SLC1A3 contributes to L-asparaginase resistance in solid tumors

Jianhui Sun; Remco Nagel; Esther A. Zaal; Alejandro Piñeiro Ugalde; Ruiqi Han; Natalie Proost; Ji Ying Song; Abhijeet Pataskar; Artur Burylo; Haigen Fu; Gerrit J. Poelarends; Marieke van de Ven; Olaf van Tellingen; Celia R. Berkers; Reuven Agami

doi:10.15252/embj.2019102147

SLC1A3 contributes to L-asparaginase resistance in solid tumors

Jianhui Sun, Remco Nagel, Esther A. Zaal, Alejandro Piñeiro Ugalde, Ruiqi Han, Natalie Proost, Ji Ying Song, Abhijeet Pataskar, Artur Burylo, Haigen Fu, Gerrit J. Poelarends, Marieke van de Ven, Olaf van Tellingen, Celia R. Berkers, Reuven Agami^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

L-asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

Original language	English
Article number	e102147
Journal	EMBO Journal
Volume	38
Issue number	21
DOIs	https://doi.org/10.15252/embj.2019102147
Publication status	Published - 4 Oct 2019

Funding

We acknowledge all the members in Agami laboratory for valuable discussions. We thank Roderick Beijersbergen for providing the CRISPR‐Cas9 library plasmid; Ron Kerkhoven, Roel Kluin, and Iris de Rink from the NKI Genomics Core Facility for assisting with deep sequencing experiments and analysis. We appreciated the assistance from NKI Experimental Animal Pathology, Radionuclides Center, and Flow cytometry facilities. We also thank the people from the Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA) at the NKI for performing the intervention studies. This work was supported by funds of the China Scholarship Council (201503250056) to J.S., the Dutch cancer society (KWF 0315/2016), and the European research council (ERC‐PoC 665317) to R.A.

Keywords

aspartate/glutamate
genome-wide CRISPR screen
L-asparaginase
SLC1A3
solid tumors

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title = "SLC1A3 contributes to L-asparaginase resistance in solid tumors",

abstract = "L-asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.",

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AU - Sun, Jianhui

AU - Nagel, Remco

AU - Zaal, Esther A.

AU - Ugalde, Alejandro Piñeiro

AU - Han, Ruiqi

AU - Proost, Natalie

AU - Song, Ji Ying

AU - Pataskar, Abhijeet

AU - Burylo, Artur

AU - Fu, Haigen

AU - Poelarends, Gerrit J.

AU - van de Ven, Marieke

AU - van Tellingen, Olaf

AU - Berkers, Celia R.

AU - Agami, Reuven

PY - 2019/10/4

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AB - L-asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

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ER -

SLC1A3 contributes to L-asparaginase resistance in solid tumors

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