Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [Caprin-1 RNA-IP-seq]

ABSTRACT: Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [Caprin-1 RNA-IP-seq]

PROVIDER: PRJNA1054982 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR27294708_1.fastq.gz	Fastqsanger.gz
	SRR27294708_2.fastq.gz	Fastqsanger.gz
	SRR27294709_1.fastq.gz	Fastqsanger.gz
	SRR27294709_2.fastq.gz	Fastqsanger.gz
	SRR27294710_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 8

Similar Datasets

Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [EXOSC10 RNA-IP-seq]

Project description:Programmed death-ligand 1, PD-L1 (CD274), is expressed by cancer cells to facilitate immune evasion. PD-L1 also exerts pro-survival functions in cancer cells, and mechanisms that regulate intracellular PD-L1 signaling remain largely unknown. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF-b-receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), which are highly resistant to immunotherapy. Mechanistically, we show here that internalized PD-L1, mediated by its cytoplasmic domain, including the S278/S279 residues, in response to CerS4/C18/C20-ceramide downregulation or genetic loss, interacts with an RNA-binding protein Caprin-1 in various metastatic breast cancer models, including 4T1 orthotopic breast allografts and mammary tumors developed in MMTV-PyMT/CerS4-/- compared to MMTV-PyMT/CerS4+/+ mice, consistent with Shh/TGFBR1/Wnt/b-catenin activation in-vivo. Genetic loss or molecular knockdown of CerS4 in breast tumors also resulted in increased infiltration of FoxP3+ T regs that are known to suppress anti-tumor immunity. Targeting the CerS4/Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody in mice containing metastatic breast tumors in which CerS4 is downregulated vastly decreased tumor growth and metastasis, leading to inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and multiple patient datasets, demonstrate a mechanism to define intracellular metastatic signaling by PD-L1 internalization in response to alterations of ceramide metabolism, providing a new therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2024-07-07 | GSE250638 | GEO

Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [Caprin-1 RNA-IP-seq]

2024-07-07 | GSE250637 | GEO

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2025-05-07 | PXD053108 | Pride

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2024-07-07 | GSE267312 | GEO

Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [EXOSC10 RNA-IP-seq]

Project description:Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [EXOSC10 RNA-IP-seq]

| PRJNA1054984 | ENA

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

| PRJNA1111042 | ENA

Endosomal sorting regulates PD-L1 trafficking and enhances immunotherapy efficacy

Project description:Immune-checkpoint inhibition affecting the PD-1/PD-L1 pathway is a robust clinical approach to treat cancer. Unfortunately, antibody-binding-caused PD-L1 internalization and recycling can lead to resistance and reduced clinical efficacy. Inhibiting lysosome-mediated PD-L1 degradation is necessary to preserve the PD-L1 level that recycles back to the cell membrane. It remains unclear whether there exists a specific mechanism that regulates the trafficking of PD-L1 into endosomes or lysosomes. We identified transmembrane-9 superfamily members 1-4 (TM9SF1-4) through a targeted CRISPR screen, with TM9SF2 emerging as a critical regulator. Mechanistically, TM9SF2 interacts with phosphoglycerate kinase 1 (PGK1), facilitating the endosomal recycling of PD-L1 back to the plasma membrane. Simultaneously, this interaction complex inhibits the pathway of lysosomal PD-L1 degradation via eliminating lysosome carrier HIP1R. Genetic or chemical inhibition of TM9SF2 or PGK1 reduced PD-L1 levels, enhancing the efficacy of immunotherapy. Furthermore, metabolomics-guided screening revealed that treatment with Cer(d18:1/26:0) or the overexpression of its synthase CERS3 disrupted the TM9SF2-PGK1 complex, shifting the process from endosomal recycling to lysosomal degradation. This transition led to a reduction in PD-L1 expression and increased immune responses in murine tumors. Our findings establish the TM9SF2-PGK1 complex as a signaling hub responsive to ceramide, regulating PD-L1 sorting in the endosomal system and contributing to cancer immune evasion. These insights highlight potential therapeutic strategies to augment immune responses by controlling PD-L1 trafficking.

2026-06-08 | PXD061780 | Pride

Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.

2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress

DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Project description:To identify the potential signaling pathway involved in DENR KO cells upon PD-L1 production, we harvested IFNγ-treated control and DENR KO cells for RNA-seq. Bioinformatic analysis of the RNA-seq data showed that 114 genes, including PD-L1, were significantly downregulated in DENR KO cells, and multiple classical signaling pathways, including JAK-STAT, and PD-L1, were enriched.

2022-02-28 | GSE183980 | GEO

DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Project description:DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

| PRJNA762565 | ENA