Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells

被引：43

作者：

Halbrook, Christopher J. ^{[1
,2
,3
,15
]}

Thurston, Galloway ^{[3
]}

Boyer, Seth ^{[3
]}

Anaraki, Cecily ^{[1
]}

Jimenez, Jennifer A. ^{[3
]}

McCarthy, Amy ^{[4
]}

Steele, Nina G. ^{[5
,16
]}

Kerk, Samuel A. ^{[3
]}

Hong, Hanna S. ^{[3
]}

Lin, Lin ^{[3
]}

Law, Fiona V. ^{[1
]}

Felton, Catherine ^{[4
]}

Scipioni, Lorenzo ^{[6
]}

Sajjakulnukit, Peter ^{[3
]}

Andren, Anthony ^{[3
]}

Beutel, Alica K. ^{[1
]}

Singh, Rima ^{[1
]}

Nelson, Barbara S. ^{[3
]}

van den Bergh, Fran ^{[3
]}

Krall, Abigail S. ^{[7
]}

Mullen, Peter J. ^{[7
]}

Zhang, Li ^{[3
]}

Batra, Sandeep ^{[8
]}

Morton, Jennifer P. ^{[9
]}

Stanger, Ben Z. ^{[10
]}

Christofk, Heather R. ^{[7
]}

Digman, Michelle A. ^{[6
]}

Beard, Daniel A. ^{[3
]}

Viale, Andrea ^{[11
]}

Zhang, Ji ^{[12
]}

Crawford, Howard C. ^{[3
,16
]}

Pasca di Magliano, Marina ^{[5
,13
]}

Jorgensen, Claus ^{[4
]}

Lyssiotis, Costas A. ^{[3
,13
,14
]}

机构：

[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA

[2] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92697 USA

[3] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[4] Univ Manchester, Canc Res UK Manchester Inst, Manchester, Lancs, England

[5] Univ Michigan, Dept Surg, Ann Arbor, MI USA

[6] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA USA

[7] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA USA

[8] Indiana Univ Hlth, Riley Hosp Children, Indianapolis, IN USA

[9] Univ Glasgow, Canc Res UK Beatson Inst, Inst Canc Sci, Glasgow, Scotland

[10] Univ Penn, Dept Med, Gastroenterol Div, Philadelphia, PA 19104 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Gen Med, Div Canc Med, Houston, TX USA

[12] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA

[13] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[14] Univ Michigan, Dept Internal Med, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA

[15] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA

[16] Henry Ford Hlth Syst, Dept Surg, Detroit, MI USA

来源：

NATURE CANCER | 2022年 / 3卷 / 11期

关键词：

METABOLIC HETEROGENEITY; TUMOR METABOLISM; BIOSYNTHESIS; ADAPTATION; GROWTH; CHAIN;

D O I：

10.1038/s43018-022-00463-1

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Halbrook et al. report two metabolic subgroups of pancreatic ductal adenocarcinoma cells defined by differential integrated stress response and asparagine production that permit symbiosis and phenformin resistance. The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

引用

页码：1386 / +

页数：32

共 61 条

[1] A Stromal Lysolipid-Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression [J].

Auciello, Francesca R. ;

Bulusu, Vinay ;

Oon, Chet ;

Tat-Mulder, Jacqueline ;

Berry, Mark ;

Bhattacharyya, Sohinee ;

Tumanov, Sergey ;

Allen-Petersen, Brittany L. ;

Link, Jason ;

Kendsersky, Nicholas D. ;

Vringer, Esmee ;

Schug, Michelle ;

Novo, David ;

Hwang, Rosa F. ;

Evans, Ronald M. ;

Nixon, Colin ;

Dorrell, Craig ;

Morton, Jennifer P. ;

Norman, Jim C. ;

Sears, Rosalie C. ;

Kamphorst, Jurre J. ;

Sherman, Mara H. .

