mTOR and HIF-1 -mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

Dulbecco Center for Cancer Research, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2009; 106(27):11137-11142. DOI: 10.1073/pnas.0900465106


Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11
serine/threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade
of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among
mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and
tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single
agent results in a dramatic suppression of preexisting GI polyps in LKB1+/− mice. However, the key targets of mTORC1 in LKB1-deficient
tumors remain unknown. We demonstrate here that these polyps, and LKB1- and AMPK-deficient mouse embryonic fibroblasts, show
dramatic up-regulation of the HIF-1α transcription factor and its downstream transcriptional targets in an rapamycin-suppressible
manner. The HIF-1α targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that
LKB1+/− mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal
hamartomas. Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1
signaling, HIF-1α, and GLUT1 levels. Furthermore, like HIF-1α and its target genes, the FDG-PET signal in the GI tract of
these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment
and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung
cancers bearing LKB1 mutations.

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    • "At the same time, AMPK also promotes catabolism, including glucose uptake and subsequent glycolysis, fatty acid oxidation, and autophagy (Hardie et al., 2012). AMPK appears to act as either a tumor suppressor or an oncogene , depending on the context (Faubert et al., 2013; Jeon et al., 2012; Shackelford et al., 2009, 2013). The indirect AMPK activator metformin has activity in cell line models of AML (Green et al., 2010). "
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    ABSTRACT: AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Cell Reports
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    • "Recently, pancreatic deletion of the LKB1/STK11 gene in mice has been shown to result in acinar polarity defects and serous cystic neoplasms [35]. LKB1 mutation also affects hypoxic signaling [36], [37]. In humans, LKB1 loss-of-function mutations have been linked to the development of Peutz-Jeghers syndrome and IPMNs, both high-risk factors for pancreatic cancer [30], [61], [62]. "
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    ABSTRACT: CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissuehigh/seralow-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.
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    • "We also observed hallmarks of the Warburg effect, notably increased intratumor glucose and lactate levels, in primary LKB1-deficient ErbB2-postive tumors, suggesting that LKB1 regulates glucose metabolism in tumors in situ. This is consistent with previous work showing enhanced glucose uptake by fluorodeoxyglucose (18F) positron emission tomography in benign LKB1+/− colon polyps [45]. Metabolic analysis also revealed that LKB1 loss promotes an increased bioenergetic state in ErbB2-positive tumors; the level of energy storage metabolites, particularly ATP and creatine, were elevated in LKB1-null tumors. "
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    ABSTRACT: Germline and somatic mutations in STK11, the gene encoding the serine/threonine kinase LKB1, are strongly associated with tumorigenesis. While loss of LKB1 expression has been linked to breast cancer, the mechanistic role of LKB1 in regulating breast cancer development, metastasis, and tumor metabolism has remained unclear. We have generated and analyzed transgenic mice expressing ErbB2 in the mammary epithelium of LKB1 wild-type or LKB1-deficient mice. We have also utilized ErbB2-expressing breast cancer cells in which LKB1 levels have been reduced using shRNA approaches. These transgenic and xenograft models were characterized for the effects of LKB1 loss on tumor initiation, growth, metastasis and tumor cell metabolism. We demonstrate that loss of LKB1 promotes tumor initiation and induces a characteristic shift to aerobic glycolysis ('Warburg effect') in a model of ErbB2-mediated breast cancer. LKB1-deficient breast cancer cells display enhanced early tumor growth coupled with increased cell migratory and invasive properties in vitro. We show that ErbB2-positive tumors deficient for LKB1 display a pro-growth molecular and phenotypic signature characterized by elevated Akt/mTOR signaling, increased glycolytic metabolism, as well as increased bioenergetic markers both in vitro and in vivo. We also demonstrate that mTOR contributes to the metabolic reprogramming of LKB1-deficient breast cancer, and is required to drive glycolytic metabolism in these tumors; however, LKB1-deficient breast cancer cells display reduced metabolic flexibility and increased apoptosis in response to metabolic perturbations. Together, our data suggest that LKB1 functions as a tumor suppressor in breast cancer. Loss of LKB1 collaborates with activated ErbB2 signaling to drive breast tumorigenesis and pro-growth metabolism in the resulting tumors.
    Full-text · Article · Aug 2013
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