TY - JOUR
T1 - Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells
AU - Halbrook, Christopher J.
AU - Thurston, Galloway
AU - Boyer, Seth
AU - Anaraki, Cecily
AU - Jiménez, Jennifer A.
AU - McCarthy, Amy
AU - Steele, Nina G.
AU - Kerk, Samuel A.
AU - Hong, Hanna S.
AU - Lin, Lin
AU - Law, Fiona V.
AU - Felton, Catherine
AU - Scipioni, Lorenzo
AU - Sajjakulnukit, Peter
AU - Andren, Anthony
AU - Beutel, Alica K.
AU - Singh, Rima
AU - Nelson, Barbara S.
AU - Van Den Bergh, Fran
AU - Krall, Abigail S.
AU - Mullen, Peter J.
AU - Zhang, Li
AU - Batra, Sandeep
AU - Morton, Jennifer P.
AU - Stanger, Ben Z.
AU - Christofk, Heather R.
AU - Digman, Michelle A.
AU - Beard, Daniel A.
AU - Viale, Andrea
AU - Zhang, Ji
AU - Crawford, Howard C.
AU - Pasca di Magliano, Marina
AU - Jorgensen, Claus
AU - Lyssiotis, Costas A.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
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U2 - 10.1038/s43018-022-00463-1
DO - 10.1038/s43018-022-00463-1
M3 - Article
C2 - 36411320
AN - SCOPUS:85142268769
SN - 2662-1347
VL - 3
SP - 1386
EP - 1403
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -