Components Of Microenvironment Research Articles

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment.

Pancreatic cancer is one of the most lethal malignancies, characterized by poor prognosis and low survival rates. Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy, often failing to capture the complexity of the disease. The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment. This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer. To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules. This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2, PLAU, and CCNA2. The results were validated in an independent dataset. This study also examined the correlations between the model risk score and various clinical features, components of the immune microenvironment, chemotherapeutic drug sensitivity, and metabolism-related pathways. Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines. The prognostic model demonstrated significant predictive value, with the risk score showing a strong correlation with clinical features: It was significantly associated with tumor grade (G) (b P < 0.01), moderately associated with tumor stage (T) (a P < 0.05), and significantly correlated with residual tumor (R) status (b P < 0.01). There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs. Furthermore, the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer. The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Intratumoral microbiota as a novel prognostic indicator in bladder cancer

Microbes are important components of the tumor microenvironment and have a close relationship with tumors. However, there is still a lack of research on the intratumoral microbiota in bladder cancer and its impact on the tumor immune microenvironment. In this study, we used fluorescence in situ hybridization (FISH) and observed a substantial presence of microbiota in bladder cancer tissues, with greater abundance compared to that in normal bladder tissues. Based on the BIC database, we found that the microbiome of bladder cancer is highly diverse and its structure is significantly different from that of other tumors. To investigate the relationships among the intratumoral microbiota, tumor immunity, and prognosis in bladder cancer patients, we analyzed bladder cancer-specific differentially expressed immune- and antimicrobial-related genes from the ImmPort, TISIDB, and TCGA databases. We identified 11 hub genes and constructed a prognostic risk model. Further analysis revealed differences at the family and genus levels between distinct groups. Using LEfSe analysis, we identified six hub biomarkers and developed a novel microbial-based scoring system. The scoring system allows subgrouping of bladder cancer patients, with significant differences in prognosis, immune cell infiltration, tumor mutation burden, and immune checkpoints among different groups. Further FISH and immunofluorescence co-staining experiments initially verified that the specific distribution of microorganisms and M2 macrophages in bladder cancer may be closely related to the poor prognosis of patients. In conclusion, this study revealed the characteristics of the intratumoral microbiota in bladder cancer and identified potential prognostic targets for clinical application.

Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry

Background Minichromosome maintenance complex component 3 (MCM3) plays a key role in various tumours. However, it remains largely unknown what the specific role and clinical significance of MCM3 in pancreatic adenocarcinoma (PAAD) are. Materials and Methods We integrated high-throughput data from PAAD worldwide to analyse the expression level of MCM3 mRNA. We used immunohistochemistry to analyse MCM3 protein expression levels in 145 cases in the PAAD group and 29 cases in the non-PAAD group. We also mainly analysed the necessity of MCM3 for PAAD growth based on CRISPR screen data. In addition, we used enrichment analysis and protein–protein interaction networks to explore the molecular mechanism of MCM3 in PAAD. We also analysed the correlation between MCM3 expression, components of the immune microenvironment in PAAD tissue and clinical prognosis. Results In PAAD, we observed for the first time that MCM3 was significantly highly expressed at both the mRNA (SMD = 0.67, 95% CI: 0.38 ∼ 0.96) and the protein level (p < 0.05). The mRNA (AUC = 0.78, 95% CI: 0.74 ∼ 0.81; sensitivity = 0.66, 95% CI: 0.55 ∼ 0.76; specificity = 0.76, 95% CI: 0.67 ∼ 0.84) and protein (AUC = 0.929) expression levels of MCM3 had a good ability to distinguish between PAAD and non-PAAD tissue. There was heterogeneity reflected by the differential expression of MCM3 protein in PAAD cells. MCM3 played an essential role in PAAD growth, through abnormal DNA replication, p53 signalling and cell cycle checkpoints. PAAD with high MCM3 expression was sensitive to c-75, brivanib, flavopiridol and VNLG/124 drugs, with stable molecular docking models. Conclusion MCM3 is likely to be a critical element in promoting the initiation and growth of PAAD. Flavopiridol may exert its anti-PAAD effect through the interaction between MCM3, classic CDK1 targets in the cell cycle checkpoint and p53 pathway as well as related molecules in other pathways.

