Single‐Cell Transcriptomic Analysis Reveals an Aggressive Basal‐Like Tumor Cell Subpopulation Associated With Poor Prognosis in Intrahepatic Cholangiocarcinoma

Journal of Gastroenterology and Hepatology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

ABSTRACT Background and Aim Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer whose incidence increasing globally. However, high tumor heterogeneity of ICC restricts efficacy available systematic therapies. We aim to dissect utilizing high‐resolution single‐cell RNA sequencing identify novel therapeutic targets. Methods performed (scRNA‐seq) 26 samples from 23 patients spatial transcriptomic six sections patients. Bulk RNA‐seq data two public datasets were used for validation. Additionally, immunohistochemical staining multiplex immunofluorescence conducted validate infiltration distribution cells in microenvironment. Results discovered that malignant exhibited a remarkably degree heterogeneity. identified basal‐like cell subpopulation characterized by expression basal epithelial related genes including KRT5, KRT6A, KRT17. The was activation MET signaling extracellular matrix organization associated with invasion correlated poor prognosis. Cell–cell communication analysis further showed significant HGF‐MET interaction between inflammatory cancer–associated fibroblasts (iCAFs) cells. found iCAFs major source HGF environment contributed phenotype formation axis. Conclusions an aggressive subpopulation, which prognosis ICC. pathway contributes aggressiveness serves as target

Язык: Английский

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Literature-scaled immunological gene set annotation using AI-powered immune cell knowledge graph (ICKG)

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Large scale application of single-cell and spatial omics in models patient samples has led to the discovery many novel gene sets, particularly those from an immunotherapeutic context. However, biological meaning sets been interpreted anecdotally through over-representation analysis against canonical annotation databases limited complexity, granularity, accuracy. Rich functional descriptions individual genes immunological context exist literature but are not semantically summarized perform set analysis. To overcome this limitation, we constructed immune cell knowledge graphs (ICKGs) by integrating over 24,000 published abstracts recent using large language (LLMs). ICKGs effectively integrate across individual, peer-reviewed studies, enabling accurate, verifiable graph-based reasoning. We validated quality data obtained independently cytokine stimulation, CRISPR knock-out, protein-protein interaction experiments. Using ICKGs, achieved rich, holistic, accurate including that were unannotated existing approaches use for clinical applications. created interactive website ( https://kchen-lab.github.io/immune-knowledgegraph.github.io/ ) ICKG-based annotations visualize supporting rationale.

Язык: Английский

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Unraveling the YAP1-TGFβ1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Abstract Due to their pivotal roles in tumor progression and therapy resistance, cancer-associated fibroblasts (CAF) are considered key therapeutic targets with loss of stromal androgen receptor (AR) a poorly understood hallmark aggressive prostate cancer (PCa). A paucity pre-clinical models however has hampered functional studies CAF heterogeneity. We demonstrate that our newly-generated biobank contains three FAP + -fibroblast subtypes, each unique molecular traits. Cultures an early-activated phenotype expressed the highest levels AR exhibited AR-dependent growth. Consistently, cells expressing early-activation markers co-expressed nuclear clinical specimens were enriched pre-neoplastic lesions/low-grade PCa. Conversely, myofibroblastic (myCAF), which low vitro vivo proliferatively-insensitive signaling modulation, constituted predominant subpopulation stromogenic high-grade PCa castration-resistant LACP9 patient-derived xenografts. Exacerbation myCAF state upon castration LAPC9-bearing hosts underscored these findings. Mechanistically, was driven by NFκB-TGFβ1-YAP1 axis, whose combined targeting synergistically repressed hallmarks impaired autophagic flux, effects potentiated enzalutamide resulting cell death. Collectively, findings provide mechanistic rationale for adjuvant YAP1-TGFβ axis improve patient outcomes.

