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Loss of PKM2 in Lgr5⁺ intestinal stem cells promotes colitis-associated colorectal cancer.

ABSTRACT: The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5⁺ intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2^ΔLgr5-Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2^ΔLgr5-Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2^ΔLgr5-Tx mice while PKM2^ΔLgr5-Veh mice had low- and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5⁺ ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5⁺ cells obtained from colon polyps of PKM2^ΔLgr5-Tx mice was significantly increased when compared with PKM2^ΔLgr5-Veh mice. Cancer organoids from PKM2^ΔLgr5-Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.

SUBMITTER: Kim Y

PROVIDER: S-EPMC6470145 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Loss of PKM2 in Lgr5<sup>+</sup> intestinal stem cells promotes colitis-associated colorectal cancer.

Kim Yeji Y Lee Yong-Soo YS Kang Sung Wan SW Kim Seungil S Kim Tae-Young TY Lee Su-Hyun SH Hwang Sung Wook SW Kim Jihun J Kim Eun Na EN Ju Jin-Sung JS Park Yun-Yong YY Kweon Mi-Na MN

Scientific reports 20190417 1

The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5<sup>+</sup> intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion o ...[more]

PMID: 30996297

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Project description:The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Dataset Information

Loss of PKM2 in Lgr5⁺ intestinal stem cells promotes colitis-associated colorectal cancer.

Publications

Loss of PKM2 in Lgr5<sup>+</sup> intestinal stem cells promotes colitis-associated colorectal cancer.

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Dataset Information

Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer.

Publications

Loss of PKM2 in Lgr5<sup>+</sup> intestinal stem cells promotes colitis-associated colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Loss of PKM2 in Lgr5⁺ intestinal stem cells promotes colitis-associated colorectal cancer.