Abstract C169: Investigating the effects of ancestry in KRAS mediated lung adenocarcinoma: Exploring intratumoral heterogeneity and mitochondrial dynamics

Abstract Demonstrating a combination of high prevalence, late detection, and low survival, Lung cancer is the leading cause of cancer related deaths worldwide (Sainz de Aja J, 2021) and Lung Adenocarcinoma (LUAD) is its most prevalent pathologic subtype (Zhou, 2021). Emerging from within the distal alveolar epithelium, LUAD presents with vast heterogeneity in histology, mutational spectra, and epigenomic dysregulation (Sainz de Aja J, 2021) (Zhou, 2021). Additionally, LUAD’s considerable intratumoral heterogeneity manifests vast genomic and phenotypic diversity across tumor cells and cellular components of the tumor microenvironment (TME) within the same tumor tissue. LUAD also reveals significant racial disparities in incidence, survival and mortality rates between White and Black men in the United States. The occurrence of LUAD is approximately 68.3 per capita for Black men and 61.5 per capita for White men, reflecting an 11% higher rate in the former. Further, survival outcomes indicate that Black men generally exhibit lower 5-year relative survival rates compared to White men, highlighting greater mortality risk and conspicuously poorer prognosis (Siegel RL et al., 2023). While addressing the social determinants of health is vital for the mitigation of health disparities, understanding the genetic and molecular foundations that underly racial health inequities is essential for developing comprehensive interventions and advancing more precise therapeutic modalities for more diverse patient populations. Single Nucleotide Polymorphisms (SNPs) can influence oncogenic transformation and may be associated with distinct molecular landscapes in tumors and adjacent TME. Furthermore, ancestry may play a pivotal role in shaping individual susceptibility and risk for mitochondrial dysfunction and ensuing oncogenic transformation. To elucidate the biological underpinnings of racial health disparities in LUAD, 10 Black and 10 White male LUAD patients’ tumor and normal corresponding adjacent tissues underwent molecular profiling for KRAS mutation status, Whole Exome Sequencing (WES) to determine ancestry, and analysis of associated LUAD induced Mitochondrial Somatic Nucleotide Variants (mtSNVs). We also employed the 10X Visium HD spatial transcriptomic platform to evaluate spatially resolved molecular and cellular differences in KRAS mediated LUAD between Black and White men. Hypothesis: Thus, we propose that global ancestry is associated with variations in intratumoral heterogeneity, TME composition, and mitochondrial dynamics, indicating a potential role in the observed disparities in susceptibility, malignancy and mortality in LUAD across diverse patient populations. Citation Format: Eun Kyu Sung, Yuxin Jin, Yonatan Amzaleg, John Carpten, William Dean Wallace, Dan Raz, Aaron M. Neely. Investigating the effects of ancestry in KRAS mediated lung adenocarcinoma: Exploring intratumoral heterogeneity and mitochondrial dynamics [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C169.

Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p

BackgroundCancer-associated fibroblasts, as a major component of the tumor microenvironment, have been shown to exhibit protumorigenic effects in pancreatic ductal adenocarcinoma. Moreover, cancer-associated fibroblasts-derived exosomes have been reported to promote tumor development, but exact mechanisms have not been elucidated. The purpose of this study was to investigate the processes by which exosomes generated from cancer-associated fibroblasts promote tumor growth.Methodstwenty-one patients with pancreatic ductal adenocarcinoma who evaluated preoperatively as potentially surgically resectable without distant metastasis and pathologically examined postoperatively as pancreatic ductal cell carcinoma were included. We determined the expression of Leptin as well as downstream proteins at the clinical and cellular levels. Cancer-associated fibroblast-derived exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. To ascertain the mechanism mediating the action of exosomal Leptin in pancreatic ductal adenocarcinoma, we performed CCK-8 assay, colony formation assays, transwell and wound healing assays in PSN1 cells to evaluate cell proliferation, migration and invasion. Western blotting was used to detect the level of Leptin, ABL2 and exosome markers. qRT-PCR was employed to evaluate miR-224-3p. Cancer-associated fibroblasts markers and exosome uptake were verified by immunofluorescence.ResultsWestern blotting assays show that Leptin is present inside tissues and cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts stimulated PSN1 cells growth, migration and invasion in vitro by secreting the exosomal Leptin. Exosomal Leptin could regulate miR-224-3p, which targets negative regulation of ABL2. Inhibiting Leptin significantly limited PSN1 cells growth, migration and invasion. In vitro analyses revealed that miR-224-3p mimics mitigate the inhibitory effect of cancer-associated fibroblasts knockdown of Leptin on PSN1 cells development, but overexpression of ABL2 partly abolished the tumor-promoting phenotype of miR-224-3p mimics.ConclusionOur results revealed that cancer-associated fibroblasts mediate pancreatic ductal adenocarcinoma development by regulating the miR-224-3p/ABL2 molecular axis through the secretion of the exosomal Leptin.

