title: LKB1 loss links serine metabolism to DNA methylation and tumorigenesis.
abstract: Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumours to inhibition of serine biosynthesis and DNA methylation. Thus, we define a hypermetabolic state that incites changes in the epigenetic landscape to support tumorigenic growth of LKB1-mutant cells, while resulting in potential therapeutic vulnerabilities.
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Filippos
authors: F
authors: Kottakis
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Brandon N
authors: BN
authors: Nicolay
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Ahlima
authors: A
authors: Roumane
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Rahul
authors: R
authors: Karnik
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Hongcang
authors: H
authors: Gu
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Julia M
authors: JM
authors: Nagle
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Myriam
authors: M
authors: Boukhali
authors: UNC, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors: Michele C
authors: MC
authors: Hayward
authors: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Yvonne Y
authors: YY
authors: Li
authors: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Ting
authors: T
authors: Chen
authors: Evans Center for Interdisciplinary Research, Department of Medicine, Mitochondria ARC, Boston University School of Medicine, Boston, Massachusetts 02118, USA.|Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, UCLA David Geffen School of Medicine, Los Angeles, California 90095, USA.
authors: Marc
authors: M
authors: Liesa
authors: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors: Peter S
authors: PS
authors: Hammerman
authors: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Kwok Kin
authors: KK
authors: Wong
authors: UNC, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
authors: D Neil
authors: DN
authors: Hayes
authors: Evans Center for Interdisciplinary Research, Department of Medicine, Mitochondria ARC, Boston University School of Medicine, Boston, Massachusetts 02118, USA.|Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, UCLA David Geffen School of Medicine, Los Angeles, California 90095, USA.
authors: Orian S
authors: OS
authors: Shirihai
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Nicholas J
authors: NJ
authors: Dyson
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Wilhelm
authors: W
authors: Haas
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Alexander
authors: A
authors: Meissner
authors: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Nabeel
authors: N
authors: Bardeesy
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D005998:Glycine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D010183:Pancreatic Ducts / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics; D012436:S-Adenosylmethionine / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D018626:Retroelements; D012694:Serine; D012436:S-Adenosylmethionine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000637:Transaminases; C022393:phosphoserine aminotransferase; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D005998:Glycine