Extracellular vesicles are nanoscale vesicles released by a diversity of cells that mediate intercellular communication by transporting an array of biomolecules. They are gaining increasing attention in cancer research due to their ability to carry specific biomarkers. This characteristic makes them potentially useful for highly sensitive, noninvasive diagnostic procedures and more precise prognostic assessments. Consequently, EVs are emerging as a transformative tool in cancer treatment, facilitating early detection and personalized medicine. Despite significant progress, clinical implementation is hindered by challenges in EV isolation, purification, and characterization. However, developing advanced biosensor technologies offers promising solutions to these obstacles. This review highlights recent progress in biosensors for EV detection and analysis, focusing on various sensing modalities including optical, electrochemical, microfluidic, nanomechanical, and biological sensors. We also explore techniques for EV isolation, characterization, and analysis, such as electron microscopy, atomic force microscopy, nanoparticle tracking analysis, and single-particle analysis. Furthermore, the review critically assesses the challenges associated with EV detection and put forward future directions, aiming to usher in a cutting-edge era of precision medicine through advanced, sensor-based, noninvasive early cancer diagnosis by detecting EV-carried biomarkers.

The role of mitochondria in tumorigenesis and progression is has been increasingly demonstrated by numerous studies, but its prognostic value in colorectal cancer (CRC) remains unclear. To address this, we developed a mitochondrial-related gene prognostic model using 101 combinations of 10 machine learning algorithms. Patients in the high-risk group exhibited significantly shorter overall survival time. The high-risk group exhibited elevated tumor immune dysfunction and exclusion score, indicating diminished immunotherapy efficacy. To address the suboptimal treatment outcomes in these patients, we identified PYR-41 and pentostatin as potential therapeutic agents, which are anticipated to enhance therapeutic efficacy in the high-risk group. Additionally, four biomarkers (HSPA1A, CHDH, TRAP1, CDC25C) were validated by quantitative real-time PCR, with significant expression differences between normal intestinal epithelial cells and colon cancer cells. Our prognostic model provides accurate CRC outcome prediction and guides personalized therapeutic strategies.

The interplay between cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mediates progress, metastasis, and therapy resistance. However, strategy of targeting ECM remodeling to enhance chemosensitivity in ovarian cancer remains elusive. Here, a 22-gene matrisome signature predicts chemotherapy response and survival in ovarian cancer. The dense, collagen-rich ECM secreted by CAFs harbors more M2 tumor-associated macrophages (TAMs) than the looser ECM based on single cell RNA-seq (scRNA-seq) of ovarian cancer, suggesting the promising approach of targeting collagen to remodel ECM. An integrated analysis identifies collagen type I alpha 1 chain (COL1A1) as a major component of the ECM that contributes to chemoresistance and poor prognosis, highlighting its potential as a therapeutic target. Halofuginone (HF), a clinically active derivative of febrifugine, is identified as a COL1A1-targeting natural compound by screening the Encyclopedia of Traditional Chinese Medicine (ETCM). Mechanistically, HF inhibits COL1A1 production via the mTOR-eIF2α-ATF4 axis in CAFs. Notably, HF disrupts collagen deposition and promotes CD8+ T cell infiltration, partially via M2-M1 macrophage polarization to enhance chemosensitivity. Overall, the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.

Peritoneal metastasis (PM) is a terminal stage of gastrointestinal cancers, often resulting in poor survival outcomes. Traditional treatments like cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown some effectiveness but are associated with significant risks. This study presents a novel nanomotor-based drug delivery system (M@MnO2-Au-mSiO2@CDDP) designed to enhance the efficacy of PM treatment. By utilizing an oxygen-driven heterojunction nanomotor (MnO2-Au-mSiO2), coated with membrane of M1-type macrophages, the system targets PM tumors with high precision through intraperitoneal perfusion. These biomimetic NMs promote deep tumor penetration, enhance reactive oxygen species (ROS) generation, and activate the STING pathway, a critical component in immune regulation. The catalytic properties of MnO2 within the nanomotors enhance drug permeability and retention, enabling targeted and controlled drug release. Both in vitro and in vivo experiments demonstrated the system's ability to significantly inhibit tumor growth, induce apoptosis, and activate immune responses. In addition, the synergistic effect of targeted drug delivery, catalytic therapy and immunotherapy of this system was further confirmed by constructing an in vitro gastric cancer organoid model, showing great clinical application potential. The study also confirmed excellent biocompatibility and stability, making these NMs a promising clinical tool for the treatment of PM. This research underscores the potential of nanotechnology to revolutionize cancer treatment by overcoming the limitations of traditional therapies and paving the way for future innovations in targeted cancer therapies.