Pregnane X receptor inhibits the transdifferentiation of hepatic stellate cells by down-regulating periostin expression.

Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that plays a key role in drug metabolism. Recently, PXR was found to attenuate the development of liver cancer by suppressing epithelial-mesenchymal transition (EMT) in liver cancer cells in a mouse model of two-stage chemical carcinogenesis. To elucidate the role of PXR in the EMT of liver cancer cells, we focused on its role in hepatic stellate cells (HSCs), which are components of the tumor microenvironment in hepatocellular carcinoma (HCC). Human HSC-derived LX-2 cells stably expressed destabilization domain (DD)-fused human PXR (hPXR-LX2 cells). Human HCC-derived HepG2 cells were transfected with the EMT marker VIM promoter-regulated reporter plasmid and co-cultured with hPXR-LX2 cells or treated with hPXR-LX2-derived conditioned medium (CM). Co-culture or CM treatment increased reporter activity in HepG2 cells. This induction was attenuated upon PXR activation in hPXR-LX2 cells by treatment with the DD-stabilizing chemical Shield-1 and the human PXR ligand rifampicin. PXR activation in hPXR-LX2 cells exhibited inhibition of TGF-β1-induced transdifferentiation, supported by observations of morphological changes and protein or mRNA levels of the transdifferentiation markers COL1A1 and FN1. PXR activation in hPXR-LX2 cells also attenuated the mRNA levels of the key transdifferentiation factor, POSTN. Treatment of hPXR-LX2 cells with recombinant POSTN restored the PXR-mediated suppression of transdifferentiation. Reporter assays with the POSTN promoter showed that PXR inhibited the NF-κB-mediated transcription of POSTN. Consequently, PXR activation in HSCs is expected to inhibit transdifferentiation by down-regulating POSTN expression, thereby suppressing EMT of liver cancer cells.

Microenvironments‐Modulated Biomaterials Enhance Spinal Cord Injury Therapy

AbstractSpinal cord injury (SCI) results from various causes, including sports‐related incidents, degenerative cervical myelopathy, traffic accidents, and falls. SCI typically leads to sensory and motor dysfunction and even paralysis. Current treatments for SCI include systemic administration of high‐dose steroids and surgical decompression and stabilization. However, excessive use of glucocorticoids may increase susceptibility to infections and systemic bleeding. The long‐term effect of surgery intervention remains unclear, with ongoing debates regarding its timing, efficacy, and safety. Therefore, innovative approaches are urgently needed to alleviate secondary injuries and promote spinal recovery. One emerging therapeutic approach for SCI is modulating the microenvironments to achieve neuroprotection and neurogenesis during recovery. Several biomaterials with favorable physicochemical properties have been developed to enhance therapeutic effects by regulating microenvironments. This Review first discusses the pathology of SCI microenvironments and then introduces biomaterials‐based regulatory strategies targeting various microenvironmental components, including anti‐inflammation, anti‐oxidation, reduction of excitotoxicity, revascularization, neurogenesis, and scar density reduction. Additionally, the research and clinical application prospects for microenvironment regulation are presented.

Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation

Alterations in nuclear structure and function are hallmarks of cancer cells. Little is known about these changes in Cancer-Associated Fibroblasts (CAFs), crucial components of the tumor microenvironment. Loss of the androgen receptor (AR) in human dermal fibroblasts (HDFs), which triggers early steps of CAF activation, leads to nuclear membrane changes and micronuclei formation, independent of cellular senescence. Similar changes occur in established CAFs and are reversed by restoring AR activity. AR associates with nuclear lamin A/C, and its loss causes lamin A/C nucleoplasmic redistribution. AR serves as a bridge between lamin A/C and the protein phosphatase PPP1. Loss of AR decreases lamin-PPP1 association and increases lamin A/C phosphorylation at Ser 301, a characteristic of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the regulatory region of CAF effector genes of the myofibroblast subtype. Expression of a lamin A/C Ser301 phosphomimetic mutant alone can transform normal fibroblasts into tumor-promoting CAFs.