CANCER DISCOVERY, 2019, 9 (05) :617-627

[2]

Barbosa-Tessmann IP, 2000, J BIOL CHEM, V275, P26976

[3] Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression [J].

Bernard, Vincent ;

Semaan, Alexander ;

Huang, Jonathan ;

San Lucas, F. Anthony ;

Mulu, Feven C. ;

Stephens, Bret M. ;

Guerrero, Paola A. ;

Huang, Yanqing ;

Zhao, Jun ;

Kamyabi, Nabiollah ;

Sen, Subrata ;

Scheet, Paul A. ;

Taniguchi, Cullen M. ;

Kim, Michael P. ;

Tzeng, Ching-Wei ;

Katz, Matthew H. ;

Singhi, Aatur D. ;

Maitra, Anirban ;

Alvarez, Hector A. .

CLINICAL CANCER RESEARCH, 2019, 25 (07) :2194-2205

[4] An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis [J].

Birsoy, Kivanc ;

Wang, Tim ;

Chen, Walter W. ;

Freinkman, Elizaveta ;

Abu-Remaileh, Monther ;

Sabatini, David M. .

CELL, 2015, 162 (03) :540-551

[5]

Boyer S, 2022, ELIFE, V11, DOI [10.7554/eLife.73796, 10.7554/eLife.73796.sa0, 10.7554/eLife.73796.sa1, 10.7554/eLife.73796.sa2]

[6] Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors [J].

Daemen, Anneleen ;

Peterson, David ;

Sahu, Nisebita ;

McCord, Ron ;

Du, Xiangnan ;

Liu, Bonnie ;

Kowanetz, Katarzyna ;

Hong, Rebecca ;

Moffat, John ;

Gao, Min ;

Boudreau, Aaron ;

Mroue, Rana ;

Corson, Laura ;

O'Brien, Thomas ;

Qing, Jing ;

Sampath, Deepak ;

Merchant, Mark ;

Yauch, Robert ;

Manning, Gerard ;

Settleman, Jeffrey ;

Hatzivassiliou, Georgia ;

Evangelista, Marie .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (32) :E4410-E4417

[7] Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance [J].

Dalin, Simona ;

Sullivan, Mark R. ;

Lau, Allison N. ;

Grauman-Boss, Beatrice ;

Mueller, Helen S. ;

Kreidl, Emanuel ;

Fenoglio, Silvia ;

Luengo, Alba ;

Lees, Jacqueline A. ;

Vander Heiden, Matthew G. ;

Lauffenburger, Douglas A. ;

Hemann, Michael T. .

CANCER RESEARCH, 2019, 79 (22) :5723-5733

[8] Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing [J].

Davis, Ryan T. ;

Blake, Kerrigan ;

Ma, Dennis ;

Gabra, Mari B. Ishak ;

Hernandez, Grace A. ;

Phung, Anh T. ;

Yang, Ying ;

Maurer, Dustin ;

Lefebvre, Austin E. Y. T. ;

Alshetaiwi, Hamad ;

Xiao, Zhengtao ;

Liu, Juan ;

Locasale, Jason W. ;

Digman, Michelle A. ;

Mjolsness, Eric ;

Kong, Mei ;

Werb, Zena ;

Lawson, Devon A. .

NATURE CELL BIOLOGY, 2020, 22 (03) :310-+

[9] The phasor approach to fluorescence lifetime imaging analysis [J].

Digman, Michelle A. ;

Caiolfa, Valeria R. ;

Zamai, Moreno ;

Gratton, Enrico .

BIOPHYSICAL JOURNAL, 2008, 94 (02) :L14-L16

[10] Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia [J].

Douer, Dan ;

Yampolsky, Henry ;

Cohen, Lewis J. ;

Watkins, Kristy ;

Levine, Alexandra M. ;

Periclou, Antonia P. ;

Avramis, Vassilios I. .

BLOOD, 2007, 109 (07) :2744-2750

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