@article{40c90c47896a4ef2923ffa3b7d0046f1,
title = "Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis",
abstract = "Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.",
keywords = "PKM2, cancer metabolism, glucose oxidation, metastasis, methionine oxidation, pancreatic cancer, redox signaling",
author = "Dan He and Huijin Feng and Belen Sundberg and Jiaxing Yang and Justin Powers and Christian, {Alec H.} and Wilkinson, {John E.} and Cian Monnin and Daina Avizonis and Thomas, {Craig J.} and Friedman, {Richard A.} and Kluger, {Michael D.} and Hollingsworth, {Michael A.} and Grandgenett, {Paul M.} and Klute, {Kelsey A.} and Toste, {F. Dean} and Chang, {Christopher J.} and Chio, {Iok In Christine}",
note = "Funding Information: We thank the members of the Chio and Chang labs, Drs. Richard Baer, Adolfo Ferrando, Swarnali Acharyya (Columbia University Irving Medical Center), and Dr. David Tuveson (Cold Spring Harbor Laboratory) for the helpful discussion; Dr. Gijs R. van den Brink (University of Amsterdam) for sharing their Noggin-FC-expressing cells and Dr. Tuveson for sharing the human organoids; Dr. Hanina Hibshoosh (Columbia University) for the procurement of surgically resected PDA specimens; A. Killiea and M. Fischer (UC Berkeley Tissue Culture Facility) and M. Salemi and B. Phinney (UC Davis Proteomics Core) for the technical assistance, and H. Iwashita (UC Berkeley) for providing the PG1-FM; A. I. Nesvizhskii (University of Michigan) for the assistance on MSFragger. This work was performed with the support of Columbia University Herbert Irving Comprehensive Cancer Center Flow Cytometry , Confocal and Specialized Microscopy , Small Animal Imaging, and Molecular Pathology Shared Resources ( NIH / NCI Cancer Center Support Grant, P30-CA13696 ); the UC Davis Proteomics Core ( S10-OD21801 ); the GCRC metabolomics Innovation Resource ( Dr. John R and Clara M. Fraser Memorial Trust , the Terry Fox Foundation , and the Qu{\'e}bec Breast Cancer Foundation ); and the University of Nebraska Medical Center{\textquoteright}s Rapid Autopsy Program for Pancreas ( P50CA127297 , U01CA210240 , P30CA36727 , and R50CA211462 ). Other support includes the Tang Distinguished Scholarship (D.H.), the National Science Foundation Graduate Fellowship (A.H.C., DGE 1106400 ), the National Institute of Health grants ( R01-GM139245 to C.J.C., R01-CA240654 to I.I.C.C., and the Division of Preclinical Innovation , National Center for Advancing Translational Research , and the Center for Cancer Research , NCI to C.J.T.), the Novartis-Berkeley Center for Proteomics and Chemical Technologies (to C.J.C. and F.D.T.), the Agilent Design Program (to C.J.C.), and the Pershing Square Sohn Research Alliance (to I.I.C.C.). Funding Information: We thank the members of the Chio and Chang labs, Drs. Richard Baer, Adolfo Ferrando, Swarnali Acharyya (Columbia University Irving Medical Center), and Dr. David Tuveson (Cold Spring Harbor Laboratory) for the helpful discussion; Dr. Gijs R. van den Brink (University of Amsterdam) for sharing their Noggin-FC-expressing cells and Dr. Tuveson for sharing the human organoids; Dr. Hanina Hibshoosh (Columbia University) for the procurement of surgically resected PDA specimens; A. Killiea and M. Fischer (UC Berkeley Tissue Culture Facility) and M. Salemi and B. Phinney (UC Davis Proteomics Core) for the technical assistance, and H. Iwashita (UC Berkeley) for providing the PG1-FM; A. I. Nesvizhskii (University of Michigan) for the assistance on MSFragger. This work was performed with the support of Columbia University Herbert Irving Comprehensive Cancer Center Flow Cytometry, Confocal and Specialized Microscopy, Small Animal Imaging, and Molecular Pathology Shared Resources (NIH/NCI Cancer Center Support Grant, P30-CA13696); the UC Davis Proteomics Core (S10-OD21801); the GCRC metabolomics Innovation Resource (Dr. John R and Clara M. Fraser Memorial Trust, the Terry Fox Foundation, and the Qu{\'e}bec Breast Cancer Foundation); and the University of Nebraska Medical Center's Rapid Autopsy Program for Pancreas (P50CA127297, U01CA210240, P30CA36727, and R50CA211462). Other support includes the Tang Distinguished Scholarship (D.H.), the National Science Foundation Graduate Fellowship (A.H.C. DGE 1106400), the National Institute of Health grants (R01-GM139245 to C.J.C. R01-CA240654 to I.I.C.C. and the Division of Preclinical Innovation, National Center for Advancing Translational Research, and the Center for Cancer Research, NCI to C.J.T.), the Novartis-Berkeley Center for Proteomics and Chemical Technologies (to C.J.C. and F.D.T.), the Agilent Design Program (to C.J.C.), and the Pershing Square Sohn Research Alliance (to I.I.C.C.). D.H. C.J.C. and I.I.C.C. conceived the study. D.H. H.F. and B.S. performed the experiments and analyzed the data. J.Y. and J.P. performed therapeutic dosing and tumor volume measurements. A.H.C. and F.D.T. provided the Ox-alkyne probes. J.E.W. performed the IHC scoring. D.A. and C.M. ran and analyzed the 13C-glucose experiments. C.J.T. provided TEPP46 and assisted with the analysis of metabolic experiments. R.A.F. performed the bioinformatic analysis. M.D.K. M.A.H. P.M.G. K.A.K. collected the patient-derived specimens. D.H. C.J.C. H.F. and I.I.C.C. interpreted the results and wrote the manuscript. All authors participated in discussing and finalizing the manuscript. C.J.C. F.D.T. and A.H.C. are inventors on patent applications related to the redox-active reagents for methionine conjugation. C.J.T. is listed as an inventor on patents related to PKM2 activators. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = aug,
day = "18",
doi = "10.1016/j.molcel.2022.06.005",
language = "English (US)",
volume = "82",
pages = "3045--3060.e11",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "16",
}