A scoring model for the expression of genes related to programmed cell death predicts immunotherapy response and prognosis in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) continues to be the leading cause of cancer death worldwide, driven by environmental factors like smoking and genetic predispositions. LUAD has a high mortality rate, and new biomarkers are urgently needed to improve treatment strategies and patient management. Programmed cell death (PCD) is involved in tumor progression and response to treatment. Therefore, there is a need for an extensive study of the role and functions of PCD-related genes (PCDRGs) in lung adenocarcinoma so as to understand the pathophysiologic features of lung adenocarcinoma.MethodsBased on TCGA and GEO databases, this research is aimed at screening differentially expressed PCD-related genes in lung adenocarcinoma. We conducted GO, and KEGG analysis to establish the link between these genes and biological processes. By applying various machine learning algorithms such as CoxBoost analysis, we developed PCD-related indices (PCDI) that were used to verify their ability to predict prognosis with the use of other datasets. This was done in addition to exploring the biological functions of PCD genes associated with lung adenocarcinoma by assessing the relationship between immune cell components of tumor microenvironment and PCD genes together with examining how they affect drug sensitivity.ResultsThe research presented in this article offers significant insights into LUAD. The authors identified 113 PCDRGs that were differentially expressed in LUAD. These genes are implicated in various biological functions, including High risk ing apoptosis, ferroptosis, and pathways specific to non-small cell lung cancer. Notably, the PCDI proved effective in distinguishing between High risk and Low risk LUAD patients, demonstrating a higher accuracy in prognosis prediction compared to traditional clinical indicators such as age and gender. This high prediction accuracy was validated in both test and validation cohorts. Additionally, these genes showed significant correlations with immune cell infiltration and drug sensitivity in LUAD patients.ConclusionWe analysed the expression and function of PCDRGs in LUAD and revealed their correlation with patient survival, the immune microenvironment and drug sensitivity. The constructed PCDI model provides a scientific basis for the personalised treatment of lung adenocarcinoma, and future optimisation of treatment strategies based on these genes may improve patient clinical outcomes.

Immune escape between endoplasmic reticulum stress-related cancer cells and exhausted CD8+T cells leads to neoadjuvant chemotherapy resistance in ovarian cancer

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC).Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed.While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT.Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT resistance.

The role of long non‐coding RNA Maternally Expressed Gene 3 in cancer‐associated fibroblasts at single cell pan‐cancer level

AbstractLong non‐coding RNAs (lncRNAs) can crucially regulate activation and transformation of cancer‐associated fibroblasts (CAFs) but have not been systematically investigated at single cell resolution. Here, by utilizing integrated single‐cell sequencing datasets, we screened the aberrantly expressed lncRNAs in CAFs, which are the major component of tumor microenvironment. Our findings revealed a consistent CAF‐specific downregulation of Maternally Expressed Gene 3 (MEG3) expression and increased MEG3+ proportion at the pan‐cancer level, which may be attributed to m6A‐related post‐transcriptional modifications. Through activation trajectory analysis of the major CAF subtypes, it was determined that elevated MEG3 expression in CAFs leads to an increase in PDGFRA expression. This, in turn, promotes CAF activation and transformation into an MEG3+ adipogenic CAF (MACAF) subtype, which is more sensitive to Dasatinib. MACAF‐related cell–cell interactions highlighted that MACAF could enhance the epithelial‐mesenchymal transition process in tumor cells via the TGF‐β pathway, promoting tumor cell migration and possibly contributing to tumor progression and invasiveness. Notably, patients with higher MACAF scores experience unfavorable prognoses and poor response rates to checkpoint inhibitor‐based immunotherapy, suggesting a correlation between MACAF and immunosuppressive microenvironment shaping. Our findings provide novel insights of the MEG3 in CAF activation and highlight the potential value of the MACAF score for therapeutic strategies design involving Dasatinib and immunotherapy.

YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment

Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N6-methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.

Diversity in gut microbiota among colorectal cancer patients: findings from a case–control study conducted at a Tunisian University Hospital

