Fascin Activates β-Catenin Signaling and Promotes Breast Cancer Stem Cell Function Mainly Through Focal Adhesion Kinase (FAK): Relation With Disease Progression

Barnawi, Rayanah; Al-Khaldi, Samiyah; Bakheet, Tala; Fallatah, Mohannad; Alaiya, Ayodele; Ghebeh, Hazem; Al‐Alwan, Monther

doi:10.3389/fonc.2020.00440

Cited by 24 publications

(22 citation statements)

References 30 publications

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“…However, this regulation of fascin-1 by ß-catenin seems to be cell typespecific as no regulation was observed in breast cancer cells 20 . On the other way around, fascin-1 was found to induce epithelial-mesenchymal transition of cholangiocarcinoma cells and promote breast cancer stem cell function by regulating Wnt/ß-catenin signaling 31,32 .…”

Section: Discussionmentioning

confidence: 99%

The ß-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas

Gest

Sena

Neaud

et al. 2021

Preprint

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BACKGROUND & AIMSß-catenin is a well-known effector of the Wnt pathway and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of ß-catenin are highly frequent in pediatric liver primary tumors. Those mutations are mostly heterozygous allowing the co-expression of wild-type (WT) and mutated ß-catenins in tumor cells. We investigated the interplay between WT and mutated ß-catenins in liver tumor cells, and searched for new actors of the ß-catenin pathway.METHODSUsing an RNAi strategy in ß-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, carried mainly by, respectively, WT and mutated proteins. Their impact was characterized using transcriptomic and functional analyses. We studied mice that develop liver tumors upon activation of ß-catenin in hepatocytes (APCKO and ß-cateninΔexon3 mice). We made use of transcriptomic data from mouse and human HB specimens and analyzed samples by immunohistochemistry.RESULTSWe highlighted an antagonist role of WT and mutated ß-catenins on hepatocyte differentiation as attested by alteration of hepatocyte markers expression and bile canaliculi formation. We characterized Fascin-1 as a target of ß-catenin involved in hepatocyte differentiation. Using mouse models that allow the formation of two phenotypically distinct tumors (differentiated or undifferentiated), we found that Fascin-1 expression is higher in undifferentiated tumors. Finally, we found that Fascin-1 is a specific marker of the embryonal component in human HBs.CONCLUSIONSIn mice and human, Fascin-1 expression is linked to loss of differentiation and polarity of hepatocytes. Thus, we highlighted Fascin-1 as a new player in the modulation of hepatocyte differentiation associated to ß-catenin pathway alteration in the liver.Data Transparency Statementstudy materials will be made available to other researchers upon request.

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Section: Discussionmentioning

confidence: 99%

The ß-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas

Gest

Sena

Neaud

et al. 2021

Preprint

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“…Recently, it was evidenced that the GD3 synthase ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (ST8SIA1) may regulate TNBC stem cell activity through the activation of the FAK/ERK/Akt/mTOR oncogenic pathway [ 154 ]. Likewise, the fascin-β-catenin complex facilitated a breast CSC-like phenotype in a FAK-dependent manner, enhancing the self-renewability of breast CSCs [ 155 ]. FAK behaves also as an interacting partner of both connexin and Nanog homeobox (NANOG) toward the formation of a ternary complex, which may lead to a sustained CSCs self-renewal and maintenance in TNBC [ 156 ].…”

Section: Role Of Fak In Csc Self-renewal and Maintenancementioning

confidence: 99%

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

Rigiracciolo

Cirillo

Talia

et al. 2021

Cancers

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Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors.

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“…Further, focal adhesion kinase (FAK) and the actin-binding protein Fascin play relevant roles in activation of the β-catenin pathway. High expression of the Fascin–FAK–β-catenin axis is associated with poor survival outcomes, so it has become an important target for targeted therapy of bCSCs [ 74 ]. Nestin, an intermediate filament protein, has been associated with a malignant phenotype and poor prognosis in patients.…”

Section: Signaling Pathways Governing the Breast Cancer Stem Cell-mentioning

confidence: 99%

LncRNAs and microRNAs as Essential Regulators of Stemness in Breast Cancer Stem Cells

et al. 2021

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Breast cancer is an aggressive disease with a high incidence in women worldwide. Two decades ago, a controversial hypothesis was proposed that cancer arises from a subpopulation of “tumor initiating cells” or “cancer stem cells-like” (CSC). Today, CSC are defined as small subset of somatic cancer cells within a tumor with self-renewal properties driven by the aberrant expression of genes involved in the maintenance of a stemness-like phenotype. The understanding of the underlying cellular and molecular mechanisms involved in the maintenance of CSC subpopulation are fundamental in the development and persistence of breast cancer. Nowadays, the hypothesis suggests that genetic and epigenetic alterations give rise to breast cancer stem cells (bCSC), which are responsible for self-renewal, tumor growth, chemoresistance, poor prognosis and low survival in patients. However, the prominence of bCSC, as well as the molecular mechanisms that regulates and promotes the malignant phenotypes, are still poorly understood. The role of non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as oncogenes or tumor suppressor genes has been recently highlighted by a plethora of studies in breast cancer. These ncRNAs positively or negatively impact on different signaling pathways that govern the cancer hallmarks associated with bCSC, making them attractive targets for therapy. In this review, we present a current summary of the studies on the pivotal roles of lncRNAs and microRNAs in the regulation of genes associated to stemness of bCSC.

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Fascin Activates β-Catenin Signaling and Promotes Breast Cancer Stem Cell Function Mainly Through Focal Adhesion Kinase (FAK): Relation With Disease Progression

Cited by 24 publications

References 30 publications

The ß-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas

The ß-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

LncRNAs and microRNAs as Essential Regulators of Stemness in Breast Cancer Stem Cells

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