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LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis [RNA-seq]

ABSTRACT: Intermediary metabolism generates substrates for covalent modification of chromatin, enabling potential coupling of metabolic states and epigenetic control. Here, we identify such a network as a major component of oncogenic transformation downstream of the LKB1 tumour suppressor. LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, however the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing genetically engineered mouse and primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced mTOR-dependent induction of the serine-glycine-one carbon network coupled to S-adenosylmethionine generation. In concert, DNA methyltransferases (DNMT1, DNMT3A) are upregulated, leading to elevation in genomic 5-methylcytosine levels, with particular enrichment at retrotransposon elements, associated with silencing of retrotransposon transcription. Correspondingly, LKB1 deficiency renders cells highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from LKB1 loss and KRAS activation that fuels changes in the epigenetic landscape. This state is critically required for the tumourigenic program of LKB1-mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets.

ORGANISM(S): Mus musculus

PROVIDER: GSE86144 | GEO | 2016/10/24

SECONDARY ACCESSION(S): PRJNA340411

REPOSITORIES: GEO

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Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. By bulk gene expression profiling, Lkb1 restoration promotes the expression of markers and functions of alveolar type II cells, suggesting that LKB1 may govern a cell-state transition within the neoplastic epithelial compartment. Purpose: To determine whether the restoration of Lkb1 drives changes in cell state and/or abundance within established oncogenic KRAS-driven lung tumors. Approach: To control LKB1 function in vivo, we generated an Lkb1XTR allele, which enables Cre-mediated disruption of Lkb1 expression during tumor development and subsequent FLPo-ERT2-mediated reactivation of Lkb1 within established tumors. Lung tumors were initiated in KT;Lkb1XTR/XTR (non-restorable) and KT;Lkb1XTR/XTR;FLPo-ERT2 (restorable) mice with Lenti-Cre. Following tumor development, lung tumor-bearing were treated with either corn oil vehicle or tamoxifen for two weeks prior to isolating specifically neoplastic cells by FACS for single cell RNA-seq. Results: Single cell analysis revealed that the neoplastic epithelial compartment was composed of alveolar type I- and type II-like subpopulations, a Krt8+ transitional state, an actively proliferating subpopulations, and an indeterminate subpopulation partially resembling the alveolar type II-like identity. Dynamic inference analyses indicated that the indeterminate population represents an intermediate state along the alveolar type II to alveolar type I trans-differentiation trajectory. Notably, the indeterminate cluster was more proliferative than the alveolar type II-like subpopulation and exhibited higher expression of Sox9, which is a marker of distal lung epithelial progenitors. There was a marked shift in the epithelial compartment from the indeterminate state to alveolar type II epithelial-like identity in response to Lkb1 restoration. Conclusions: LKB1 governs the transition between a proliferative progenitor-like population and mature alveolar type II-like identity within oncogenic KRAS-driven lung tumors

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LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis [RNA-seq]

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