This study introduces TG-ME, an innovative computational framework that integrates transformer with graph variational autoencoder (GraphVAE) models for dissection of tumoral niches using spatial transcriptomics data and morphological images. TG-ME effectively identifies and characterizes niches in bench datasets and a high resolution NSCLC dataset. The pipeline consists in different stages that include normalization, spatial information integration, morphological feature extraction, gene expression quantification, single cell expression characterization, and tumor niche characterization. For this, TG-ME leverages advanced deep learning techniques that achieve robust clustering and profiling of niches across cancer stages. TG-ME can potentially provide insights into the spatial organization of tumor microenvironments (TME), highlighting specific niche compositions and their molecular changes along cancer progression. TG-ME is a promising tool for guiding personalized treatment strategies by uncovering microenvironmental signatures associated with disease prognosis and therapeutic outcomes.

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME), playing significant roles in regulating cancer progression. However, the underlying mechanism of CAFs activation remains elusive. In this study, we aim to investigates the mechanisms by which CAFs promote the conversion of normal fibroblasts (NFs) to CAFs in lung cancer, with a focus on the role of p53 mutations and the CXCL12/STAT3 signaling axis. We found that CAFs significantly induced NFs to acquire CAFs properties (called CEFs), including upregulation of α-SMA and Vimentin, enhanced proliferation and migration, and increased ability to promote lung cancer cell migration. In vivo, CEFs accelerated A549 xenograft growth and induced spontaneous lung metastasis. CXCL12 was identified as a key factor in NFs-to-CEFs conversion, with its expression positively correlated with CAFs markers in lung cancer. Further investigation confirmed that CXCL12 is sufficient to reprogram NFs into CAFs through the STAT3 pathway. Notably, inhibiting CXCL12 signaling and the STAT3 pathway reduced the conversion of NFs to CAFs, thereby hindering lung cancer progression progression both in vitro and in vivo. Our study reveals CAFs could promote the conversion of NFs to CAFs-like cells through the CXCL12/STAT3 axis, enhancing tumor growth and metastasis in lung cancer. Therefore, inhibition of the CXCL12/STAT3 axis is a promising strategy for the treatment of lung cancers and other CXCL12-dependent malignancies.

Our team previously reported that MACC1 levels are closely related to a variety of tumors and the efficacy of immune checkpoint blockade (ICB) therapy. However, the predictive value of MACC1 levels for lung adenocarcinoma (LUAD) immunotherapy has not been studied. This study aimed to investigate the predictive effect of the oncogene MACC1 on ICB reactivity in patients with LUAD. First, the expression patterns and clinical features of MACC1 in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were comprehensively evaluated using R packages. We subsequently assessed the correlations between MACC1 and immunological characteristics in the LUAD tumor microenvironment (TME) using the CIBERSORT algorithm. The results revealed that MACC1 overexpression was significantly correlated with 3 immune checkpoints, 14 tumor-infiltrating immune cells (TIICs), 9 immunomodulators, 5 anticancer immune process activities, and 3 effector genes of TIICs in LUAD. Additionally, on the basis of the prognostic genes from LASSO analysis, we developed the MACC1-related Risk Score (MRRS), which can accurately predict the prognosis and response to cancer immunotherapy in LUAD patients (HR = 3.50, AUC at 1, 2, and 3 years = 0.737, 0.744, and 0.724, respectively). Finally, in vivo experiments revealed that the combination of MACC1 silencing and PD-L1 inhibitors significantly inhibits tumor progression. These findings increase our understanding of MACC1 as a potential prognostic biomarker and potential therapeutic target for cancer immunotherapy. The MRRS may play a critical role in predicting the response of LUAD patients to ICB therapy.

Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Apc, the most common initiating event in conventional adenomas3, activates Wnt signalling, thus conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arise by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear whether both generate tumours equally well in uninjured intestines. It is also unknown whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source, but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs that are not associated with adenomas. These cis elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumorigenesis.

Primary liver cancer is a major global health challenge, of which hepatocellular carcinoma is the most common. For patients with advanced liver cancer, Sorafenib is a first-line targeted drug that occupies a dominant position in clinical applications. Sorafenib is a multi-kinase inhibitor commonly used in clinical practice, which can effectively inhibit tumor cell proliferation, promote cell apoptosis, and inhibit angiogenesis. However, the emergence of drug resistance has hindered the development of treatment programs, which is an urgent problem to be solved. Recent studies have revealed many mechanisms and influencing factors of Sorafenib resistance (such as epigenetic regulation, programmed cell death, metabolic reprogramming, and tumor microenvironment changes). This review not only summarizes the above mechanisms, but also summarizes the combined application of Sorafenib with other drugs (such as molecular targeted drugs, other anti-angiogenesis drugs, cytotoxic drugs, immunotherapy drugs, etc .). Finally, potential strategies and research directions to overcome drug resistance (such as targeting epigenetic pathways or metabolic reprogramming) are discussed to provide suggestions for future in-depth research and clinical applications.

