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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE269446 | GEO | 2025/06/07

REPOSITORIES: GEO

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In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

Project description:Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.

2025-06-07 | GSE269445 | GEO

In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vitro]

2025-06-07 | GSE269444 | GEO

In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion

Project description:In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion

| PRJNA1121930 | ENA

In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vitro]

Project description:In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vitro]

| PRJNA1121934 | ENA

In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

Project description:In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vivo]

| PRJNA1121933 | ENA

Development of a cellularly degradable PEG hydrogel to promote articular cartilage extracellular matrix deposition.

Project description:Healing articular cartilage remains a significant clinical challenge because of its limited self-healing capacity. While delivery of autologous chondrocytes to cartilage defects has received growing interest, combining cell-based therapies with scaffolds that capture aspects of native tissue and promote cell-mediated remodeling could improve outcomes. Currently, scaffold-based therapies with encapsulated chondrocytes permit matrix production; however, resorption of the scaffold does not match the rate of production by cells leading to generally low extracellular matrix outputs. Here, a poly (ethylene glycol) (PEG) norbornene hydrogel is functionalized with thiolated transforming growth factor (TGF-β1) and cross-linked by an MMP-degradable peptide. Chondrocytes are co-encapsulated with a smaller population of mesenchymal stem cells, with the goal of stimulating matrix production and increasing bulk mechanical properties of the scaffold. The co-encapsulated cells cleave the MMP-degradable target sequence more readily than either cell population alone. Relative to non-degradable gels, cellularly degraded materials show significantly increased glycosaminoglycan and collagen deposition over just 14 d of culture, while maintaining high levels of viability and producing a more widely-distributed matrix. These results indicate the potential of an enzymatically degradable, peptide-functionalized PEG hydrogel to locally influence and promote cartilage matrix production over a short period. Scaffolds that permit cell-mediated remodeling may be useful in designing treatment options for cartilage tissue engineering applications.

| S-EPMC4487633 | biostudies-literature

Long Noncoding RNA MIAT Modulates the Extracellular Matrix Deposition in Leiomyomas by Sponging MiR-29 Family.

Project description:The objective of this study was to determine the expression and functional role of a long noncoding RNA (lncRNA) MIAT (myocardial infarction-associated transcript) in leiomyoma pathogenesis. Leiomyoma compared with myometrium (n = 66) expressed significantly more MIAT that was independent of race/ethnicity and menstrual cycle phase but dependent on MED12 (mediator complex subunit 12) mutation status. Leiomyomas bearing the MED12 mutation expressed higher levels of MIAT and lower levels of microRNA 29 family (miR-29a, -b, and -c) compared with MED12 wild-type leiomyomas. Using luciferase reporter activity and RNA immunoprecipitation analysis, MIAT was shown to sponge the miR-29 family. In a 3-dimensional spheroid culture system, transient transfection of MIAT siRNA in leiomyoma smooth muscle cell (LSMC) spheroids resulted in upregulation of miR-29 family and downregulation of miR-29 targets, collagen type I (COL1A1), collagen type III (COL3A1), and TGF-β3 (transforming growth factor β-3). Treatment of LSMC spheroids with TGF-β3 induced COL1A1, COL3A1, and MIAT levels, but repressed miR-29 family expression. Knockdown of MIAT in LSMC spheroids blocked the effects of TGF-β3 on the induction of COL1A1 and COL3A1 expression. Collectively, these results underscore the physiological significance of MIAT in extracellular matrix accumulation in leiomyoma.

| S-EPMC8459448 | biostudies-literature

MicroRNA-375 Suppresses Extracellular Matrix Degradation and Invadopodial Activity in Head and Neck Squamous Cell Carcinoma.

Project description:ContextHead and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer with an association with locoregional recurrence and lymph node metastasis. We have previously reported that low microRNA-375 (miR-375) expression levels correlate with poor patient survival, increased locoregional recurrence, and distant metastasis. Increasing miR-375 expression in HNSCC cell lines to levels found in normal cells results in suppressed invasive properties. HNSCC invasion is mediated in part by invadopodia-associated degradation of the extracellular matrix.ObjectiveTo determine whether elevated miR-375 expression in HNSCC cell lines also affects invadopodia formation and activity.DesignFor evaluation of the matrix degradation properties of the HNSCC lines, an invadopodial matrix degradation assay was used. The total protein levels of invadopodia-associated proteins were measured by Western blot analyses. Immunoprecipitation experiments were conducted to evaluate the tyrosine phosphorylation state of cortactin. Human protease arrays were used for the detection of the secreted proteases. Quantitative real time-polymerase chain reaction measurements were used to evaluate the messenger RNA (mRNA) expression of the commonly regulated proteases.ResultsIncreased miR-375 expression in HNSCC cells suppresses extracellular matrix degradation and reduces the number of mature invadopodia. Higher miR-375 expression does not reduce cellular levels of selected invadopodia-associated proteins, nor is tyrosine phosphorylation of cortactin altered. However, HNSCC cells with higher miR-375 expression had significant reductions in the mRNA expression levels and secreted levels of specific proteases.ConclusionsMicroRNA-375 regulates invadopodia maturation and function potentially by suppressing the expression and secretion of proteases.

| S-EPMC4628565 | biostudies-literature

Immune Evasion by Head and Neck Cancer: Foundations for Combination Therapy.

Project description:Head and neck cancer is disfiguring and deadly, and contemporary treatment has fallen short in terms of morbidity and mortality. The rich immune infiltrate within these tumors designates them as prime candidates for immunotherapy and success with these drugs has been documented for recurrent and metastatic head and neck cancer. Still, single-agent immunotherapy has generated either only transient responses or durable response in only a minority subset of patients. Mapping the immune escape mechanisms enacted by head and neck cancer within the tumor microenvironment allows for rational design of strategies to overcome this tolerance. We outline the immune pathway derangements within the head and neck cancer microenvironment and discuss combination treatment strategies to overcome the limitations of immunologic monotherapy.

| S-EPMC7304339 | biostudies-literature

In vivo CRISPR screens reveal NOTCH regulators suppressing Head and Neck Squamous Cell Carcinoma in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-02-04 | GSE140497 | GEO