198 member B (FAM198B) has been found to contribute to the progression of gastric cancer (GC). However, the role and molecular mechanism of FAM198B in GC remains poorly understood. This work found a link between FAM198B and quercetin, and the regulatory effect of FAM198B on the MAPK pathway of GC.

FAM198B expression was identified through multiple public data sets and verified in clinical tissue samples. The associations between FAM198B and the prognosis of patients with GC were analyzed via the Kaplan‒Meier plotter and Cox regression analysis. Gene set enrichment analysis, coexpressed genes, and RNA sequencing were used to explore the related functions and signaling pathways of FAM198B in GC. In vitro assays assessed the effects of FAM198B knockdown on GC cells. FAM198B was found as a quercetin target by the HERB database and in vitro assays.

FAM198B was highly expressed in tissues from GC patients (p<0.001) and was positively associated with poor prognosis (p<0.001) and immune cell infiltration in GC patients. FAM198B knockdown inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of GC cells (all p<0.05). In addition, FAM198B knockdown decreased the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.01). Quercetin inhibited FAM198B expression and the phosphorylation of p-Erk1/2 and p-p38 in GC cells (all p<0.05).

Quercetin inhibits the proliferation, migration, invasion, and EMT of GC cells by inhibiting the FAM198B/MAPK signaling pathway. These discoveries lay the groundwork for developing the treatment of GC by quercetin and targeting FAM198B. In the future, more preclinical and clinical studies are needed to confirm the efficacy and safety of quercetin and target FAM198B in GC.

Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes.

Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide, characterized by heterogeneity at the molecular, cellular and anatomical levels. Most patients are diagnosed at an advanced stage, characterized by widespread peritoneal metastasis. Despite optimal cytoreductive surgery and platinum-based chemotherapy, peritoneal spread and recurrence of OC are common, resulting in poor prognoses. The overall survival of patients with OC has not substantially improved over the past few decades, highlighting the urgent necessity of new treatment options. Unlike the classical lymphatic and hematogenous metastasis observed in other malignancies, OC primarily metastasizes through widespread peritoneal seeding. Tumor cells (the "seeds") exhibit specific affinities for certain organ microenvironments (the "soil"), and metastatic foci can only form when there is compatibility between the "seeds" and "soil." Recent studies have highlighted the tumor microenvironment (TME) as a critical factor influencing the interactions between the "seeds" and "soil," with ascites and the local peritoneal microenvironment playing pivotal roles in the initiation and progression of OC. Prior to metastasis, the interplay among tumor cells, immunosuppressive cells, and stromal cells leads to the formation of an immunosuppressive pre-metastatic niche in specific sites. This includes characteristic alterations in tumor cells, recruitment and functional anomalies of immune cells, and dysregulation of stromal cell distribution and function. TME-mediated crosstalk between cancer and stromal cells drives tumor progression, therapy resistance, and metastasis. In this review, we summarize the current knowledge on the onset and metastatic progression of OC. We provide a comprehensive discussion of the characteristics and functions of TME related to OC metastasis, as well as its association with peritoneal spread. We also outline ongoing relevant clinical trials, aiming to offer new insights for identifying potential effective biomarkers and therapeutic targets in future clinical practice.

Cancer-associated fibroblasts (CAFs) are prominent components of the lung tumor stroma and are known to foster tumor growth, invasion, and metastasis through extracellular matrix (ECM) and tumor stroma remodeling. The interactions of CAFs with cancer cells and other stromal components contribute significantly to the aggressive nature of lung cancer and pose challenges to conventional treatment approaches. Simultaneously, the ECM, which contains numerous proteins and other molecules surrounding cancer cells, serves as more than just a structural scaffold. In lung cancer, alterations in ECM composition and organization not only promote tumor cell proliferation and survival but also impact drug penetration, immune cell infiltration, and therapeutic resistance. Targeting the intricate interplay between CAFs and the dynamic ECM in lung cancer represents a crucial frontier in oncology research. This review aims to delve deeply into the pivotal roles of CAFs and the ECM in the tumorigenesis and progression of lung cancer. Then, the potential of utilizing adjuvants, phytochemicals, and nanoparticles to modulate the functions of CAFs and remodel the ECM in the lung tumor will be reviewed.

The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive.

Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters.

Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy.

We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.

