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STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging

ABSTRACT: STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging

PROVIDER: PRJNA741475 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14915316.fastq.gz	Fastqsanger.gz
	SRR14915317.fastq.gz	Fastqsanger.gz
	SRR14915318.fastq.gz	Fastqsanger.gz
	SRR14915319.fastq.gz	Fastqsanger.gz
	SRR14915320.fastq.gz	Fastqsanger.gz

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STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging

Project description:Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these new immuno-modulatory agents is the lack of pharmacodynamic biomarkers indicative of increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe [18F]-fluorothymidine ([18F]FLT). Accordingly, IFN treatment stimulates cancer cell [18F]FLT uptake in the presence of thymidine and this effect is dependent on TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR widely expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Treatment with a small molecule STING agonist triggers IFN signaling-dependent TYMP expression in PDAC cells and enhances both subcutaneous and orthotopic tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a novel pharmacodynamic biomarker for PRR agonist-based immunotherapies in PDAC and possibly other malignancies characterized by elevated STING expression.

2021-08-30 | GSE178901 | GEO

68Ga-FAPI PET imaging assesses tumor immunity and guides TGF-β inhibition to sensitize metastatic colorectal cancer to immunotherapy

Project description:BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor β (TGF-β) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of cancer immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using gallium 68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) for PET/CT imaging to guide TGF-β inhibition and sensitize metastatic colorectal cancer (CRC) to immunotherapy. A total of 131 patients with metastatic CRC underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Fourteen patients underwent surgery after the imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed. Mouse cohorts of metastatic CRC were treated with TGF-β receptor (TGF-βR) inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to stratify and guide patients with CRC for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.

2023-12-19 | GSE247303 | GEO

Molecular imaging of lymphoid organs and immune activation using PET with a new 18F-labeled 2’-deoxycytidine analog

Project description:Differential gene expression between naive and activated CD8+ T cells was assessed using microarray analysis to determine target genes for new positron emission tomography (PET) probe screening, in particular for molecular imaging of lymphoid organs and immune activation. Keywords: cell activation comparison

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RNA-seq of Sting overexpressing orthotopic pancreas tumors

Project description:Murine pancreatic PKCY tumor cells (p53fl/+;KrasLSL-G12D/+;Pdx1-Cre;Rosa26LSL-YFP) were engineered to overexpress Sting or empty vector control. Tumor cells were orthotopically transplanted into the pancreas of syngeneic littermates. Tumors were harvested and RNA seq for transcriptomic differences was performed.

2021-09-06 | E-MTAB-10722 | biostudies-arrayexpress

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Project description:Interventions: 18F-Fluciclatide PET scan Primary outcome(s): Assess feasibility and sensitivity of imaging tumor angiogenesis in PDAC and colorectal adenocarcinoma, using 18F-Fluciclatide. When successful, the data of this study will allow for a larger trial. Study Design: N/A: single arm study, Open (masking not used), N/A , unknown, Other

| 2442142 | ecrin-mdr-crc

Glucose metabolic profiles evaluated by PET associated with molecular characteristic landscape of gastric cancer

Project description:Although FDG-PET is widely used in cancer, its role in gastric cancer (GC) is still controversial due to variable [18F]fluorodeoxyglucose ([18F]FDG) uptake. Here, we investigate the molecular landscape of GC and its association with glucose metabolic profiles noninvasively evaluated by [18F]FDG PET. Based on a genetic signature, PETscore, representing [18F]FDG avidity, was developed by imaging data acquired from thirty patient-derived xenografts (PDX). Five genes, PLS1, PYY, HBQ1, SLC6A5, NAT16, were identified for the PETscore, which was validated in independent cohorts by qRT-PCR and RNA-sequencing. By applying the PETscore on the Cancer Genome Atlas (TCGA), a significant association between glucose uptake and tumor mutational burden as well as genomic alterations was identified in GC. Our findings suggest that molecular characteristics are underlying the diverse metabolic profiles of GC. Diverse glucose metabolic profiles may apply to precise diagnostic and therapeutic approaches for GC.

2022-04-05 | GSE164961 | GEO

Imaging tumor bloodvessels using 18F-Fluciclatide PET scan.

Project description:Primary objectives: Assess feasibility and sensitivity of imaging tumor angiogenesis in PDAC and colorectal adenocarcinoma, using 18F-Fluciclatide. When successful, the data of this study will allow for a larger trial. Primary endpoints: Sensitivity of 18F-Fluciclatide.

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[18F]FLT-PET as a Predictive Imaging Biomaker of Treatment Responses to Regorafenib

Project description:Regorafenib is approved in the treatment for metastatic colorectal cancer patients who have been progressed after standard therapies, however, there has not been a predictive biomarker. The investigators designed this study to investigate whether [18F]FLT-PET might paly a role as a predictive imaging biomarker of treatment responses to regorafenib.

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Functional Genomics and Molecular Imaging of Liver Disease and Cancer

Project description:<p>Molecular imaging with 18F-fluorocholine PET/CT reveals two distinct imaging phenotypes for hepatocellular carcinoma (HCC) as a potential source of non-invasive insight into its molecular heterogeneity. Using gene set enrichment analyses, we found 18F-fluorocholine-avid tumors to be significantly enriched by genes comprising a subset of previously published HCC-related gene signatures. Significant gene sets included those from existing molecular classification systems for HCC as well as gene signatures predictive of clinical outcomes after tumor resection. PET/CT imaging using 18F-fluorocholine might therefore provide surrogate information about tumor molecular characteristics and prognosis in HCC.</p>

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