Cancer-associated fibroblasts (CAFs) significantly influence tumor progression and therapeutic resistance in colorectal cancer (CRC). However, the distributions and functions of CAF subpopulations vary across the four consensus molecular subtypes (CMSs) of CRC. This study performed single-cell RNA and bulk RNA sequencing and revealed that myofibroblast-like CAFs (myCAFs), tumor-like CAFs (tCAFs), inflammatory CAFs (iCAFs), CXCL14+CAFs, and MT+CAFs are notably enriched in CMS4 compared with other CMSs of CRC. Multiplex immunohistochemistry was used to validate the distribution of CAF subtypes in patients with different CMSs. Prognosis-related CAF subtypes were identified, leading to the selection of four key genes (COL3A1, COL1A2, GEM, and TMEM47). Through machine learning, we developed a CAF poor-prognosis gene (CAFPRG) model to predict outcomes of patients with CMS4. High levels of CAFPRGs were identified as independent poor-risk factors for prognosis (p < 0.001). Tumors with elevated CAFPRGs exhibited increased infiltration of immune-suppressive cells and resistance to chemotherapy. The expression of these key genes was confirmed to be significantly higher in CAFs than in normal fibroblasts (NFs). Therefore, CAFPRGs may be valuable for precisely predicting patient survival and may present potential therapeutic opportunities for CMS4 CRC.

The interaction between stromal cells and the tumor immune microenvironment (TIME) is acknowledged as a critical driver in the progression of prostate cancer (PCa). Monoamine oxidase A (MAOA), a mitochondrial enzyme that catalyzes the degradation of monoamine neurotransmitters and dietary amines, has been linked to the promotion of prostate tumorigenesis, particularly when upregulated in stromal cells. However, the detailed mechanisms of MAOA's interaction with TIME have not been fully elucidated.

We reanalyzed a single-cell sequencing dataset to evaluate the role of MAOA in the stroma, verify the impact of stromal MAOA alterations on CD8+ T cell responses by co-culturing stromal cells and immune cells in vitro. Furthermore, C57BL/6J mouse subcutaneous transplant tumor models and dual humanized mouse models were established to investigate the function of MAOA in vivo and the potential of its inhibitors for immunotherapy.

Our study demonstrates that inhibiting MAOA in stromal cells facilitates the conversion of myofibroblastic cancer-associated fibroblasts (myCAFs), thereby improving the immunosuppressive environment of PCa. The strategic combination of MAOA inhibition with immune checkpoint inhibitors elicits a synergistic antitumor effect. Specifically, MAOA inhibition in stromal cells leads to increased production of WNT5A, which subsequently activates the cytotoxic capacity of CD8+ T cells through the Ca2+-NFATC1 signaling pathway.

Our findings highlight the critical role of MAOA in modulating cancer-associated fibroblasts within the PCa immune microenvironment, presenting a novel therapeutic strategy to augment the efficacy of immunotherapy for PCa.

This meta-analysis aimed to compare the diagnostic effectiveness of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET for detecting lymph node metastasis in digestive system cancer patients.

A comprehensive search of PubMed, Web of Science, and Embase databases was conducted to identify relevant articles up to June 2024. Studies were included if they evaluated the diagnostic performance of [68Ga]Ga-FAPI-04 PET and [18F]FDG PET in detecting lymph node metastasis in digestive system cancer patients. Sensitivity and specificity were assessed using the DerSimonian and Laird method and were transformed using the Freeman-Tukey double arcsine transformation.

Fifteen articles, encompassing a total of 617 patients, were included in this study. The overall sensitivity of [68Ga]Ga-FAPI-04 PET for diagnosing lymph node metastasis in digestive system cancers was 0.82 (95% CI: 0.67-0.93), and the specificity was 0.91 (95% CI: 0.84-0.97). In comparison, the sensitivity of [18F]FDG PET was 0.51 (95% CI: 0.38-0.63), with a specificity of 0.81 (95% CI: 0.64-0.94). These results suggest that [68Ga]Ga-FAPI-04 PET has a significantly higher sensitivity (P < 0.01) and similar specificity (P = 0.20) compared to [18F]FDG PET in detecting lymph node metastasis in digestive system cancers.

Our meta-analysis indicates that [68Ga]Ga-FAPI-04 PET has higher sensitivity and similar specificity compared to [18F]FDG PET in diagnosing lymph node metastasis in digestive system cancers. However, the high heterogeneity among the studies may impact the robustness of the current evidence. Therefore, future research should prioritize larger prospective studies with more diverse populations and specific cancer subtypes to draw more definitive conclusions.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42024572412, Unique Identifier: CRD42024572412.

Head and neck squamous cell carcinoma (HNSCC) is among the most aggressive malignancies, underscoring the need for early diagnosis to improve patient outcomes. Tumor-derived exosomes, which can be non-invasively obtained and reflect the metabolic state of tumors in real-time, are under increasing investigation for their diagnostic potential. Herein we analyzed metabolite differences in exosomes, serum, and tissues from patients with HNSCC to identify potential diagnostic biomarkers of clinical relevance.