The process of epithelial-mesenchymal transition (EMT) is crucial in various physiological/pathological circumstances such as development, wound healing, stem cell behavior, and cancer progression. It involves the conversion of epithelial cells into a mesenchymal phenotype, which causes the cells to become highly motile. This reprogramming is initiated and controlled by various signaling pathways and governed by several key transcription factors, including Snail 1, Snail 2 (Slug), TWIST 1, TWIST2, ZEB1, ZEB2, PRRX1, GOOSECOID, E47, FOXC2, SOX4, SOX9, HAND1, and HAND2. The intracellular signaling pathways are activated/inactivated by signals received from the extracellular environment and the transcription factors are carefully regulated at the transcriptional, translational, and post-translational levels to maintain tight regulatory control of EMT. One of the most important pathways involved in this process is the transforming growth factor-β (TGFβ) family signaling pathway. This review will discuss the role of EMT in promoting epithelial cancer progression and the convergence/interplay of multiple signaling pathways and transcription factors that regulate this phenomenon.

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.

In this study, we utilized the yeast two-hybrid system to screen for proteins interacting with USP24. Out of 250 such proteins, functional enrichment analysis using MetaCore™ indicated that 33 of them were involved in lung cancer progression. We then investigated gene expression and survival rates of these 33 proteins in lung cancer patients and cell lines through TCGA databases, Kaplan-Meier Plotter databases, and RNA-seq profile from A549/A549-T24 cells. By employing the patients' survival rate and gene expression profile of these 33 USP24-interacting proteins as gene signatures, we identified 10 potential drugs for inhibiting lung cancer progression or drug resistance via drug repurposing strategy using the Connectivity Map (CMap) database. Of these 10 drugs, six showed similar indicators in Clinical Trials, while the other four candidates (15-delta prostaglandin J2, Astemizole, Trifluoperazine, and 1,4-chrysenequinone) were chosen to evaluate their effect on re-sensitizing cytotoxicity of Taxol and Gefitinib in drug-resistant cancer cells. Experiments demonstrated that treatment with USP24-i-101 and Astemizole alone significantly inhibited drug resistance and re-sensitized the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer cells. Notably, combination therapy with USP24-i-101and Astemizole re-sensitized the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer, which could benefit in inhibiting drug resistance during cancer therapy.

Non-functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, and liver metastasis is the leading cause of death in patients with GEP-NENs. Due to the difficulty in conducting large cohort studies, no reliable tool currently exists to predict the risk of liver metastasis in these patients. This study aimed to develop and validate a nomogram model based on large cohort clinical data to accurately predict the risk of liver metastasis in patients with non-functional GEP-NENs.

A retrospective cohort study was conducted, encompassing 838 patients with non-functional GEP-NENs diagnosed between 2009 and 2023. Independent risk factors for liver metastasis were identified through univariate and multivariate logistic regression analyses. A nomogram was constructed based on significant predictors, including T stage, N stage, Ki-67 index, primary tumor site, and BMI. The model's performance was evaluated using the C-index, calibration curves, and decision curve analysis (DCA) for both training and validation cohorts.

The nomogram demonstrated excellent predictive performance, with C-index values of 0.839 and 0.823 for the training and validation sets, respectively. Risk stratification using the nomogram's total score effectively differentiated high-risk from low-risk patients. Kaplan-Meier survival analysis revealed significant survival differences between these groups (P < 0.0001). Moreover, the calibration curves indicated strong agreement between predicted and observed outcomes.

The developed nomogram is a reliable tool for predicting the risk of liver metastasis in non-functional GEP-NENs. It facilitates early identification of high-risk patients, thereby enabling personalized treatment and timely intervention. Future research should focus on multicenter validation and the integration of molecular markers to enhance the robustness and clinical applicability of the model.

