Rewiring cell polarity signaling in cancer

Halaoui, Ruba; McCaffrey, Luke

doi:10.1038/onc.2014.59

Cited by 157 publications

(164 citation statements)

References 204 publications

(194 reference statements)

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“…We also show that TAZ overexpression is associated with a loss of E-cadherin while augmenting the N-cadherin protein in the endometrial cancer cell lines, and that TAZ silencing decreases vimentin expression while increasing that of claudin-1. The loss of E-cadherin could be associated with the loss of Scribble activity, 41 consistent with the effects on cell polarity and the triggering of epithelial to mesenchymal transition provoked by TAZ overexpression. In addition to this loss of epithelial features, we detected a negative correlation between the expression of miR-200s and WWTR1, showing that miR-200s expression is dampened during the transition from endometrioid endometrial carcinoma to endometrial carcinosarcoma, while WWTR1 expression increases.…”

Section: Discussionsupporting

confidence: 74%

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

et al. 2015

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Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer. Modern Pathology (2015Pathology ( ) 28, 1492Pathology ( -1503 doi:10.1038/modpathol.2015 published online 18 September 2015 In developed countries, endometrial carcinoma is the most common malignant tumor of the female genital tract. 1 On the basis of epidemiological, clinical, pathological, and molecular features, endometrial carcinoma can be classified into at least two main categories: 2 type I estrogen-dependent carcinomas that account for 80-85% of cases and that are typically represented by low-grade (grade 1 and 2) endometrioid carcinomas, and type II endometrial carcinomas that are not estrogen dependent and that are mainly represented by a serous subtype but also by other high-grade histological tumors like clear cell or undifferentiated carcinomas. 2 In endometrial carcinoma, the epithelial to mesenchymal transition has been associated with high-grade and aggressive features. [3][4][5][6] Epithelial to

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Section: Discussionsupporting

confidence: 74%

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

et al. 2015

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“…In most multicellular organisms, these two processes are precisely tuned to control cell shape and function, to specify cell fate and differentiation, and to enable cell adhesion and migration (Feigin and Muthuswamy, 2009;Godde et al, 2010;Halaoui and McCaffrey, 2014;Lauffenburger and Horwitz, 1996). These properties are dependent on proper cell polarization.…”

Section: Introductionmentioning

confidence: 99%

A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

Hercyk

Rich

Das

2018

Preprint

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Cdc42, a conserved regulator of cell polarity, is activated by two GEFs, Gef1 and Scd1, in fission yeast. While gef1 and scd1 mutants exhibit distinct phenotypes, how they do so is unclear given that they activate the same GTPase. Using the GEF localization pattern during cytokinesis as a paradigm, we report a novel interplay between Gef1 and Scd1 that spatially modulates Cdc42. We find that Gef1 promotes Scd1 localization to the division site during cytokinesis and to the new end during polarized growth through the recruitment of the scaffold Scd2 via a Cdc42 feedforward pathway. Gef1-mediated Scd1 recruitment at the new end enables the transition from monopolar to bipolar growth. Reciprocally, Scd1 restricts Gef1 localization to prevent ectopic Cdc42 activation during cytokinesis to promote cell separation and during interphase to maintain cell shape. Our findings reveal an elegant regulatory pattern in which Gef1 establishes new sites of Scd1-mediated Cdc42 activity, while Scd1 restricts Gef1 to functional sites. We propose that crosstalk between GEFs is a conserved mechanism that orchestrates Cdc42 activation during complex cellular processes.Summary StatementCdc42 GEFs Gef1 and Scd1 crosstalk to fine-tune Cdc42 activity. This crosstalk promotes bipolar growth and maintains cell shape in fission yeast.

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“…It remains to be determined if the modulation of Msln is an epiphenomenon associated with cholangiocarcinoma progression or whether CAFs interacting with cholangiocarcinoma cells provoke particular mechanisms contributing to the increase in the 40‐kDA Msln form over the 50‐kDa form that determine the changing pattern of expression of Msln. One intriguing avenue to explore in attempting to provide mechanistic insight for this change is the investigation of regulators of cell polarity and disruption of protein signaling mechanisms that regulate apical‐basal polarity38 on Msln isoform expression patterns in relation to increasing cholangiocarcinoma cell anaplasia.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

Manzanares

Campbell

Maldonado

et al. 2017

Hepatology Communications

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Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three‐dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ∼40 kDa and the other, a more heavily glycosylated form, at ∼50 kDa. Increased expression of the 40‐kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three‐dimensional culture. Moreover, coculturing of cancer‐associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40‐kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155–172)

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Rewiring cell polarity signaling in cancer

Cited by 157 publications

References 204 publications

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

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