Non-targeted metabolomics based on liquid chromatography-mass spectrometry was employed to quantify metabolites in exosome, serum, and tissue samples from 11 patients with HNSCC and six patients without cancer. The metabolic profiles of HNSCC were analyzed through univariate and multivariate statistical methods, differential metabolite analysis, and pathway enrichment analysis.

We identified three differential metabolites in exosomes, 45 in serum, and 33 in tissues. Notably, patients with HNSCC exhibited significant disruptions in protein and amino acid metabolism. Spermine was exclusively detected in exosomes and tissues from patients with HNSCC. We hypothesize that spermine is extracellularly secreted by malignant cells via exosomes and subsequently enters the bloodstream. Moreover, spermine synthase was highly expressed in HNSCC tissues. Knocking down spermine synthase markedly impaired HNSCC cell proliferation and migration.

This study provides a preliminarily characterization of the metabolic profile of HNSCC and highlights spermine and its synthetic pathways as potential diagnostic and therapeutic targets. Future studies are warranted to elucidate the mechanism of action of spermine in HNSCC and explore its utility in early diagnosis and therapeutic development.

Bladder cancer (BLCA) is a prevalent and deadly form of urinary cancer, and there is a need for effective therapies, particularly for muscle-invasive bladder cancer (MIBC). Cell cycle inhibitors show promise in restoring control of the cell cycle in BLCA cells, but their clinical prognosis evaluation is limited.

Transcriptome and scRNA-seq data were collected from the Cancer Genome Atlas Program (TCGA)-BLCA and GSE190888 cohort, respectively. R software and the Seurat package were used for data analysis, including cell quality control, dimensionality reduction, and identification of differentially expressed genes. Genes related to the cell cycle were obtained from the genecards website, and a protein-protein interaction network analysis was performed using cytoscape software. Functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular docking were conducted using various tools and packages. BLCA cell lines were cultured and transfected for in vitro experimental assays, including RT-qPCR analysis, and CCK-8 cell viability assays.

We identified 32 genes as independent risk or protective factors for BLCA prediction. Functional enrichment analysis revealed their involvement in cell cycle regulation, apoptosis, and various signaling pathways. Using these genes, we developed a nomogram for predicting BLCA survival, which displayed high prognosis stratification efficacy in BLCA patients. Four cell cycle associated key genes identified, including NCAM1, HBB, CKD6, and CTLA4. We also identified the main cell types in BLCA patients and investigated the functional differences between epithelial cells based on their expression levels of key genes. Furthermore, we observed a high positive correlative relationship between the infiltration of cancer-associated fibroblasts and the risk score value. Finally, we conducted in vitro experiments to demonstrate the suppressive role of NCAM1 in BLCA cell proliferation.

These findings suggest that cell cycle associated genes could serve as potential biomarkers for predicting BLCA prognosis and may represent therapeutic targets for the development of more effective therapies. Hopefully, these findings provide valuable insights into the molecular mechanisms and potential therapeutic targets in BLCA from the perspective of cell cycle. Moreover, NCAM1 was a novel cell proliferation suppressor in the BLCA carcinogenesis.

As the mechanisms underlying tumorigenesis become better understood, the dynamic roles of cellular components of the tumor microenvironment, and their cross-talk with tumor cells, have come to light as key drivers of disease progression and have emerged as important targets of new cancer therapies. In the field of oncolytic virus (OV) therapy, stromal cells have been considered as potential barriers to viral spread, thus limiting virus replication and therapeutic outcome. However, new evidence indicates that intratumoral fibroblasts could support virus replication. We have demonstrated in a rat model of stromal-rich intrahepatic cholangiocarcinoma (CCA) that vesicular stomatitis virus (VSV) can be localized within intratumoral hepatic stellate cells (HSCs), in addition to tumor cells, when the virus was applied via hepatic arterial infusion. Furthermore, VSV was shown to efficiently kill CCA cells and activated HSCs, and co-culture of CCA and HSCs increased viral titers. Interestingly, this effect is also observed when each cell type is cultured alone in a conditioned medium of the other cell type, indicating that secreted cell factors are at least partially responsible for this phenomenon. Partial reduction in sensitivity to type I interferons was observed in co-culture systems, providing a possible mechanism for the increased viral titers. Together, the results indicate that targeting activated HSCs with VSV could provide an additional mechanism of OV therapy, which, until now has not been considered. Furthermore, these findings suggest that VSV is a potentially powerful therapeutic agent for stromal-rich tumors, such as CCA and pancreatic cancer, both of which are very difficult to treat with conventional therapy and have a very poor prognosis.

