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Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

ABSTRACT: Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

PROVIDER: PRJNA850408 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19736878_1.fastq.gz	Fastqsanger.gz
	SRR19736878_2.fastq.gz	Fastqsanger.gz
	SRR19736879_1.fastq.gz	Fastqsanger.gz
	SRR19736879_2.fastq.gz	Fastqsanger.gz
	SRR19736880_1.fastq.gz	Fastqsanger.gz

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Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

Project description:To investigate the effects of ADI-PEG20 and chloroquine treatment alone and in combination on the growth of Ass1 KO murine sarcomas, the BVMA01R murine sarcoma cell line was grafted into syngeneic C57BL/6J mice, and tumors were treated as indicated. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 tumors from each of the 4 treatment groups.

2023-06-19 | GSE206382 | GEO

Discovery and Targeting of a Noncanonical Mechanism of Sarcoma Resistance to ADI-PEG20 Mediated by the Microenvironment.

Project description:PurposeMany cancers lack argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 reexpression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20.Experimental designTumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and in vivo.ResultsConditional Ass1 KO affected neither tumor initiation nor growth rates in a sarcoma model, contradicting the prevalent idea that ASS1 silencing confers a proliferative advantage. Ass1 KO cells grew robustly through arginine starvation in vivo, while ADI-PEG20 remained completely lethal in vitro, evidence that pointed toward a novel mechanism of resistance mediated by the microenvironment. Coculture with Ass1-competent fibroblasts rescued growth through macropinocytosis of vesicles and/or cell fragments, followed by recycling of protein-bound arginine through autophagy/lysosomal degradation. Inhibition of either macropinocytosis or autophagy/lysosomal degradation abrogated this growth support effect in vitro and in vivo.ConclusionsNoncanonical, ASS1-independent tumor resistance to ADI-PEG20 is driven by the microenvironment. This mechanism can be targeted by either the macropinocytosis inhibitor imipramine or the autophagy inhibitor chloroquine. These safe, widely available drugs should be added to current clinical trials to overcome microenvironmental arginine support of tumors and improve patient outcomes.

| S-EPMC10425734 | biostudies-literature

Brachypodium distachyon strain:Adi-15 | cultivar:Adi-15

Project description:Brachypodium distachyon strain:Adi-15 | cultivar:Adi-15 Genome sequencing

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Brachypodium distachyon strain:Adi-4 | cultivar:Adi-4

Project description:Brachypodium distachyon strain:Adi-4 | cultivar:Adi-4 Genome sequencing

| PRJNA333716 | ENA

Brachypodium distachyon strain:Adi-9 | cultivar:Adi-9

Project description:Brachypodium distachyon strain:Adi-9 | cultivar:Adi-9 Genome sequencing

| PRJNA333717 | ENA

Identifying the differentially expressed genes between ADI-PEG20 resistant and parental Ju77 cell line

Project description:Identifying the differentially expressed genes between ADI-PEG20 resistant and parental Ju77 cell line

2016-07-12 | GSE73970 | GEO

Effect of ADI-PEG 20 treatment on murine liver chromatin landscape at single cell resolution.

Project description:We demonstrate the effects of 4-week ADI-PEG 20 on murine liver chromatin accessibility by single-cell ATAC-sequencing

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Brachypodium distachyon cultivar:Adi-12

Project description:Brachypodium distachyon cultivar:Adi-12 Genome sequencing

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Brachypodium distachyon cultivar:Adi-10

Project description:Brachypodium distachyon cultivar:Adi-10 Genome sequencing

| PRJNA337383 | ENA

Brachypodium hybridum cultivar:Adi-P1

Project description:Brachypodium hybridum Adi-P1 Resequencing genome sequencing

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