This work optimized proteoglycan-degrading enzymes through targeted mutagenesis to enhance their interaction with the tumor microenvironment in Renal Cell Carcinoma (RCC). A comprehensive mutagenesis approach identified 60 key mutations significantly improving enzymatic activity, stability, and structural integrity. When compared to Wild Type (WT) enzyme, a remarkable increase in specific activity by 35 % (p < 0.001) and a considerable decrease in the Km values for hyaluronidases from 2.5 mM to 1.5 mM (p < 0.05), as a result of these modifications. Computational methods are then employed to analyze the active site of the enzymes to detect potential residues that may alter. These computational techniques include molecular docking and protein structure prediction. The structural models of the enzymes are created by utilizing homology modeling and crystallography. These models demonstrate the spatial arrangement of the amino acid enzymes. It also illustrated the specific mutations to improve the potential of enzymes to relate to the Extracellular Matrix (ECM) of tumors. The computational screening methods effectively predicted how the modifications impact enzyme catalytic efficiency and stability. The modified enzymes retained 85 % of the enzyme activity, while the WT retained 60 %. Thus, the modified enzymes demonstrated better thermal stability than WT. Vitro test analyses show that the proteoglycan breakdown was significantly reduced by 70 % (p < 0.001), and for effective proteoglycan breakdown, hyaluronidase concentration is needed. This work proposed a novel therapeutic approach called proteoglycan-degrading enzymes for the treatment of RCC. These proteoglycan-degrading enzymes are more stable and effective for treating RCC, as demonstrated in the outcomes. Customized proteoglycan-degrading enzymes make the therapy more effective. The effective breakdown of the tumor's ECM in RCC models establishes this customized proteoglycan-degrading enzyme. These enzymes are effective for this customized cancer treatment as they improve stability, activity, and interaction with the TME.

Tumor metastasis represents a stepwise progression and stands as a principal determinant of unfavorable prognoses among cancer patients. Consequently, an in-depth exploration of its mechanisms holds paramount clinical significance. Cancer-associated fibroblasts (CAFs), constituting the most abundant stromal cell population within the tumor microenvironment (TME), have garnered robust evidence support for their pivotal regulatory roles in tumor metastasis.

This review systematically explores the roles of CAFs at eight critical stages of tumorigenic dissemination: 1) extracellular matrix (ECM) remodeling, 2) epithelial-mesenchymal transition (EMT), 3) angiogenesis, 4) tumor metabolism, 5) perivascular migration, 6) immune escape, 7) dormancy, and 8) premetastatic niche (PMN) formation. Additionally, we provide a compendium of extant strategies aimed at targeting CAFs in cancer therapy.

This review delineates a structured framework for the interplay between CAFs and tumor metastasis while furnishing insights for the potential therapeutic developments. It contributes to a deeper understanding of cancer metastasis within the TME, facilitating the utilization of CAF-targeting therapies in anti-metastatic approaches.

Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and gastric adenocarcinoma - in part by evading surveillance and attack by the host immune system. In this article we review the main molecular mechanisms by which EBV-encoded proteins and RNAs interact with key molecules of the host immune system to inhibit Toll-like receptor (TLR)-nuclear factor κB (NF-κB), retinoic acid-inducible gene I (RIG-I), and interferon (IFN) signaling pathways, affect antigen presentation, prevent the cytotoxic effects of CD8+ effector cells, regulate the tumor microenvironment (TME) and cell metastasis and invasion, and inhibit cell apoptosis. These interactions not only contribute to the persistence of the virus but also provide potential targets for developing new immunotherapy strategies.

The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.

WFDC1 encodes an extracellular matrix protein involved in cell proliferation, migration, and epithelial-mesenchymal transition in disease conditions. Despite this, Wfdc1-null mice display no discernible malformations while cattle bearing a WFDC1 mutation present multiple ocular defects, leaving the role of WFDC1 during embryonic development unclear. To address this, we used the chicken embryo as a model to investigate WFDC1 developmental roles in amniotes. We performed a comparative expression analysis during chicken and mouse development, which revealed expression in ectodermal and mesodermal derivatives, with both conserved and species-specific domains. Conserved expression was observed in the eye, otic vesicle, central and peripheral nervous systems, and neural crest cells. Chicken-specific expression was identified in mesodermal structures, including the notochord, limbs and heart. However, even in the conserved sites like the eyes, WFDC1 localizes to different retinal layers, indicating potential divergence roles in retinal development and function across species. In contrast, WFDC1 expression in the limb buds is specific to chicken, encompassing the distal mesenchyme, interdigital membranes, and blastemas. Functional enrichment analysis links WFDC1 to limb patterning, morphogenesis, and Wnt signaling. The species-specific differences likely stem from evolutionary changes in gene regulation, supported by differences in proximal cis-regulatory elements of the WFDC1 loci between chicken and mouse. The complexity of WFDC1 expression in the chicken embryo, along with WFDC1 regulatory conservation within birds, indicates that this gene may play specific roles in avian development, possibly contributing to features specific to this lineage. Future studies using the chicken model will be valuable in further uncovering the specific roles of WFDC1.