Accurate predictions on prognosis and neoadjuvant therapy response are crucial for esophagogastric junction adenocarcinoma (EGJA) patients. Therefore, we aimed to investigate the predictive abilities of several indicators, including tumor stroma ratio (TSR), tumor stroma maturity (TSM), and the density and spatial distribution of tumor-infiltrating immune cells (TIICs), such as T cells, B cells, and tumor-associated macrophages (TAMs). Resection and biopsy specimens of a total of 695 patients were included, obtained from the National Cancer Center (NCC) and The Cancer Genome Atlas (TCGA) cohorts. TSR and TSM were evaluated based on histological assessment. TIICs were quantified by QuPath following immunohistochemical (IHC) staining in resection specimens, while the Klintrup-Mäkinen (KM) grade was employed for evaluating TIIC in biopsy specimens. Patients with high stromal levels or immature stroma had relatively worse prognoses. Furthermore, high CD8+T cell count in the tumor periphery, as well as low CD68+ TAM count either in the tumor center or in the tumor periphery, was an independent favorable prognostic factor. Significantly, the combination model incorporating TSM and CD163+TAMs emerged as an independent prognostic factor in both two independent cohorts (HR 3.644, 95% CI 1.341-9.900, p = 0.011 and HR 1.891, 95% CI 1.195-2.99, p = 0.006, respectively). Additionally, high stromal levels in preoperative biopsies correlated with poor neoadjuvant therapy response (p < 0.05). In conclusion, our findings suggest that TSR, TSM, CD8+T cell, CD68+TAMs, and CD163+TAMs predict the prognosis to some extent in patients with EGJA. Notably, the combined model incorporating TSM and CD163+TAM can contribute significantly to prognostic stratification. Additionally, high stromal levels evaluated in preoperative biopsy specimens correlated with poor neoadjuvant therapy response.

Cancer is a highly heterogeneous disease, and thus treatment responses vary greatly between patients. To improve therapy efficacy and outcome for cancer patients, more representative and patient-specific preclinical models are needed. Organoids and tumoroids are 3D cell culture models that typically retain the genetic and epigenetic characteristics, as well as the morphology, of their tissue of origin. Thus, they can be used to understand the underlying mechanisms of cancer initiation, progression, and metastasis in a more physiological setting. Additionally, co-culture methods of tumoroids and cancer-associated cells can help to understand the interplay between a tumor and its tumor microenvironment. In recent years, tumoroids have already helped to refine treatments and to identify new targets for cancer therapy. Advanced culturing systems such as chip-based fluidic devices and bioprinting methods in combination with tumoroids have been used for high-throughput applications for personalized medicine. Even though organoid and tumoroid models are complex in vitro systems, validation of results in vivo is still the common practice. Here, we describe how both animal- and human-derived tumoroids have helped to identify novel vulnerabilities for cancer treatment in recent years, and how they are currently used for precision medicine.

The present study aimed to investigate the role of a recombinant protein based on human collagen type I (RCPhC1) as a scaffold in maintaining the human tumor microenvironment within a patient-derived tumor xenograft (PDTX) model. RCPhC1, synthesized under animal component-free conditions, was explored for its potential to support the human-specific stroma associated with tumor growth. PDTX models were established using resected colorectal cancer liver metastasis specimens, and stromal cell populations from humans and mice were compared using three scaffolds: No scaffold (control), Matrigel and recombinant human collagen type I, across two passages. Specific antibodies for human Lamin B and mouse Lamin B were used for immunostaining to distinguish between human and mouse cells. Additionally, the impact of each scaffold on the invasive ability of mouse fibroblasts was assessed using an invasion assay. Patient-derived tumor tissues embedded with RCPhC1 hydrogels had significantly more human Lamin B-positive cells and fewer mouse Lamin B cells than those embedded with no scaffolds or Matrigel. The human Lamin B-positive cells in PDTX tumors with RCPhC1 hydrogels were recognized as fibroblasts. Additionally, these hydrogels significantly reduced the invasion of mouse fibroblast cell lines in vitro compared with Matrigel. The present study investigated RCPhC1 hydrogels as a new scaffold material for tumor engraftment in PDTX mouse models, and identified a promising experimental tool for maintaining the tumor microenvironment.

Breast cancer had been the most frequently diagnosed cancer among women, making up nearly one-third of all female cancers. Hormone receptor-positive breast cancer (HR+BC) was the most prevalent subtype of breast cancer and exhibited significant heterogeneity. Despite advancements in endocrine therapies, patients with advanced HR+BC often faced poor outcomes due to the development of resistance to treatment. Understanding the molecular mechanisms behind this resistance, including tumor heterogeneity and changes in the tumor microenvironment, was crucial for overcoming resistance, identifying new therapeutic targets, and developing more effective personalized treatments.

The study utilized single-cell RNA sequencing (scRNA-seq) data sourced from the Gene Expression Omnibus database and The Cancer Genome Atlas to analyze HR+BC and identify key cellular characteristics. Cell type identification was achieved through Seurat's analytical tools, and subtype differentiation trajectories were inferred using Slingshot. Cellular communication dynamics between tumor cell subtypes and other cells were analyzed with the CellChat. The pySCENIC package was utilized to analyze transcription factors regulatory networks in the identified tumor cell subtypes. The results were verified by in vitro experiments. A risk scoring model was developed to assess patient outcomes.

