Src-transformed cells hijack mitosis to extrude from the epithelium

Anton, Katarzyna A.; Kajita, Mihoko; Narumi, Rika; Fujita, Yasuyuki; Tada, Masazumi

doi:10.1038/s41467-018-07163-4

Cited by 35 publications

(24 citation statements)

References 69 publications

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“…This is consistent with reports that membranous PA directly binds cytoplasmic Sphk1, thereby recruiting it to cell membrane compartments (Delon et al, 2004). Plasma membrane localization of Sphk1 in turn would allow the release of S1P into the extracellular space, where it could act in an autocrine and/or paracrine manner to facilitate cell extrusion, in agreement with previous reports of extruding vSrc-transformed cells (Anton et al, 2018).…”

Section: Matriptase As a Tumor Suppressorsupporting

confidence: 93%

Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

Armistead

Hatzold

Roye

et al. 2019

Journal of Cell Biology

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The type II transmembrane serine protease Matriptase 1 (ST14) is commonly known as an oncogene, yet it also plays an understudied role in suppressing carcinogenesis. This double face is evident in the embryonic epidermis of zebrafish loss-of-function mutants in the cognate Matriptase inhibitor Hai1a (Spint1a). Mutant embryos display epidermal hyperplasia, but also apical cell extrusions, during which extruding outer keratinocytes carry out an entosis-like engulfment and entrainment of underlying basal cells, constituting a tumor-suppressive effect. These counteracting Matriptase effects depend on EGFR and the newly identified mediator phospholipase D (PLD), which promotes both mTORC1-dependent cell proliferation and sphingosine-1-phosphate (S1P)–dependent entosis and apical cell extrusion. Accordingly, hypomorphic hai1a mutants heal spontaneously, while otherwise lethal hai1a amorphs are efficiently rescued upon cotreatment with PLD inhibitors and S1P. Together, our data elucidate the mechanisms underlying the double face of Matriptase function in vivo and reveal the potential use of combinatorial carcinoma treatments when such double-face mechanisms are involved.

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Section: Matriptase As a Tumor Suppressorsupporting

confidence: 93%

Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

Armistead

Hatzold

Roye

et al. 2019

Journal of Cell Biology

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“…While BCE is reminiscent of cytokinesis, Fig. 4h and other images show the nucleus remains beneath the contractile ring, disfavouring asymmetric cell division as an invasion mechanism, seen in Src-expressing cells 34 .…”

Section: Resultsmentioning

confidence: 90%

KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion

et al. 2021

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Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. Here, using transparent zebrafish epidermis to model simple epithelia, we can directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death—cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Following invasion, cells divide, enter the bloodstream, and differentiate into stromal, neuronal-like, and other cell types. Yet, only invading KRasV12 cells deficient in p53 survive and form internal masses. Together, we demonstrate that KRas-transformation alone causes cell invasion and partial dedifferentiation, independently of mass formation.

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“…A related phenomenon was also observed in a zebrafish model of pancreatic tumour initiation, in which labelling tumour-initiating cells with a marker of differentiation revealed that oncogene expression blocked differentiation, leading to tumourigenesis [26]. Interestingly, live imaging has also led to the observation that cells expressing oncogenic Ras or v-Src can be extruded from the epidermis by healthy neighbouring cells, indicative of a potential tumour-suppressive defence mechanism [32][33][34].The main limitation in the use of transgenic models to study tumour initiation is that oncogene expression is dependent upon tissue-specific promoters, for which timing of activation can vary. This also restricts the study of early events to larval zebrafish.…”

mentioning

confidence: 76%

Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

Elliot

Myllymäki

Feng

2020

Cells

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The zebrafish is now an important model organism for cancer biology studies and provides unique and complementary opportunities in comparison to the mammalian equivalent. The translucency of zebrafish has allowed in vivo live imaging studies of tumour initiation and progression at the cellular level, providing novel insights into our understanding of cancer. Here we summarise the available transgenic zebrafish tumour models and discuss what we have gleaned from them with respect to cancer inflammation. In particular, we focus on the host inflammatory response towards transformed cells during the pre-neoplastic stage of tumour development. We discuss features of tumour-associated macrophages and neutrophils in mammalian models and present evidence that supports the idea that these inflammatory cells promote early stage tumour development and progression. Direct live imaging of tumour initiation in zebrafish models has shown that the intrinsic inflammation induced by pre-neoplastic cells is tumour promoting. Signals mediating leukocyte recruitment to pre-neoplastic cells in zebrafish correspond to the signals that mediate leukocyte recruitment in mammalian tumours. The activation state of macrophages and neutrophils recruited to pre-neoplastic cells in zebrafish appears to be heterogenous, as seen in mammalian models, which provides an opportunity to study the plasticity of innate immune cells during tumour initiation. Although several potential mechanisms are described that might mediate the trophic function of innate immune cells during tumour initiation in zebrafish, there are several unknowns that are yet to be resolved. Rapid advancement of genetic tools and imaging technologies for zebrafish will facilitate research into the mechanisms that modulate leukocyte function during tumour initiation and identify targets for cancer prevention.

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Src-transformed cells hijack mitosis to extrude from the epithelium

Cited by 35 publications

References 69 publications

Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion

Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

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