Bladder cancer (BLCA) is the most common type of malignancy affecting the urinary tract, characterized by high recurrence rates, propensity for progression, metastatic potential, and multidrug resistance, all of which ultimately contribute to an unfavorable prognosis. RNA-binding proteins (RBPs) play a critical role in cancer development and have been associated with the progression and prognosis of the disease. However, comprehensive investigations into the biological functions and molecular mechanisms of RBPs in BLCA remain limited. The study aims to explore the relationship between RBPs and prognosis in BLCA, and to develop and validate an RBPs-based prognostic signature, providing new insights for the diagnosis and treatment of BLCA.

Clinical data and RBPs expression profiles of BLCA patients were sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A systematic bioinformatics analysis was conducted to identify differentially expressed RBPs and assess their prognostic significance. The optimal predictive model was selected by integrating multiple machine learning algorithms, enabling the identification of hub genes associated with BLCA prognosis and developing an RBP-related gene signature. To evaluate the prognostic signature's efficacy, survival curves and receiver operating characteristic (ROC) curves were generated. A nomogram was constructed and validated to predict the survival of BLCA patients at 1, 3, and 5 years. Furthermore, analyses of immune infiltration and gene set enrichment analysis (GSEA) were conducted to explore the roles of RBPs in immune cell interactions and elucidate underlying biological pathways.

A prognostic signature was effectively developed using nine RBPs (OAS1, MTG1, DUS4L, IGF2BP3, NOL12, PABPC1L, ZC3HAV1L, TRMT2A and TRMU), represented as risk score, through the integration of 13 combinatorial machine learning algorithms. Kaplan-Meier analysis revealed that the high-risk group exhibited a significantly poorer overall survival (OS) probability compared to the low-risk group. The areas under the ROC curves for the risk score model at 1, 3, and 5 years were 0.661, 0.655, and 0.676, respectively. The nomogram, which integrated clinical characteristics and risk scores, demonstrated robust prognostic accuracy. Furthermore, single-sample gene set enrichment analysis (ssGSEA) demonstrated significant correlations between both the risk score model and hub RBPs with the immune status of BLCA patients. GSEA indicated that major signaling pathways enriched in the high-risk group included extracellular matrix (ECM) components and interaction, as well as cytokine and receptor interaction.

This study successfully identified and developed a prognostic signature based on nine RBPs, accompanied by a nomogram for predicting survival probability in BLCA patients. Our findings demonstrate that these nine RBPs function as significant biomarkers for forecasting the prognosis and immune status in BLCA, suggesting their potential as therapeutic targets for BLCA.

Non-small cell lung cancer (NSCLC) represents the vast majority of lung cancer cases, comprising 80-85% of all diagnoses, and continues to be a primary contributor to cancer-related deaths. Early detection is essential for improving patient outcomes, yet current diagnostic markers lack both sensitivity and specificity. This study aims to identify novel biomarkers that could enhance early diagnosis.

We conducted a comprehensive gene expression analysis of three NSCLC datasets (GSE33479, GSE18842, and GSE32863) and identified seven genes with relevance to the extracellular region and space: MMP11, SPP1, ERO1L, CTHRC1, SPINK1, LAD1, and SFN. We further assessed these markers through serum protein analysis involving 200 NSCLC patients and 200 healthy controls, employing receiver operating characteristic (ROC) curve analysis to evaluate their diagnostic efficacy.

Among the identified genes, MMP11 and SPP1 exhibited significant upregulation and strong discriminatory power in NSCLC tissues, achieving area under the curve (AUC) values exceeding 0.9. Serum protein levels of MMP11 and SPP1 were significantly higher in NSCLC patients compared to healthy controls. ROC curve analysis confirmed the diagnostic potential of MMP11 (AUC: 0.9896) and SPP1 (AUC: 0.9053), both outperforming the existing marker carcinoembryonic antigen (CEA) (AUC: 0.7109). MMP11 demonstrated sensitivity of 94.53% and specificity of 94.97%, while SPP1 showed sensitivity of 83.17% and specificity of 83.84%. In contrast, CEA exhibited a sensitivity of 66.83% and specificity of 67.69%.

