Epithelial delamination and migration

Parisi, Federica; Vidal, Marcos

doi:10.4161/cam.5.4.17524

Cited by 23 publications

(17 citation statements)

References 65 publications

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“…The second important difference is that DIAPH1 knock down cells had lost the ability for collective migration, which is not impaired in cortactin knock down cells. As in most cases metastasis of colorectal cancer is not dependent on epithelial‐mesenchymal‐transition but on collective invasion and migration, control and also cortactin knock down cells may have invaded and left the blood vessels as large cell aggregates. DIAPH1 knock down cells, by contrast, may have invaded the blood vessels and the lungs as single cells or loose cell populations of which, due to impaired extravasation, only a few had the potential to leave the blood vessels and to colonize the lungs.…”

Section: Discussionmentioning

confidence: 99%

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Expression of DIAPH1 is up‐regulated in colorectal cancer and its down‐regulation strongly reduces the metastatic capacity of colon carcinoma cells

Lin

Izbicki

König

et al. 2013

Intl Journal of Cancer

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In most cases, metastatic colorectal cancer is not curable, thus new approaches are necessary to identify novel targets for colorectal cancer therapy. Actin-binding-proteins (ABPs) directly regulate motility of metastasising tumor cells, and for cortactin an association with colon cancer metastasis has been already shown. However, as its depletion only incompletely inhibits metastasis, additional, more suitable cellular targets have to be identified. Here we analyzed expression of the ABPs, DIAPH1, VASP, N-WASP, and fascin in comparison with cortactin and found that, besides cortactin, DIAPH1 was expressed with the highest frequency (63%) in colorectal cancer. As well as cortactin, DIAPH1 was not detectable in normal colon tissue and expression of both proteins was positively correlated with metastasis of colorectal cancer. To analyse the mechanistic role of DIAPH1 for metastasis of colon carcinoma cells in comparison with cortactin, expression of the proteins was stably downregulated in the human colon carcinoma cell lines HT-29, HROC-24 and HCT-116. Analysis of metastasis of colon carcinoma cells in SCID mice revealed that depletion of DIAPH1 reduced metastasis 60-fold and depletion of cortactin 16-fold as compared with control cells. Most likely the stronger effect of DIAPH1 depletion on colon cancer metastasis is due to the fact that in vitro knock down of DIAPH1 impaired all steps of metastasis; adhesion, invasion and migration while down-regulation of cortactin only reduced adhesion and invasion. This very strong reducing effect of DIAPH1 depletion on colon carcinoma cell metastasis makes the protein a promising therapeutic target for individualized colorectal cancer therapy.Formation of metastasis is a complex process, starting with strong morphological and functional changes of tumor cells.

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Section: Discussionmentioning

confidence: 99%

“…Formation of metastasis is a complex process, starting with strong morphological and functional changes of tumor cells. [1][2][3] The morphological changes mainly result from cytoskeletal rearrangements, which are controlled by dynamic changes of actin filaments. Invading cells form invadopodia, consisting of bundled and branched actin filaments (F-actin).…”

mentioning

confidence: 99%

Expression of DIAPH1 is up‐regulated in colorectal cancer and its down‐regulation strongly reduces the metastatic capacity of colon carcinoma cells

Lin

Izbicki

König

et al. 2013

Intl Journal of Cancer

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“…Several modes of tissue invasion by cancer cells have been described 28 , most of them relying on the departure of the tumour cells from the epithelial layer 29 . This study suggests that some oncogenes may also drive tissue destruction and invasion by inducing ectopic cell intercalation between cancerous and healthy cells, and subsequent healthy cell elimination.…”

Section: Letter Researchmentioning

confidence: 99%

Cell mixing induced by myc is required for competitive tissue invasion and destruction

Levayer

Hauert

Moreno

2015

Nature

127

162

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Cell-cell intercalation is used in several developmental processes to shape the normal body plan. There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition. Cell competition is a conserved mechanism driving the elimination of slow-proliferating cells (so-called 'losers') by faster-proliferating neighbours (so-called 'winners') through apoptosis and is important in preventing developmental malformations and maintain tissue fitness. Here we show, using long-term live imaging of myc-driven competition in the Drosophila pupal notum and in the wing imaginal disc, that the probability of elimination of loser cells correlates with the surface of contact shared with winners. As such, modifying loser-winner interface morphology can modulate the strength of competition. We further show that elimination of loser clones requires winner-loser cell mixing through cell-cell intercalation. Cell mixing is driven by differential growth and the high tension at winner-winner interfaces relative to winner-loser and loser-loser interfaces, which leads to a preferential stabilization of winner-loser contacts and reduction of clone compactness over time. Differences in tension are generated by a relative difference in F-actin levels between loser and winner junctions, induced by differential levels of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate. Our results establish the first link between cell-cell intercalation induced by a proto-oncogene and how it promotes invasiveness and destruction of healthy tissues.

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“…Drosophila cancer models allow in vivo analysis of genetically defined tumors in a highly tractable invertebrate model. With respect to cell invasion and migration, many of the morphogenetic movements required to complete Drosophila development provide great models for the study of these processes in vivo and these have been reviewed elsewhere (Montell, 2003;Parisi and Vidal, 2011). These developmental stages are tightly regulated by signaling pathways that are also deregulated during cancer progression (e.g., Wnt, TGF-b and Notch were first discovered in Drosophila) (Raftery and Sutherland, 1999).…”

Section: Introductionmentioning

confidence: 98%

“…The fly life cycle consists of an embryonic stage, followed by three instar larval stages, pupation (metamorphosis) and finally the adult stage. Some aspects of invasive migration are studied using the embryo, whereas genetic screens for tumor suppressor genes are usually scored using larval phenotypes (Brumby and Richardson, 2003;Pagliarini and Xu, 2003;Parisi and Vidal, 2011). As with all models there are caveats, importantly how closely these models can be associated to specific cancer types.…”

Section: Introductionmentioning

confidence: 99%