Язык: Английский

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Antigen-presenting cancer associated fibroblasts enhance antitumor immunity and predict immunotherapy response

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 4, 2025

Cancer-associated fibroblasts (CAF) play a crucial role in tumor progression and immune regulation. However, the functional heterogeneity of CAFs remains unclear. Here, we identify antigen-presenting (apCAF), characterized by high MHC II expression, gastric cancer (GC) tumors find that apCAFs are preferentially located near tertiary lymphoid structures. Both vivo vitro experiments demonstrate promote T cell activation enhances its cytotoxic proliferative capacities, thereby strengthening cell-mediated anti-tumor immunity. Additionally, facilitate polarization macrophages toward pro-inflammatory phenotype. These polarized macrophages, turn, formation apCAFs, creating positive feedback loop amplifies responses. Notably, baseline immunotherapy responders across various types exhibit higher levels infiltration. This study advances understanding GC highlights as potential biomarker for predicting response pan-cancer.

Язык: Английский

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The fibroinflammatory response in cancer

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Язык: Английский

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Immune-featured stromal niches associate with response to neoadjuvant immunotherapy in oral squamous cell carcinoma

Cell Reports Medicine, Год журнала: 2025, Номер 6(3), С. 102024 - 102024

Опубликована: Март 1, 2025

Язык: Английский

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Single-cell sequencing reveals tumor microenvironment features associated with the response to neoadjuvant immunochemotherapy in oral squamous cell carcinoma

Cancer Immunology Immunotherapy, Год журнала: 2025, Номер 74(5)

Опубликована: Март 19, 2025

In recent years, immune checkpoint inhibitors have shown promise as neoadjuvant therapies in the treatment of locally advanced oral squamous cell carcinoma (OSCC). However, factors affecting tumor response to (ICIs) remain unclear. This study aimed analyze impact chemoimmunotherapy (NACI) on microenvironment OSCC via single-cell RNA sequencing, with goal optimizing strategies. We analyzed biopsy, primary tumor, matched metastatic lymph node, and normal node samples from four patients receiving two cycles tislelizumab (200 mg), albumin-bound paclitaxel (260 mg/m2), cisplatin (60–75 3-week intervals between each cycle. explored characteristics tumors nodes NACI. identified major subpopulations (C9 C11), high expression C11 subgroup-specific genes had a lower survival rate. FOXP3+ CD4 eTreg cells were found potentially suppress response. that NACI enhances antitumor immunity by promoting proliferation granzyme-expressing CD8+ T effector while simultaneously diminishing effect CD4+ Treg-mediated suppression. Furthermore, was effective suppressing inflammatory processes mediated myeloid tumors, contributing its effects. The CCL19+ fibroblastic reticular (FRC) subgroup significantly associated efficacy OSCC. FRCs primarily exert their effects through interactions lymphocytes –CXCL12‒CXCR4 axis. landscape relation clinical Our findings offer valuable insights into patient responses highlight potential new therapeutic targets for future management

Язык: Английский

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Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 17, 2025

Wnt5a, a representative Wnt ligand that activates the β-catenin-independent pathway, has been shown to promote tumorigenesis. However, it is unclear where Wnt5a produced and how affects colon cancer aggressiveness. In this study, we demonstrate expressed in fibroblasts near luminal side of tumor, its depletion suppresses mouse formation. To characterize specific fibroblast subtype, meta-analysis human single-cell RNA-seq data performed. The results show hypoxia-induced inflammatory (InfFib), accompanied by activation HIF2. Moreover, maintains InfFib through suppression angiogenesis mediated soluble VEGF receptor1 (Flt1) secretion from endothelial cells, thereby inducing further hypoxia. also produces epiregulin, which promotes growth. Here, acts on hypoxic environment InfFib, contributing progression InfFib.

Язык: Английский

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Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans

Nature Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 22, 2025

Язык: Английский

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Research Progress of Fibroblasts in Human Diseases

Biomolecules, Год журнала: 2024, Номер 14(11), С. 1478 - 1478

Опубликована: Ноя. 20, 2024

Fibroblasts, which originate from embryonic mesenchymal cells, are the predominant cell type seen in loose connective tissue. As main components of internal environment that cells depend on for survival, fibroblasts play an essential role tissue development, wound healing, and maintenance homeostasis. Furthermore, also involved several pathological processes, such as fibrosis, cancers, some inflammatory diseases. In this review, we analyze latest research progress fibroblasts, summarize biological characteristics physiological functions delve into disease pathogenesis explore treatment approaches fibroblast-related

Язык: Английский

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