Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Bierie, Brian; Pierce, Sarah E.; Kroeger, Cornelia; Stover, Daniel G.; Pattabiraman, Diwakar R.; Thiru, Prathapan; Donaher, Joana Liu; Reinhardt, Ferenc; Chaffer, Christine L.; Keckesova, Zuzana; Weinberg, Robert A.

doi:10.1073/pnas.1618298114

Cited by 302 publications

(278 citation statements)

References 48 publications

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“…4E). Again, these results reinforce the idea of partial and transitional EMT states in iTICs that vary upon changing microenvironments (34)(35)(36)(37).…”

Section: A Partial Emt State Characterizes Itics In Changing Environmsupporting

confidence: 82%

MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions

Hillebrand

Wickberg²,

Gomez-Auli³

et al. 2018

FASEB j.

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Tumor‐initiating cells (TICs) existing in breast cancer are thought to be involved in initiation, progression, and relapse of tumors. In these processes, the epithelial‐to‐mesenchymal transition (EMT) and proteases are crucial factors that also dependent on the tumor milieu, including hypoxic nutrient‐deprived, as well as normoxic nutrient‐rich, environments. Therefore, we investigated EMT and proteases in TICs and their response to different environments by means of a newly generated immortalized TIC (iTIC) line. With the use of primary CD24+CD90+CD45− TICs from the mouse mammary tumor virus‐polyoma middle T mouse breast cancer model, iTICs were generated by single cell‐initiated sphere and subsequent 2‐dimensional monolayer culture. Our data demonstrate the possibility to generate iTICs that are highly tumorigenic in culture and in mouse mammary fat pad. Contrasting environmental conditions provide these cells with a phenotypic and molecular plasticity that has a growth‐promoting character in nutrient‐rich normoxia and a motile character in nutrient‐deprived hypoxia. Expression profiling revealed partial and dynamically changing EMT states, as well as a significantly up‐regulated proteolytic signature, including many metalloproteinases, such as matrix metalloproteinase 14 (Mmp14). Inhibitor treatment of metalloproteinases, as well as short hairpin RNA‐mediated knockdown of Mmp14 strongly impacted TIC characteristics, including tumor initiation, cell growth, migration, and invasion, especially in starved environments. We conclude that metalloproteinases empower TICs to adapt to changing environments.—Hillebrand, L. E., Wickberg, S. M., Gomez‐Auli, A., Folio, M., Maurer, J., Busch, H., Boerries, M., Reinheckel, T. MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions. FASEB J. 33, 4124–4140 (2019). http://www.fasebj.org

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“…4E). Again, these results reinforce the idea of partial and transitional EMT states in iTICs that vary upon changing microenvironments (34)(35)(36)(37).…”

Section: A Partial Emt State Characterizes Itics In Changing Environmsupporting

confidence: 82%

MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions

Hillebrand

Wickberg²,

Gomez-Auli³

et al. 2018

FASEB j.

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“…The strong correlation between ARRDC3 expression and tumor progression indicates that loss of ARRDC3 expression is linked to dysregulation of important cancer drivers. One target of ARRDC3 previously described is the membrane protein integrin β4 (39), which is enriched in triple-negative breast cancer and a marker of poor prognosis (54,55) (59). Thus, future studies are important to determine if integrin b4 is integrated in PAR1-driven breast cancer progression.…”

Section: Discussionmentioning

confidence: 99%

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Arakaki

Pan

Lin

et al. 2018

Journal of Biological Chemistry

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Aberrant G protein-coupled receptor (GPCR) expression and activation has been linked to tumor initiation, progression, invasion and metastasis. However, compared with other cancer drivers, the exploitation of GPCRs as potential therapeutic targets has been largely ignored, despite the fact that GPCRs are highly druggable. Therefore, to advance the potential status of GPCRs as therapeutic targets, it is important to understand how GPCRs function together with other cancer drivers during tumor progression. We now report that the a-arrestin domain-containing protein-3 (ARRDC3) acts as a tumor suppressor in part by controlling signaling and trafficking of the GPCR, protease-activated receptor-1 (PAR1). In a series of highly invasive basal-like breast carcinomas, we found that expression of ARRDC3 is suppressed while PAR1 is aberrantly overexpressed because of defective lysosomal sorting that results in persistent signaling. Using a lentiviral doxycycline-inducible system, we demonstrate that re-expression of ARRDC3 in invasive breast carcinoma is sufficient to restore normal PAR1 trafficking through the ALGinteracting protein X (ALIX)-dependent lysosomal degradative pathway. We also show that ARRDC3 re-expression attenuates PAR1-stimulated persistent signaling of c-Jun NH2-terminal kinase (JNK) in invasive breast cancer. Remarkably, restoration of ARRDC3 expression significantly reduced activated PAR1-induced breast carcinoma invasion, which was also dependent on JNK signaling. These findings are the first to identify a critical link between the tumor suppressor ARRDC3 and regulation of GPCR trafficking and signaling in breast cancer.G protein-coupled receptors (GPCRs) are a large family of cell surface signaling receptors that play a critical role in cancer growth and development by regulating cellular proliferation, invasion, migration, immune cell-mediated functions, angiogenesis and survival at metastatic sites (1-3). GPCR function can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, mutations in downstream G protein signaling effectors, and increased production and secretion of GPCR activating ligands by both tumor cells and surrounding stromal cells (4-7). As cell surface receptors with highly druggable sites, GPCRs are the largest class of drug targets, with over 30% of current FDAhttp://www.jbc.org/cgi

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“…This finding explains why increasing attention is being placed on the ‘partial EMT’ state, which seems to be critical for the maximal tumorigenic activity of CSCs 148 . More specifically, in a model of claudin-low breast cancer, in which most carcinoma cells display a highly mesenchymal phenotype, a subpopulation of cells with relatively epithelial characteristics exhibited greater tumorigenic activity than the bulk population of the cells 149 . Together, these observations indicate that the contribution of the EMT programme to the CSC phenotype is variable, most likely depending on cell type and/or coexisting genetic/epigenetic abnormalities.…”

Section: The Relationship Between Emt and Cscsmentioning

confidence: 99%

“…In general, migration of individual cells, which requires the strong activation of the EMT programme, results in faster tissue invasion than occurs by multicellular migration, the mode of migration that predominates when the EMT programme is only weakly activated 189 . The tumour-initiating ability of carcinoma cells is also affected by the level of EMT-programme activation, peaking at an intermediate level of EMT in these cells; extensive EMT activation is usually detrimental to tumour-initiating ability 149 . The drug resistance of carcinoma cells also seems to be maximal at an intermediate level of EMT-programme activation, but plateaus (rather than declines) with further activation of this programme 149,184 .…”

Section: Figurementioning

confidence: 99%

“…The tumour-initiating ability of carcinoma cells is also affected by the level of EMT-programme activation, peaking at an intermediate level of EMT in these cells; extensive EMT activation is usually detrimental to tumour-initiating ability 149 . The drug resistance of carcinoma cells also seems to be maximal at an intermediate level of EMT-programme activation, but plateaus (rather than declines) with further activation of this programme 149,184 . MET, mesenchymal-to-epithelial transition.…”

Section: Figurementioning

confidence: 99%

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EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

2017

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The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity — that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.

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Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

Cited by 302 publications

References 48 publications

MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions

MMP14 empowers tumor‐initiating breast cancer cells under hypoxic nutrient‐depleted conditions

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

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