LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

Liu, Wenjin; Monahan, Kimberly B.; Pfefferle, Adam D.; Shimamura, Takeshi; Sorrentino, Jessica A.; Chan, Keefe T.; Roadcap, David W.; Ollila, David W.; Thomas, Nancy E.; Castrillón, Diego H.; Miller, C. Ryan; Perou, Charles M.; Wong, Kwok-Kin; Bear, James E.; Sharpless, Norman E.

doi:10.1016/j.ccr.2012.03.048

Cited by 116 publications

(128 citation statements)

References 50 publications

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“…Consistent with previous work (Carretero et al, 2010;Liu et al, 2012), we observed delayed closure upon reintroduction of LKB1 compared with the null cells (Fig. 2 E).…”

Section: Loss Of Lkb1 Does Not Affect Invadopodia Formation In Melanosupporting

confidence: 82%

“…S1 A; Liu et al, 2012). We confirmed that reexpression of LKB1 (addback) promoted phosphorylation of AMPK and its downstream effector acetyl-CoA carboxylase in three LKB1-deficient cell lines (LKB498, LKB878, and TKL2; Fig.…”

Section: Introductionsupporting

confidence: 64%

“…+ subpopulation (Liu et al, 2012), Src family kinase regulation (Carretero et al, 2010;Liu et al, 2012), cellular metabolism via AMPK (Shaw et al, 2004b), and resistance to anoikis (Cheng et al, 2009). Our data suggest a new mechanism by which LKB1 may limit tumor progression, directly related to invasion and metastasis: loss of LKB1 leads to loss of responsiveness to inhibitory ECM cues.…”

Section: Cd24mentioning

confidence: 86%

“…For example, Kras expression rapidly cooperates with inactivation of several other tumor suppressor genes (e.g., p53 and p16/INK4a) to promote locally aggressive melanoma or nonsmall cell lung cancer, but only Lkb1-deficient tumors exhibit widespread hematogenous and lymphatic metastasis (Ji et al, 2007;Carretero et al, 2010;Liu et al, 2012). In both models, Lkb1 inactivation is associated with increased expression of CD24, expansion of tumor-initiating fractions, and activation of Src family kinases, but the direct mechanism whereby LKB1 loss facilitates metastasis is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

Chan¹,

Asokan²,

King³

et al. 2014

J Exp Med

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Abbreviations used in this paper: 4-OHT, 4-hydroxy-tamoxifen; AMPK, AMPactivated protein kinase; ANOVA, analysis of variance; BRSK, brain-specific kinase; DN, dominant negative; FMI, forward migration index; MARK, microtubule affinity-regulating kinase; MMP, matrix metalloproteinase; NUAK, nua kinase; PDMS, polymethylsiloxane; qRT-PCR, quantitative RT-PCR; SIK, salt-inducible kinase; YAP, Yes-associated protein.

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“…Consistent with previous work (Carretero et al, 2010;Liu et al, 2012), we observed delayed closure upon reintroduction of LKB1 compared with the null cells (Fig. 2 E).…”

Section: Loss Of Lkb1 Does Not Affect Invadopodia Formation In Melanosupporting

confidence: 82%

Section: Introductionsupporting

confidence: 64%

Section: Cd24mentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

Chan¹,

Asokan²,

King³

et al. 2014

J Exp Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Disruption of polarity, as altered metabolism, is a hallmark of epithelial cancer progression [11], and the relative roles of these processes downstream of LKB1 in growth control is an area of active investigation. Indeed, inactivation of LKB1 produces dramatic invasive and migratory phenotypes in different cancer models [12][13][14]. The findings of Jeon et al [9] may thus presage that the LKB1-AMPK axis is only a minor component of the LKB1 tumor suppressor program compared to its functions in metabolic adaptation and cell survival.…”

mentioning

confidence: 85%

LKB1-AMPK axis revisited

Kottakis

Bardeesy

2012

Cell Res

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The LKB1 tumor suppressor encodes a serine-threonine kinase whose substrates control cell metabolism, polarity, and motility. LKB1 is a major mediator of the cellular response to energy stress via activation of the master regulator of energy homeostasis, AMPK. While mutational inactivation of LKB1 promotes the development of many types of epithelial cancer, a recent report in Nature by Jeon et al. demonstrates that the LKB1-AMPK pathway can also have an unexpected positive role in tumorigenesis, acting to maintain metabolic homeostasis and attenuate oxidative stress thereby supporting the survival of cancer cells.Normal mammalian cells possess adaptive mechanisms that enable coupling of nutrient availability with demand via integrated control of growth and metabolism. The widespread deregulation of these processes is now recognized as a prominent hallmark of all cancers. A key nutrient sensor in normal and cancer cells is the LKB1-AMPK axis, which is critical for maintenance of metabolic homeostasis [1]. In response to energy stress (and resulting increase in AMP:ATP ratio), LKB1 phosphorylates AMPK, which in turn phosphorylates numerous substrates controlling diverse metabolic processes, with the net effect of shifting the balance from anabolic to catabolic function and thereby restoring cellular ATP levels.

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The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer

Wang,

Liu,

Zheng

et al. 2023

FEBS Letters

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The liver kinase B1 (LKB1)/AMP‐activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/β‐catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/β‐catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and β‐catenin and supports the phase transition of β‐catenin. Both processes suppress Wnt/β‐catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/β‐catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation.

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LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma

Cited by 116 publications

References 50 publications

LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

LKB1-AMPK axis revisited

The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer

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