EphB–ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells

Cortina, Carme; Palomo-Ponce, Sergio; Iglesias, Mar; Fernández-Masip, Juan Luis; Vivancos, Ana; Whissell, Gavin; Humà, Mireia; Peiró, Nerea; Gallego, Lourdes; Jonkheer, Suzanne; Davy, Alice; Lloreta, Josep; Sancho, Elena; Batlle, Eduard

doi:10.1038/ng.2007.11

Cited by 242 publications

(279 citation statements)

References 19 publications

Supporting

Mentioning

263

Contrasting

Unclassified

Order By: Relevance

“…Previous studies also demonstrated that activation of EphB receptors by ephrin-B1 or ephrin-B2 results in the activation of E-cadherin adhesion (41,42). These studies are consistent with our observations here that the loss of ephrin-A5 leads to the disruption of N-cadherin-␤-catenin interactions, resulting in a loss of cell-cell adhesion.…”

Section: Regulation Of N-cadherin and ␤-Cateninsupporting

confidence: 82%

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Cooper

Son

Komlos³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

Cell-cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell-cell interactions. Lens fiber cells in mice lacking ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of ephrin-A5 KO mice. We further demonstrate that ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of ␤-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.␤-catenin ͉ Eph receptor ͉ N-cadherin C ataract, or the opacification of the lens, is the leading cause of visual impairment and blindness worldwide (1). The molecular events underlying lens development and the processes by which the lens maintains transparency over a lifetime are unclear (2). In addition, the cellular and biochemical mechanisms underlying the pathological changes leading to cataract remain poorly understood.The lens is composed of a single layer of epithelial cells on the anterior surface, which, over a lifetime, divide and differentiate into the underlying lens fiber cells that comprise the bulk of the lens (3, 4). Initially during lens development, primary lens fiber cells differentiate and elongate from the posterior pole. In later embryogenesis and throughout life, secondary lens fiber cells differentiate from lens epithelial cells located at the equator. In cross section, the lens fiber cells resemble flattened hexagons with two broad and four short sides (3). These cells are organized in a highly ordered and closely packed manner, and interact through extensive intercellular adhesion complexes including gap and adherens junctions (5). Fiber cell gap junctions are composed of connexins (Cx) 46 and 50 (6), inactivation of which leads to the degeneration of the inner fiber cells and the development of cataract in mice (7,8). Mutations in human Cx genes have also been associated with cataractogenesis (9, 10). As the lens is completely enclosed by an acellular, avascular capsule, it is believed that these cell-cell junctions are critical for providing nutrient transport, removal of metabolic wastes, and maintenance of homeostasis (11,12). In addition to gap junctions, widespread adherens junctions containing N-cadherin and its associated protein ␤-catenin exist between lens fiber cells (13-16), and may play important roles in lens development and function.Although cell-cell interaction is critical for maintaining lens transparency, little is known about the molecular mechanisms underlying these interactions. We have identified an unexpected regulator of lens fiber cell-cell interaction, the axon guidance molecule ephrin-A5 (17)(18)(19), and have shown that the loss...

show abstract

Section: Regulation Of N-cadherin and ␤-Cateninsupporting

confidence: 82%

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Cooper

Son

Komlos³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

123

View full text Add to dashboard Cite

show abstract

“…We investigated vascular morphogenesis in our model upon blocking of both forward and reverse ephrinB2/EphB4, taking into account the complexity and distinct effects of this bidirectional signaling. Our study showed that both inhibitions disturb pericyte adherence to endothelial cells, a fact reported previously [50,51]. However, with the ephrinB2/EphB4 inhibition, no stimulation of intussusceptive angiogenesis was observed, contrary to Notch inhibition.…”

Section: Discussioncontrasting

confidence: 42%

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

et al. 2013

View full text Add to dashboard Cite

Notch is an intercellular signaling pathway related mainly to sprouting neo-angiogenesis. The objective of our study was to evaluate the angiogenic mechanisms involved in the vascular augmentation (sprouting/ intussusception) after Notch inhibition within perfused vascular beds using the chick area vasculosa and MxCreNotch1(lox/lox) mice. In vivo monitoring combined with morphological investigations demonstrated that inhibition of Notch signaling within perfused vascular beds remarkably induced intussusceptive angiogenesis (IA) with resultant dense immature capillary plexuses. The latter were characterized by 40 % increase in vascular density, pericyte detachment, enhanced vessel permeability, as well as recruitment and extravasation of mononuclear cells into the incipient transluminal pillars (quintessence of IA). Combination of Notch inhibition with injection of bone marrow-derived mononuclear cells dramatically enhanced IA with 80 % increase in vascular density and pillar number augmentation by 420 %. Additionally, there was down-regulation of ephrinB2 mRNA levels consequent to Notch inhibition. Inhibition of ephrinB2 or EphB4 signaling induced some pericyte detachment and resulted in upregulation of VEGFRs but with neither an angiogenic response nor recruitment of mononuclear cells. Notably, Tie-2 receptor was down-regulated, and the chemotactic factors SDF-1/CXCR4 were up-regulated only due to the Notch inhibition. Disruption of Notch signaling at the fronts of developing vessels generally results in massive sprouting. On the contrary, in the already existing vascular beds, down-regulation of Notch signaling triggered rapid augmentation of the vasculature predominantly by IA. Notch inhibition disturbed vessel stability and led to pericyte detachment followed by extravasation of mononuclear cells. The mononuclear cells contributed to formation of transluminal pillars with sustained IA resulting in a dense vascular plexus without concomitant vascular remodeling and maturation.

show abstract

“…They suggest that it may act in this malignancy in a manner similar to the reported actions of the EphB2 receptor, a known hallmark of colorectal cancer TICs (Merlos‐Suárez et al , 2011) that is also downregulated to allow colorectal cancer tumor progression (Cortina et al , 2007). Our description of this complex action of FUT9 identifies an entirely new player in colorectal cancer and adds another intriguing member to the rather short list of metabolic genes that have been shown to play a critical role in tumor biology.…”

Section: Discussionmentioning

confidence: 78%

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Auslander

Cunningham

Toosi

et al. 2017

Molecular Systems Biology

View full text Add to dashboard Cite

Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced‐stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor‐initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer.

show abstract

EphB–ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells

Cited by 242 publications

References 19 publications

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Contact Info

Product

Resources

About