PurposeGlobally, colorectal cancer (CRC) is among the most prevalent cancers. One distinctive feature of colorectal cancer is its close relationship to the gut microbiota, which is a crucial component of the tumor microenvironment. Over the last ten years, research has demonstrated that colorectal cancer is accompanied with dysbiosis of gut bacteria, fungi, viruses, and Archaea, and that these alterations may be causal. Objectives: This study aimed to evaluate the disruption of the microorganism composition in the intestine, especially bacteria and to determine their relationship with colorectal cancer.MethodsAn evaluation system for determining colorectal cancer (CRC) risk and prognosis can be established more easily with the help of accurate gut microbiota profiling. Stool samples from 14 CRC patients and 13 controls were collected and the flora relative abundance was measured using targeted quantitative PCR (qPCR) assays to evaluate diagnostic potential of selected biomarkers: Streptococcus gallolyticus and Enterococcus faecalis. Culture and MALDI-TOF mass spectrometry were coupled to identify the gut microbiota in both colorectal cancer and control groups.ResultsCompared with controls, the gut microbiota of CRC patients showed an increase in the abundance of Enterococcus, Fusobacterium and Streptococcus. At the species level, the CRC enriched bacterium including Escherichia coli, Enterococcus faecalis, Fusobacterium nucleatum, Streptococcus gallolyticus, Flavoni fractorplautii and Eggerthella lenta acted as promising biomarkers for early detection of CRC.ConclusionThis study highlights the potential of gut microbiota biomarkers as a promising non-invasive tool for the accurate detection and distinction of individuals with CRC.

Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.

Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis. We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

Regulation and Crosstalk of Cells and Factors in the Pancreatic Cancer Microenvironment.

Pancreatic cancer is a highly malignant form of cancer that distinguishes itself from other gastrointestinal tumors through significant fibrosis and unique perineural invasion. These characteristics underscore the complexity of neural regulation within the pancreatic cancer Tumor Microenvironment (TME). This review aimed to explore the regulatory mechanisms and crosstalk among stromal cells and their factors within the pancreatic cancer microenvironment. We begin by reviewing the major components of the pancreatic cancer microenvironment, analyzing interactions among crucial cell types, such as Cancer-associated Fibroblasts (CAFs) and immune cells, and revealing the dynamic changes between tumor cells and surrounding nerves, immune, and stromal cells. We discuss the role of neural factors, including the Nerve Growth Factor (NGF) and Brain-derived Neurotrophic Factor (BDNF), in the progression of pancreatic cancer and the mechanisms by which the sympathetic and parasympathetic nervous systems regulate tumor cell growth, migration, and invasion. Interactions among stromal cells, cytokines, and neural factors in the pancreatic cancer microenvironment promote fibrosis and perineural invasion. A deeper understanding of the regulation and crosstalk among components in the pancreatic cancer microenvironment offers new perspectives for inhibiting fibrosis and perineural invasion in pancreatic cancer.

Pancreatic stellate cells and the interleukin family: Linking fibrosis and immunity to pancreatic ductal adenocarcinoma (Review).

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of cancer with a low survival rate. A successful treatment strategy should not be limited to targeting cancer cells alone, but should adopt a more comprehensive approach, taking into account other influential factors. These include the extracellular matrix (ECM) and immune microenvironment, both of which are integral components of the tumor microenvironment. The present review describes the roles of pancreatic stellate cells, differentiated cancer‑associated fibroblasts and the interleukin family, either independently or in combination, in the progression of precursor lesions in pancreatic intraepithelial neoplasia and PDAC. These elements contribute to ECM deposition and immunosuppression in PDAC. Therapeutic strategies that integrate interleukin and/or stromal blockade for PDAC immunomodulation and fibrogenesis have yielded inconsistent results. A deeper comprehension of the intricate interplay between fibrosis, and immune responses could pave the way for more effective treatment targets, by elucidating the mechanisms and causes of ECM fibrosis during PDAC progression.

Metformin impacts the differentiation of mouse bone marrow cells into macrophages affecting tumour immunity

BackgroundEpidemiological studies suggest that metformin reduces the risk of developing several types of cancer, including gliomas, and improves the overall survival in cancer patients. Nevertheless, while the effect of metformin on cancer cells has been extensively studied, its impact on other components of the tumour microenvironment, such as macrophages, is less understood. ResultsMetformin-treated mouse bone marrow cells differentiate into spindle-shaped macrophages exhibiting increased phagocytic activity and tumour cell cytotoxicity coupled with modulated expression of co-stimulatory molecules displaying reduced sensitivity to inflammatory cues compared with untreated cells. Transcriptional analyses of metformin-treated mouse bone marrow-derived macrophages show decreased expression levels of pro-tumour genes, including Tgfbi and Il1β, related to enhanced mTOR/HIF1α signalling and metabolic rewiring towards glycolysis. SignificanceOur study provides novel insights into the immunomodulatory properties of metformin in macrophages and its potential application in preventing tumour onset and in cancer immunotherapy.

