LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

Chan, Keefe T.; Asokan, Sreeja B.; King, Samantha J.; Tang, Bo; Dubose, Evan S.; Liu, Wenjin; Berginski, Matthew E.; Simon, Jeremy M.; Davis, Ian J.; Gomez, Shawn M.; Sharpless, Norman E.

doi:10.1084/jem.21112oia68

Cited by 7 publications

(16 citation statements)

References 34 publications

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“…Small differences across a cell in the signaling pathways and protrusion dynamics are summed over time, leading to larger differences in cell movement and, ultimately, the haptotactic response. This might be a unique feature of slow moving mesenchymal cells such as fibroblasts, but it could also be a useful paradigm for studying directional migration in other contexts, such as in 1 dimensional migration, collective migration of epithelial cells or the invasion of tumor cells (Chan et al, 2014).…”

Section: Discussion a Working Model For Haptotaxismentioning

confidence: 99%

“…In that work, we demonstrated that loss of LKB1 and its direct downstream target MARK in melanoma leads to the loss of haptotaxis and of more invasive migration phenotypes (Chan et al, 2014). Tumor cells are known to ignore tissue boundaries, and failure to sense differences in the ECM could be one mechanism by which they ignore these boundaries.…”

Section: The Relevance Of Haptotaxis For Tumor Progression and Metastmentioning

confidence: 94%

“…In order to dissect the mechanism of haptotaxis, we utilized microfluidic chambers to generate gradients of fluorescent fibronectin and directly observed cells during directional migration, as described previously (Wu et al, 2012;Chan et al, 2014). Two methods were developed to control for gradient differences between chambers.…”

Section: Differential Lamellipodial Protrusion Dynamics Regulate Haptmentioning

confidence: 99%

“…7A). 3D haptotaxis fibronectin gradients can be formed by plating fibroblasts inside the central chamber of our microfluidics chamber in 3D collagen gels (Chan et al, 2014). Fluorescent fibronectin is then added through the source channel, whereby it forms a gradient across the collagen gel that interacts with the fibrils.…”

Section: Differential Lamellipodial Protrusion Dynamics Regulate Haptmentioning

confidence: 99%

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Lamellipodia are crucial for haptotactic sensing and response

King

Asokan

Haynes

et al. 2016

Journal of Cell Science

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Haptotaxis is the process by which cells respond to gradients of substrate-bound cues, such as extracellular matrix proteins (ECM); however, the cellular mechanism of this response remains poorly understood and has mainly been studied by comparing cell behavior on uniform ECMs with different concentrations of components. To study haptotaxis in response to gradients, we utilized microfluidic chambers to generate gradients of the ECM protein fibronectin, and imaged the cell migration response. Lamellipodia are fan-shaped protrusions that are common in migrating cells. Here, we define a new function for lamellipodia and the cellular mechanism required for haptotaxisdifferential actin and lamellipodial protrusion dynamics lead to biased cell migration. Modest differences in lamellipodial dynamics occurring over time periods of seconds to minutes are summed over hours to produce differential whole cell movement towards higher concentrations of fibronectin. We identify a specific subset of lamellipodia regulators as being crucial for haptotaxis. Numerous studies have linked components of this pathway to cancer metastasis and, consistent with this, we find that expression of the oncogenic Rac1 P29S mutation abrogates haptotaxis. Finally, we show that haptotaxis also operates through this pathway in 3D environments.

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Section: Discussion a Working Model For Haptotaxismentioning

confidence: 99%

Section: The Relevance Of Haptotaxis For Tumor Progression and Metastmentioning

confidence: 94%

Section: Differential Lamellipodial Protrusion Dynamics Regulate Haptmentioning

confidence: 99%

Section: Differential Lamellipodial Protrusion Dynamics Regulate Haptmentioning

confidence: 99%

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Lamellipodia are crucial for haptotactic sensing and response

King

Asokan

Haynes

et al. 2016

Journal of Cell Science

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“…Some effects of LKB1 are independent of AMPK and they are mediated via microtubule affinity-regulating kinase, synapses of the amphid defective kinase, and salt-inducible kinase. [18][19][20] Kidney fibrosis is the histologic manifestation of CKD. Kidney fibrosis is characterized by accumulation of matrix and inflammatory cells.…”

mentioning

confidence: 99%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

109

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Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1 flox/flox ) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers b-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-a (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism. 27: 439-453, 201627: 439-453, . doi: 10.1681 Renal tubular epithelial cells (TECs) display strict apico-basal polarity. They allow a highly regulated uptake or excretion of substances at its apical surface, while keeping a closed, impenetrable surface through the formation of tight intercellular junctions in the basolateral membrane. The establishment and maintenance of TEC polarity is incompletely understood. The liver kinase B1 (LKB1) is an important regular of polarity. Early studies indicated that single intestinal epithelial cells polarize in a cell-autonomous fashion in response to LKB1 expression. 1 The LKB1 or STK11 gene encodes an evolutionarily conserved serine/threonine protein kinase. Following LKB1 expression, intestinal epithelial cells reorganized their cytoskeleton to form an apical brush border, demonstrating LKB1's critical role in establishing epithelial polarity. On the other hand, the effect of LKB1 on cell polarity appears to be cell type specific and deletion of LKB1 did not alter polarity of lung epithelial and pancreatic cells. 2 J Am Soc Nephrol

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STK11 Loss: A Novel Mechanism for Melanoma Metastasis with Therapeutic Implications

Azin

Demehri

2022

Journal of Investigative Dermatology

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STK11 is implicated as a tumor suppressor in epithelial cancer invasion and metastasis. In their new article in the Journal of Investigative Dermatology, Dzung et al. (2021) show that loss of STK11 in cutaneous melanoma cells leads to an invasive metastatic phenotype through the activation of the signal transducer and activator of transcription (STAT) 3/5 and FAK signaling pathways. These results suggest that inhibition of STAT3/5 and FAK in STK11-deficient melanoma cells could serve as a novel therapeutic strategy against metastatic melanoma.

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LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

Cited by 7 publications

References 34 publications

Lamellipodia are crucial for haptotactic sensing and response

Lamellipodia are crucial for haptotactic sensing and response

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

STK11 Loss: A Novel Mechanism for Melanoma Metastasis with Therapeutic Implications

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