The results indicate that MMP11 and SPP1, detectable in serum, may serve as valuable non-invasive biomarkers for the early diagnosis of NSCLC, particularly within health screening contexts. However, further research within larger and more diverse cohorts is imperative to validate these biomarkers and investigate the mechanisms underlying MMP11 and SPP1 expression in NSCLC. This study highlights the potential of these biomarkers to enhance diagnostic accuracy and improve patient outcomes in NSCLC.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

Each stage of tumor development is intrinsically linked to the tumor microenvironment (TME), wherein the extracellular matrix (ECM) serves as a vital and abundant component in tumor tissues. The ECM is a non-cellular, three-dimensional macromolecular network scaffold that provides structural support to cells, stores bioactive molecules, and mediates signaling pathways through specific binding to cell surface receptors. Moreover, the ECM in tumor tissues plays a crucial role in impeding drug diffusion and resisting apoptosis induced by conventional anti-cancer therapies that primarily target cancer cells. Therefore, directing attentions towards the tumor ECM can facilitate the identification of novel targets and the development of new therapies. This review aims to summarize the composition, structure, remodeling, and function of tumor ECM, its association with drug resistance, and current targeting strategies, with a specific emphasis on nanoparticles (NPs).

Stomach adenocarcinoma (STAD) represents the predominant subtype of gastric cancer, known for its drug resistance, unfavorable prognosis, and low cure rates. IFN-γ serves as a cytokine generated by immune cells, instrumental in tumor immune clearance and essential to the tumor microenvironment. The aging-associated secretory phenotype (SASP) can modify the local tissue environment, facilitating gastric cancer progression and chemotherapy resistance.

This study intends to identify STAD subtypes based on IFN-γ and SASP-related genes and to develop a risk prognostic model for predicting patient survival, tumor immune microenvironment, and responses to drug treatment.

The genomic and clinical datasets originate from the Cancer Genome Atlas (TCGA) database, while the genes associated with IFN-γ and SASP come from pertinent scholarly articles. We discovered the prognostic genes linked to IFN-γ and SASP in STAD using Cox regression analysis. Next, we applied non-negative matrix factorization (NMF) to categorize LIHC into distinct molecular subtypes, identifying differentially expressed genes across these subtypes. Following this, we developed a predictive model using Cox and LASSO regression analyses to stratify patients into specific risk categories, validating the model to assess the prognostic significance of the identified signatures. Lastly, we integrated single-cell data to elucidate the immune landscape of STAD and identified potential drugs along with their sensitivity profiles.

We identified 17 prognostic genes related to IFN-γ and SASP, successfully classifying patients into two distinct molecular subtypes. These subtypes exhibited notable differences in immune profiles and prognostic outcomes. We pinpointed three differentially expressed genes to establish risk characteristics and created a prognostic model capable of accurately predicting patient outcomes. Our findings revealed a strong association between STAD and the extracellular matrix, low-risk group exhibited favorable prognosis, and may derive greater benefits from immunotherapy.

We developed a risk model using IFN-γ and SASP-associated genes to predict the prognosis of STAD patients more accurately. Additionally, we assessed the immune landscape of STAD by integrating bulk RNA and single-cell sequencing analyses. This approach may yield valuable insights for clinical decision-making and immunotherapy strategies in STAD.

Triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases with poorer prognosis and clinical outcomes compared to other BC subtypes due to greater tumor heterogeneity and few therapeutically targetable oncogenic drivers. To reveal actionable pathways for anti-cancer treatment, we use a proteomic approach to quantitatively compare the abundances of 6306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances. Analyses of clinicopathological characteristics revealed associations between the proteomic profiles and clinical phenotypes exhibited by each subtype. We validate the findings by inferring immune and stromal cell type composition from genome-wide DNA methylation profiles. Finally, quantitative proteomics on TNBC cell lines was conducted to identify in vitro models for each subtype. Collectively, our data provide subtype-specific insights into molecular drivers, clinicopathological phenotypes, tumor microenvironment (TME) compositions, and potential pharmacologic vulnerabilities for further investigations.

The pre-diagnosis plasma proteomic contexture of colon cancer patients may reflect host immune and biological conditions and potentially associate with survival outcomes. We aimed to characterize pre-diagnosis proteomic contextures in colon cancer patients and determine potential association with overall survival of the patients.

Baseline plasma samples collected at an average of 7.90 years before diagnosis from colon cancer patients in the UK Biobank cohort were analyzed using Olink proteomics technology. Cox-regression analysis was applied to identify distinct pre-diagnosis proteomic contextures and determine their association with survival outcomes.