This study employed scRNA-seq to conduct a comprehensive analysis of HR+BC tumor subtypes, identifying the C3 PCLAF+ tumor cells subtype, which demonstrated high proliferation and differentiation potential. C3 PCLAF+ tumor cells subtype was found to be closely associated with cancer-associated fibroblasts through the MK signaling pathway, facilitating tumor progression. Additionally, we discovered that MAZ was significantly expressed in C3 PCLAF+ tumor cells subtype, and in vitro experiments confirmed that MAZ knockdown inhibited tumor growth, accentuating its underlying ability as a therapeutic target. Furthermore, we developed a novel prognostic model based on the expression profile of key prognostic genes within the PCLAF+/MAZ regulatory network. This model linked high PCLAF+ tumor risk scores with poor survival outcomes and specific immune microenvironment characteristics.

This study utilized scRNA-seq to reveal the role of the C3 PCLAF+ tumor cells subtype in HR+BC, emphasizing its association with poor prognosis and resistance to endocrine therapies. MAZ, identified as a key regulator, contributed to tumor progression, while the tumor microenvironment had a pivotal identity in immune evasion. The findings underscored the importance of overcoming drug resistance, recognizing novel treatment targets, and crafting tailored diagnosis regimens.

Patient-derived organoids (PDO) have the potential to be used as preclinical cancer models for testing anti-cancer drug efficiency. Cancer-associated fibroblasts (CAFs), which have been closely linked with colorectal carcinoma (CRC) progression and drug resistance, however, are generally not included (or gradually lost during culture) in the PDO models, leading to a major limitation in this cancer model. In this study, we established a new in vitro model with CRC organoids and co-cultured with CAFs and compared it with the organoid-only model. Through testing with anti-cancer drug, we demonstrated a significant difference in drug sensitivity between the two models, and the co-culture model showed higher drug resistance. RNA and whole exome sequencing were performed to reveal gene expression profiles in organoids and organoids co-culture with CAFs to assess interactions between drug sensitivity and gene copy number variation. We found that the expression levels of several pathway protein genes, which are highly expressed in original surgical specimens of colorectal carcinomas, were downregulated in organoids but restored in organoids by co-culturing with CAFs. In summary, the PDO-CAF joint model for CRC can recapitulate a more biomimetic tumor microenvironment and the drug resistance lead by changes in multiple signaling pathways that we discovered; thus, it could be a suitable model for future usage in drug discovery and precision medicine research.

Jianpi Jiedu Formula (JPJDF) is a traditional Chinese medicinal decoction clinically used for its anti-cancer properties, particularly in colorectal cancer (CRC).

This study aims to investigate the therapeutic effects of JPJDF on CRC and elucidate its potential molecular mechanisms, with a focus on its impact on hypoxia-inducible factor 1 alpha (HIF1α) and cancer-associated fibroblasts (CAFs) both in vitro and in vivo.

UPLC-Q-TOF-MS was used to identify the constituents of JPJDF. A chemical-induced colorectal cancer model was established and treated with JPJDF to evaluate its effects. Tumor size was measured, and histopathological analyses were performed to examine JPJDF's regulatory potential on CRC. The functional mechanism of JPJDF was predicted through network pharmacology, molecular docking, and transcriptomics. Co-culture techniques involving CRC cells and CCD-18Co fibroblasts were used to assess JPJDF's impact on fibroblast activation. The effects of HIF1α on CAFs were evaluated using CCK-8 proliferation, clonal formation, and apoptotic assays, with differential marker expression quantified via qPCR and Western blotting.

Pharmacodynamic assessment demonstrated that JPJDF reduced tumor size without affecting body weight, indicating its safety in the chemical-induced murine CRC model. Network pharmacology analysis, combined with molecular docking and transcriptomics, revealed that JPJDF regulates HIF-1 signaling pathways and identified HIF1α as a potential target for JPJDF's anti-CRC effect. JPJDF effectively suppressed CRC growth in vivo by attenuating fibroblast activation, reducing α-SMA expression and POSTN secretion through HIF1α inhibition. HIF1α knockdown in CRC cells inhibited fibroblast proliferation and clonal formation, while overexpression promoted these processes. Additionally, downregulating HIF1α suppressed α-SMA and POSTN expression in fibroblasts, whereas overexpression enhanced fibroblast activation.

JPJDF emerges as a promising therapeutic candidate for inhibiting CAFs activation by targeting HIF1α, offering potential avenues for modulating fibroblast activation towards CAFs in CRC therapy.

