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Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production [Ribo-Seq]

ABSTRACT: Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has propelled the development of systemic arginine depletion strategies, which are clinically safe but have limited clinical benefit. Here, we demonstrate that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference is caused by a selective decrease in tRNAArg(UCU) levels after arginine deprivation, linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein production at the endogenous level. We further demonstrate that such inducible neopeptides are immunogenic, laying the foundation for improved cancer therapy combining systemic arginine depletion strategies with T-cell receptor-based targeting of non-classical neoantigens.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309063 | GEO | 2026/04/28

REPOSITORIES: GEO

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Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production

Project description:Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has propelled the development of systemic arginine depletion strategies, which are clinically safe but have limited clinical benefit. Here, we demonstrate that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference is caused by a selective decrease in tRNAArg(UCU) levels after arginine deprivation, linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein production at the endogenous level. We further demonstrate that such inducible neopeptides are immunogenic, laying the foundation for improved cancer therapy combining systemic arginine depletion strategies with T-cell receptor-based targeting of non-classical neoantigens.

2026-04-28 | GSE309074 | GEO

Arginine deprivation of ASS1-deficient cancers drives mistranslation and shared neoepitope production

Project description:Arginine biosynthesis is frequently suppressed in human cancer due to loss of argininosuccinate synthetase 1 (ASS1) expression, rendering cancer cells reliant on extracellular arginine. This observation propelled the development of systemic arginine depletion strategies, which are clinically safe but showed limited efficacy. Here, we show that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon-preference is caused by a selective decrease of tRNAArg(UCU) levels after arginine deprivation, which is linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein and neoepitope production at the endogenous level.

2026-04-28 | PXD068912 | Pride

Characterization of Gene Expression in ASS1-Deficient Breast Cancer Cells

Project description:Analysis of mechanism underlying the metabolic effects of ADI-PEG20 at gene expression level. The hypothesis tested in the present study was that ASS1-deficient breast cancer cells would be arginine-auxotrophs and would therefore be sensitive to arginine starvation. Results provide important information of the response of ASS1-deficient breast cancer cells to ADI-PEG20-treatment, such as the suppression of mRNAs encoding mitochondrial respiratory chain proteins. Total RNA obtained from ADI-treated, or ADI- and L-arginine-treated 231 cells compared to untreated cells.

2014-05-20 | E-GEOD-53838 | biostudies-arrayexpress

Characterization of Gene Expression in ASS1-Deficient Breast Cancer Cells

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Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production

Project description:Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production

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Decreased DEPTOR expression is involved in enhanced cell motility and invasion capability of ASS1 (Argininosuccinate synthetase 1) -KO cells

Project description:To elucidate the mechanisms underlying the enhanced sensitivity to arginine in the absence of ASS1 expression in endometrial cancer cells, we performed DNA microarray-based gene expression profiling using HEC1B harboring the empty vector (EV) and ASS1-knockout (KO) HEC1B cells. Since accumulating evidence has shown that arginine regulates mTORC1 activity, we focused on the expression patterns of genes related to the mTOR complex. ASS1-KO HEC1B cells had lower DEPTOR transcript abundance than EV cells, while no significant difference was observed in the expression levels of genes coding for other mTOR complex components such as mTOR, RAPTOR, or RICTOR. Indeed, immunoblot analysis confirmed that the expression level of DEPTOR protein was significantly decreased in ASS1-KO HEC1B cells, which were cultured in arginine-replete conditions.

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ASS1 deficiency defines a therapeutic vulnerability in Philadelphia chromosome-positive acute lymphoblastic leukaemia

Project description:Amino acid deprivation with L-asparaginase is a cornerstone of treatment in acute lymphoblastic leukaemia (ALL), but clinical challenges limit its use in adults. Deficiency in the enzyme argininosuccinate synthase (ASS1-low) confers arginine auxotrophy, defining a dependence on extracellular arginine, and represents an analogue metabolic vulnerability that is targetable through arginine deprivation. We analysed transcriptomic data across >550 adult B-ALL cases to establish clinico-biologic characteristics of low ASS1 expression identifying the Philadelphia chromosome-positive (Ph+) ALL subgroup as a stereotypical arginine auxotroph within molecularly diverse B-ALL. Functionally, arginine deprivation with pegargiminase induced robust apoptosis in both Ph+ ALL cell lines and primary samples in an ASS1 dependant manner and was highly effective as a monotherapy treatment in independent Ph+ ALL patient derived xenografts. Mechanistically, arginine deprivation induces endoplasmic reticulum stress mediated apoptosis which was orthogonal to tyrosine kinase inhibition (TKI) mediated outcomes. Using in vitro and in vivo models of non-genetically mediated TKI-resistance, we demonstrate pegargiminase and TKI combinations robustly eradicates TKI resistant leukaemia. Thus, we establish ASS1 deficiency (ASS1-low) as a therapeutically actionable vulnerability in Ph+ ALL and a strategy to bypass TKI-resistance, supporting clinical evaluation of arginine deprivation as a novel adjunct to chemotherapy-free treatment.

2026-05-25 | GSE330924 | GEO

Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production [Ribo-Seq]

Project description:Arginine deprivation of ASS1-deficient cancers drives mistranslation and neoepitope production [Ribo-Seq]

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Stenotrophomonas sp. ASS1

Project description:Stenotrophomonas sp. ASS1 Genome sequencing

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Chromatin accessibility governs the differential response of cancer and T-cells to arginine starvation (Illumina HumanHT-12 V4.0 beadchip)

Project description:Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase but it is unclear how these cancers, but not T-cells, tolerate arginine depletion. Here, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPbeta binding to a previously uncharacterized enhancer within ASS1. T-cells cannot induce ASS1, despite the presence of active ATF4 and CEBPbeta, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation which disrupts ATF4/CEBPbeta binding and target gene transcription. We find that T-cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T-cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.

2021-05-10 | GSE137033 | GEO

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