AI drives the assessment of lung cancer microenvironment composition

PurposeThe abundance and distribution of tumor-infiltrating lymphocytes (TILs) as well as that of other components of the tumor microenvironment is of particular importance for predicting response to immunotherapy in lung cancer (LC). We describe here a pilot study employing artificial intelligence (AI) in the assessment of TILs and other cell populations, intending to reduce the inter- or intra-observer variability that commonly characterizes this evaluation. DesignWe developed a machine learning-based classifier to detect tumor, immune, and stromal cells on hematoxylin and eosin-stained sections, using the open-source framework QuPath. We evaluated the quantity of the aforementioned three cell populations among 37 LC whole slide images regions of interest, comparing the assessments made by five pathologists, both before and after using graphical predictions made by AI, for a total of 1110 quantitative measurements. ResultsOur findings indicate noteworthy variations in score distribution among pathologists and between individual pathologists and AI. The AI-guided pathologist's evaluations resulted in reduction of significant discrepancies across pathologists: three comparisons showed a loss of significance (p > 0.05),whereas other four showed a reduction in significance (p > 0.01). ConclusionsWe show that employing a machine learning approach in cell population quantification reduces inter- and intra-observer variability, improving reproducibility and facilitating its use in further validation studies.

Roles of intralesional bacteria in the initiation and progression of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the predominant form of head and neck cancer, often diagnosed at late stages, resulting in a poor prognosis. Recent studies indicate a potential association between OSCC and microbial presence. Microorganisms have been identified in various tumors and lesions, including OSCC and oral potentially malignant disorders (OPMDs). Intralesional microbiota are considered important components of the tumor microenvironment (TME) and may contribute to carcinogenesis. Sources were collected through thorough searches of databases PubMed and Embase. The review focused on microbial characteristics, potential origins, and their impact on cancer progression. Bacteria display varying abundance and diversity throughout the stages of OSCC and OPMDs. Intraleisional bacteria may have diverse sources, including not only oral plaque and saliva but also potentially the gut. Intralesional bacteria have both pro-carcinogenic and anti-carcinogenic effects, affecting processes like cell proliferation, invasion, and immune response. Intralesional microbiota are crucial in OSCC and OPMDs, influencing both disease progression and treatments. Despite their significance, challenges like inconsistent sampling and microbial identification remain. Future research is required to fully understand their role and improve clinical applications.

Eupafolin hinders cross-talk between gastric cancer cells and cancer-associated fibroblasts by abrogating the IL18/IL18RAP signaling axis

BackgroundCancer-associated fibroblasts (CAFs) are involved in the progression of gastric cancer (GC) as a critical component of the tumor microenvironment (TME), yet specific interventions remain limited. Natural products hold a promising application prospect in the field of anti-tumor in view of their high activity and ease of binding with biological macromolecules. However, the role of natural products in modulating the cross-talk between CAFs and GC cells has not been fully investigated. PurposeThe aim of this study was to identify a potential therapeutic target in CAFs and then screen for natural small molecule drugs with anti-tumor activity against this target. MethodsIntegrating bioinformatics analysis of public databases and experimental validation of human samples and cell lines to identify a candidate target in CAFs. Molecular docking and biolayer interferometry technique were utilized for screening potential natural small molecule drugs. The efficacy and underlying mechanisms of the candidates were explored in vitro and in vivo through techniques such as lentiviral infection, cell spheroids culture, immunoprecipitation and cells-derived xenografts. ResultsIL18 receptor accessory protein (IL18RAP) was found to be overexpressed in CAFs derived from GC tissues and facilitated the protumor function of CAFs on GC. Based on virtual screening and experimental validation, we identified a natural product, eupafolin, that interfered with IL18 signaling. Phenotyping studies confirmed that the proliferation, spheroids formation and tumorigenesis of GC cells facilitated by CAFs were greatly attenuated by eupafolin both in vitro and in vivo. Mechanistically, eupafolin impeded the formation of IL18 receptor (IL18R) complex by directly binding to IL18RAP, thus blocking IL18-mediated nuclear factor kappa B (NF-κB) activation and reduced the synthesis and secretion of IL6 in CAFs. As a consequence, it inactivated signal transducer and activator of transcription 3 (STAT3) in GC cells. ConclusionThis study provides new evidence that IL18 signaling regulates the cross-talk between GC cells and CAFs. And it highlights a novel pharmacological role of eupafolin in inhibiting IL18 signaling, thereby curbing the development of GC via modulating CAFs.