The hepatocyte growth factor (HGF) along with its receptor (c-MET) are crucial in preserving standard cellular physiological activities, and imbalances in the c-MET signaling pathway can lead to the development and advancement of tumors. It has been extensively demonstrated that immune checkpoint inhibitors (ICIs) can result in prolonged remission in certain patients. Nevertheless, numerous preclinical studies have shown that MET imbalance hinders the effectiveness of anti-PD-1/PD-L1 treatments through various mechanisms. Consequently, clarifying the link between the c-MET signaling pathway and the tumor microenvironment (TME), as well as uncovering the effects of anti-MET treatment on ICI therapy, is crucial for enhancing the outlook for tumor patients. In this review, we examine the impact of abnormal activation of the HGF/c-MET signaling pathway on the control of the TME and the processes governing PD-L1 expression in cancer cells. The review thoroughly examines both clinical and practical evidence regarding the use of c-MET inhibitors alongside PD-1/PD-L1 inhibitors, emphasizing that focusing on c-MET with immunotherapy enhances the effectiveness of treating MET tumors exhibiting elevated PD-L1 expression.

Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis1 and provide a niche that supports adjacent epithelial stem cells. Here we report that Pdgfra-expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+ fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids ex vivo. Genetic reduction of Cdx2 in the β-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo. These results demonstrate that Pdgfra+ fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.

Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.

Gastric cancer (GC) is characterized by a complex and heterogeneous tumor microenvironment (TME) that significantly influences disease progression and treatment outcomes. The tumor stroma, which is composed of a variety of cell types such as cancer‑associated fibroblasts, immune cells and vascular components, displays significant spatial and temporal diversity. These stromal elements engage in dynamic crosstalk with cancer cells, shaping their proliferative, invasive and metastatic potential. Furthermore, the TME is instrumental in facilitating resistance to traditional chemotherapy, specific treatments and immunotherapy strategies. Understanding the underlying mechanisms by which the GC microenvironment evolves and supports tumor growth and therapeutic resistance is critical for developing effective treatment strategies. The present review explores the latest progress in understanding the intricate interactions between cancer cells and their immediate environment in GC, highlighting the implications for disease pathogenesis and therapeutic interventions.

Cancer-associated fibroblasts (CAFs), which are the most frequent stromal cells in the tumor microenvironment (TME), play a key role in the metastasis of tumor cells. Generally speaking, CAFs in cooperation with tumor cells can secrete various cytokines, proteins, growth factors, and metabolites to promote angiogenesis, mediate immune escape of tumor cells, enhance endothelial-to-mesenchymal transition, stimulate extracellular matrix remodeling, and preserve tumor cell stemness. These activities of CAFs provide a favorable exogenous pathway for tumor progression and metastasis, and a microenvironment that allows rapid growth of tumor cells, which always lead to poor prognosis for patients. More importantly, it seems that targeting CAFs is also a potential precision therapeutic strategy in clinical practice. Hence, this review outlines the origin of CAFs, the relationship between CAFs and cancer metastasis, and targeting CAFs as a potential strategy for cancer patients, which could give some inspirations for cancer treatment in clinic.

Cancer associated fibroblasts (CAFs) are the predominant stromal cells in the tumor microenvironment of gastric cancer (GC), interacting with both immune and tumor cells to drive cancer progression. However, the precise link between these interactions and their potential as therapeutic targets remains poorly understood. In this study, we identified for the first time that nicotinamide N-methyltransferase (NNMT) derived from CAFs promoted M2 macrophage polarization, which, in turn, facilitated the proliferation and migration of GC cells. Additionally, we discovered that NNMT expression in CAFs was regulated by the Fat mass and obesity related protein (FTO) via m6A demethylation. Both NNMT and FTO were highly expressed in tumor tissues and CAFs, with a positive correlation between FTO and NNMT levels in clinical samples. Mechanistically, FTO bound to NNMT mRNA, reducing m6A modification and enhancing NNMT expression. Knockdown of either NNMT or FTO in CAFs effectively inhibited M2 macrophage polarization and suppressed GC progression. These findings were validated in patient-derived organoid models and nude mouse models of GC. Collectively, our data revealed that FTO promoted M2 macrophage polarization by regulating the m6A demethylation of NNMT in CAFs, thereby driving GC progression. This identified a potential novel target for GC diagnosis and therapy.

Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.

This review presents a thorough investigation of the role of CD47 in gastrointestinal cancers. We performed a comprehensive, in-depth review of over 100 preclinical and clinical studies focused on inhibiting CD47. The research highlights the potential of targeted CD47 to enhance existing treatments by boosting the immune response to cancer cells. Considering the essential need to balance the toxicity and efficacy of CD47 inhibition, our review emphasizes the need to optimize CD47 inhibitors. We also demonstrate the necessity of combining CD47 antibodies with conventional chemotherapy, radiotherapy, or other targeted therapies to enhance treatment effectiveness. Finally, we propose the integration of CD47-targeted therapies into treatment plans as a promising approach to reshape the therapeutic landscape of gastrointestinal cancers. Continued research in this field holds great potential for improving the outcomes of gastrointestinal cancer patients and overcoming the challenges associated with this formidable spectrum of diseases.

Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.

Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.

Pancreatic ductal adenocarcinoma (PDAC) represents the complexity of interaction between cancer and cells of the tumor microenvironment (TME). Immune cells affect tumor cell behavior, thus driving cancer progression. Cancer-associated fibroblasts (CAFs) are responsible of the desmoplastic and fibrotic reaction by regulating deposition and remodeling of extracellular matrix (ECM). As tumor-promoting cells abundant in PDAC ECM, CAFs represent promising targets for novel anticancer interventions. However, relevant clinical trials are hampered by the lack of specific markers and elusive differences among CAF subtypes. Indeed, while single-cell transcriptomic analyses have provided important information on the cellular constituents of PDACs and related molecular pathways, studies based on the identification of protein markers in tissues aimed at identifying CAF subtypes and new molecular targets result incomplete.

Herein, we applied multiplexed Imaging Mass Cytometry (IMC) at single-cell resolution on 8 human PDAC tissues to depict the PDAC composing cells, and profiling immune cells, endothelial cells (ECs), as well as endocrine cells and tumor cells.

We focused on CAFs by characterizing up to 19 clusters distinguished by phenotype, spatiality, and interaction with immune and tumor cells. We report evidence that specific subtypes of CAFs (CAFs 10 and 11) predominantly are enriched at the tumor-stroma interface and closely associated with tumor cells. CAFs expressing different combinations of FAP, podoplanin and cadherin-11, were associated with a higher level of CA19-9. Moreover, we identified specific subsets of FAP+ and podoplanin+/cadherin-11+ CAFs enriched in patients with negative prognosis.

The present study provides new general insights into the complexity of the PDAC microenvironment by defining phenotypic heterogeneities and spatial distributions of CAFs, thus suggesting different functions of their subtypes in the PDAC microenvironment.

Human oral squamous cell carcinoma (OSCC) is the most common type of oral cancer and has a poor survival rate. Cell-cell communication between OSCC cells and cancer-associated fibroblasts (CAFs) plays important roles in OSCC progression. We previously demonstrated that CAFs promote OSCC cell migration and invasion. However, how OSCC cells influence CAFs proliferation is unknown.

Knockdown of PVT1 was confirmed using lentivirus infection technique. CAFs in tissues were identified by staining the cells with α-SMA using immunohistochemical technique. CCK-8 assay was used to evaluate cell proliferation. The mRNA level of a gene was measured by qRT-PCR. Secreted TGF-β were detected using ELISA assay.

We found that knockdown of the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was associated with a low density of CAFs in xenograft tumors in mice; further analysis revealed that PVT1 in OSCC cells induced CAF proliferation through transforming growth factor (TGF)-β.

Our results demonstrate that lncRNA PVT1 in tumor cells participates in CAF development in OSCC by regulating TGF-β. This study revealed a new mechanism by which PVT1 regulates OSCC progression and PVT1 is a potential therapeutic target in OSCC.

The tumor microenvironment (TME) harbors a hidden universe of interactions that profoundly shape the behavior of head and neck cancers (HNCs). HNCs are not merely localized afflictions; they constitute a pressing global health crisis that impacts millions, frequently resulting in severe prognoses due to late-stage diagnosis and intrinsic resistance to conventional therapies. In this intricate interplay, cancer cells function as strategic players, adeptly manipulating their microenvironment to foster proliferation, evade immune detection, and withstand therapeutic interventions. Central to this dynamic play are exosomes, the enigmatic pawns of cellular communication, carrying vital messages across the board. This review elucidates the multifaceted roles of exosomes within the TME, highlighting their capacity to transmit critical signals that not only promote tumor progression but also modulate immune responses, ultimately playing a crucial role in the evolving narrative of HNC. Our insights aim to catalyze further research and exploration into exosome-targeted therapies, potentially transforming the landscape of HNC treatment and improving clinical outcomes in this formidable battle against cancer.

Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment. IgA contributes to inflammation and dismantling antitumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in Pil Soo Sung the tumor microenvironment of HCC.

CAF dynamics in HCC tumor microenvironment were analyzed through single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of patients with advanced HCC treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels ( p <0.05). Single-cell analysis showed that subcluster proportions in the CAF-fibroblast activation protein-α matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of fibroblast activation protein in the CD68 + cells from patients with high serum IgA levels ( p <0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 expression levels than those in mock-treated CAFs ( p <0.05). Coculture with CAFs attenuated the cytotoxic function of activated CD8 + T cells. Interestingly, activated CD8 + T cells cocultured with IgA-treated CAFs exhibited increased programmed death-1 expression levels than those cocultured with mock-treated CAFs ( p <0.05).

Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T-cell function. Our study highlighted their potential roles in tumor progression and immune suppression.

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.