In early-stage colon cancer, a 10-protein pre-diagnosis profile was identified, involving biological processes of extracellular matrix remodeling and immune evasion through deregulation of innate immune activation. Increased activity in these pathways before diagnosis was associated with poor survival outcomes. In late-stage cases, an 8-protein pre-diagnosis profile was linked to pathways involving in cell adhesion, angiogenesis, and pro-inflammatory response. Similarly, heightened activity in these pathways prior to diagnosis correlated with worse survival. When combined with two demographic factors age and sex, these proteomic profiles demonstrated strong predictive associations with survival outcomes at multiple time points post-diagnosis. The area under the receiver operating characteristic curve values were 0.85, 0.82, and 0.89 for early-stage cancer at 1, 5, and 10 years, respectively, and 0.71, 0.72, and 0.79 for late-stage cancer over the same periods.

Biological processes like extracellular matrix remodeling and pro-inflammatory response are active well before diagnosis and may play a critical role in shaping colon cancer progression.

Gastric cancer (GC), a prevalent aggressive form of tumor, imposes a significant burden in terms of morbidity and mortality. Prolyl 4-hydroxylase, alpha polypeptide I (P4HA1), a key enzyme in collagen synthesis, comprises two identical alpha subunits and two beta subunits. Studies on the expression and impact of P4HA1 in GC cells are limited.

The expression and prognosis of P4HA1 in GC were analyzed using bioinformatics. To confirm the P4HA1 level in GC tissues and cells, Western blot (WB) and RT-qPCR experiments were conducted. The signaling pathways related to P4HA1 in GC were examined using the DAVID database. Moreover, the expression of P4HA1 was downregulated by transfecting GC cell lines (HGC-27 and SGC-7901) with siRNA technology. Furthermore, GC proliferation, migration, and invasion were detected via plate cloning, CCK-8, and Transwell assays. The epithelial-mesenchymal transition (EMT) genes (E-cadherin, N-cadherin, Vimentin) and the stemness marker CD44 protein expression in GC cells were detected using WB. The sphere-forming ability of GC cells was analyzed using a sphere-forming assay to determine the effect of P4HA1.

Bioinformatics and experimental analyses demonstrated that P4HA1 expression was extensively detected in GC tissues and cells, and strongly related to a poor prognosis for GC. In vitro studies demonstrated that P4HA1 suppression hindered the proliferation, migration, and invasion of GC cells and suppressed EMT characteristics. Both sphere-forming and WB assays revealed that the sphere-forming potential of GC cells and the level of CD44 protein decreased after knocking down the expression of P4HA1, indicating that suppression of P4HA1 could inhibit the stemness of GC cells.

The study concluded that P4HA1 has the potential to be expressed substantially in GC tissues and cells and is capable of enhancing the proliferation, metastasis, and stemness of GC.

Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteolytic enzymes that are crucial for the remodeling of the extracellular matrix, a process that is often co-opted by cancers, including brain tumors, to facilitate growth, invasion, and metastasis. In gliomas, MMPs contribute to a complex interplay involving tumor proliferation, angiogenesis, and immune modulation, thereby influencing tumor progression and patient prognosis. This review provides a comprehensive analysis of the roles of various MMPs in different types of gliomas, from highly malignant gliomas to metastatic lesions. Emphasis is placed on how the dysregulation of MMPs impacts tumor behavior, the association between specific MMPs and the tumor grade, and their potential as biomarkers for diagnosis and prognosis. Additionally, the current therapeutic approaches targeting MMP activity are discussed, exploring both their challenges and future potential. By synthesizing recent findings, this paper aims to clarify the broad significance of MMPs in gliomas and propose avenues for translational research that could enhance treatment strategies and clinical outcomes.

This study employed a multi-omics integration approach to identify circulating biomarkers for gastric cancer (GC). We analyzed plasma and tumor tissue single-cell RNA sequencing data, along with gene and protein quantitative trait loci analyses. Leveraging data from UK Biobank and FinnGen, we investigated genetic associations with GC. Through colocalization, Mendelian Randomization, and various filtering analyses, we identified four genes (IQGAP1, KRTCAP2, PARP1, MLF2) and four proteins (EGFL9 [DLK2], ECM1, PDIA5, TIMP4) as potential GC biomarkers. These were selected based on significant genetic colocation probabilities and significant associations with GC. Seven of these biomarkers demonstrated predictive capability for GC occurrence, with AUC ranging from 0.61 to 0.99. Drug prediction analysis identified seven protein biomarkers as potential targets for immunotherapy, targeted therapies, and tumor chemotherapy. Further scRNA-seq analysis revealed significant expression differences between gastric tumor and normal tissues, particularly the upregulation of IQGAP1, which highlights its role in tumor growth.

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.