FBP17-mediated finger-like membrane protrusions in cell competition between normal and RasV12-transformed cells

Fascin is an actin-bundling protein that is found in membrane ruffles, microspikes, and stress fibers. The expression of fascin is greatly increased in many transformed cells, as well as in specialized normal cells including neuronal cells and antigen-presenting dendritic cells. A morphological characteristic common to these cells expressing high levels of fascin is the development of many membrane protrusions in which fascin is predominantly present. To examine whether fascin contributes to the alterations in microfilament organization at the cell periphery, we have expressed fascin in LLC-PK1 epithelial cells to levels as high as those found in transformed cells and in specialized normal cells. Expression of fascin results in large changes in morphology, the actin cytoskeleton, and cell motility: fascin-transfected cells form an increased number of longer and thicker microvilli on apical surfaces, extend lamellipodia-like structures at basolateral surfaces, and show disorganization of cell–cell contacts. Cell migration activity is increased by 8–17 times when assayed by modified Boyden chamber. Microinjection of a fascin protein into LLC-PK1 cells causes similar morphological alterations including the induction of lamellipodia at basolateral surfaces and formation of an increased number of microvilli on apical surfaces. Furthermore, microinjection of fascin into REF-52 cells, normal fibroblasts, induces the formation of many lamellipodia at all regions of cell periphery. These results together suggest that fascin is directly responsible for membrane protrusions through reorganization of the microfilament cytoskeleton at the cell periphery.

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A role of the sphingosine-1-phosphate (S1P)–S1P receptor 2 pathway in epithelial defense against cancer (EDAC)

Molecular Biology of the Cell ◽

10.1091/mbc.e15-03-0161 ◽

2016 ◽

Vol 27 (3) ◽

pp. 491-499 ◽

Cited By ~ 24

Author(s):

Sayaka Yamamoto ◽

Yuta Yako ◽

Yoichiro Fujioka ◽

Mihoko Kajita ◽

Takeshi Kameyama ◽

...

Keyword(s):

Epithelial Cells ◽

Single Cells ◽

Initial Step ◽

Transformed Cells ◽

Cell Competition ◽

Positive Role ◽

Normal Cells ◽

Apical Extrusion ◽

Sphingosine 1 Phosphate ◽

S1p Receptor

At the initial step of carcinogenesis, transformation occurs in single cells within epithelia, where the newly emerging transformed cells are surrounded by normal epithelial cells. A recent study revealed that normal epithelial cells have an ability to sense and actively eliminate the neighboring transformed cells, a process named epithelial defense against cancer (EDAC). However, the molecular mechanism of this tumor-suppressive activity is largely unknown. In this study, we investigated a role for the sphingosine-1-phosphate (S1P)–S1P receptor 2 (S1PR2) pathway in EDAC. First, we show that addition of the S1PR2 inhibitor significantly suppresses apical extrusion of RasV12-transformed cells that are surrounded by normal cells. In addition, knockdown of S1PR2 in normal cells induces the same effect, indicating that S1PR2 in the surrounding normal cells plays a positive role in the apical elimination of the transformed cells. Of importance, not endogenous S1P but exogenous S1P is involved in this process. By using FRET analyses, we demonstrate that S1PR2 mediates Rho activation in normal cells neighboring RasV12-transformed cells, thereby promoting accumulation of filamin, a crucial regulator of EDAC. Collectively these data indicate that S1P is a key extrinsic factor that affects the outcome of cell competition between normal and transformed epithelial cells.

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Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes

Nature Cell Biology ◽

10.1038/ncb3509 ◽

2017 ◽

Vol 19 (5) ◽

pp. 530-541 ◽

Cited By ~ 67

Author(s):

Shunsuke Kon ◽

Kojiro Ishibashi ◽

Hiroto Katoh ◽

Sho Kitamoto ◽

Takanobu Shirai ◽

...

Keyword(s):

Epithelial Cells ◽

Metabolic Changes ◽

Transformed Cells ◽

Cell Competition ◽

Apical Extrusion

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A cell competition-based drug screen identifies a novel compound that induces dual c-Myc depletion and p53 activation

10.1101/2020.05.16.089755 ◽

2020 ◽

Author(s):

Dagim Shiferaw Tadele ◽

Joseph Robertson ◽

Richard Crispin ◽

Maria C. Herrera ◽

Marketa Chlubnova ◽

...

Keyword(s):

Stem Cells ◽

Transformed Cells ◽

Drug Screen ◽

Bone Marrow Niche ◽

Leukemic Stem Cells ◽

Cell Competition ◽

Dna Intercalator ◽

Strong Activity ◽

Hematopoietic Stem ◽

Wide Range

AbstractBCR-Abl is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells. Leukemic stem cells are cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. Using BCR-Abl as a model oncogene, we performed a drug screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells, and identified several compounds that selectively target BCR-Abl-transformed cells. Systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. c-Myc depletion occurred in a wide range of tumor types, including leukemia, lymphoma, lung, glioblastoma and breast cancer. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest and cell differentiation, and primary leukemic stem cells were particularly sensitive to DJ34. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against leukemic stem cells.

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