Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models

Liu, Xia; Taftaf, Rokana; Kawaguchi, Masashi; Chang, Yi‐Han; Chen, Wenjing; Entenberg, David; Zhang, Youbin; Gerratana, Lorenzo; Huang, Simo; Patel, Dhwani; Tsui, Elizabeth; Adorno-Cruz, Valery; Chirieleison, Steven M.; Cao, Yue; Harney, Allison S.; Patel, Shivani; Patsialou, Antonia; Shen, Yang; Avril, Stefanie; Gilmore, Hannah; Lathia, Justin D.; Abbott, Derek W.; Cristofanilli, Massimo; Condeelis, John S.; Liu, Huiping

doi:10.1158/2159-8290.cd-18-0065

Cited by 276 publications

(393 citation statements)

References 65 publications

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“…1). 48 Targeted removal of HA and HS increased permeability of the MVNs to 70 kDa dextran by 1.4-and 49 1.7-fold compared to untreated control networks, respectively ( Fig. 1b), consistent with the idea 50 that the EC GCX can sterically hinder passage of macromolecules 32 .…”

Section: Introductionsupporting

confidence: 75%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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The glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a novel mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Transendothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

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Section: Introductionsupporting

confidence: 75%

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Offeddu

Hajal

Foley

et al. 2020

Preprint

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“…Similar to ITGA2based KM Plots, CCND1 and ACLY expression show a similar pattern of correlation with a short RFS in breast cancer patients (Fig 7F-G), whereas miR-206 expression indicates an extended RFS in ERbreast cancer (Fig 7H). Our recent discoveries and other reports demonstrated that circulating tumor cell (CTC) clusters are enriched with cancer stemness and proliferation Page 11 of 27 compared to single CTCs 11,[30][31][32] . Notably, shown by single cell sequencing, both ACLY and CCND1 expression levels are upregulated in CTC clusters versus single CTCs isolated from patients with breast cancer and patient-derived xenografts (Fig 7I), correlating with their effects on improved self-renewal and cell cycle progression respectively.…”

Section: Itga2 Expression Levels Are Mainly Observed In Basal a (Baa)mentioning

confidence: 95%

“…Over the last two decades, human tumor cells with stem cell properties (stemness) have been identified and demonstrated to initiate tumorigenesis and accelerate progression, coupled with therapy resistance, immune evasion and distant metastases [5][6][7][8][9][10][11][12] . However, targeting cancer stemness has yet to be widely achieved in the cancer clinic and therefore demands a better understanding and identification of targetable stemness regulators.…”

Section: Introductionmentioning

confidence: 99%

ITGA2is a target of miR-206 promoting cancer stemness and lung metastasis through enhancedACLYandCCND1expression in triple negative breast cancer

Adorno-Cruz

Hoffmann²,

Liu

et al. 2019

Preprint

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AbstractAccumulating evidence demonstrates that cancer stemness is essential for both tumor development and progression, regulated by multi-layer factors at genetic, epigenetic and micro-environmental levels. However, how to target stemness-driven plasticity and eliminate metastasis remains one of the biggest challenges in the clinic. We aim to identify novel molecular mechanisms underlying stemness of triple negative breast cancer (TNBC) which frequently metastasizes to the visceral organs but lacks targeted therapies. Following our previous discovery of miR-206 as an epigenetic suppressor of tumorigenesis and metastasis, we now report that the integrin receptor CD49b-encodingITGA2is an oncogenic target of miR-206 in TNBC.ITGA2knockdown abolished cancer stemness (mammosphere formation, pluripotency marker expression, and FAK phosphorylation), inhibited cell cycling, compromised migration and invasion, and thereby decreasing lung metastasis of TNBC. RNA sequencing analyses of breast cancer cells revealed thatITGA2knockdown inhibits gene expression essential for both classical integrin-regulated pathways (cell cycle, wounding response, protein kinase, etc) and newly identified pathways such as lipid metabolism. Notably,ACLY-encoded ATP citrate lyase is one of the top targets in CD49b-regulated lipid metabolism andCCND1-encoded Cyclin D1 represents regulation of cell cycle and many other pathways. ACLY, known to catalyze the formation of cytosolic acetyl-CoA for fatty acid biosynthesis, is indispensable for cancer stemness. Overexpression ofCCND1rescues the phenotype ofITGA2knockdown-induced cell cycle arrest. High expression levels of theITGA2/ACLY/CCND1axis are correlated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifiesITGA2as a potential therapeutic target of TNBC stemness and metastasis.

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“…Ultimately, a key event during metastasis is that cells with a tumor-initiating capacity reach and establish at distant sites to form new colonies, which requires cell adhesion (31). We hypothesize that the increased adhesive potential and sphere formation capacity following overexpression of miR-10b, might not only increase cell survival in the circulation, but also facilitate extravasation at new sites, and explains in part the propensity of aggressive cSCCs to metastasize (41).…”

Section: Discussionmentioning

confidence: 99%

MiRNA-10b marks aggressive squamous cell carcinomas, and confers a cancer stem cell-like phenotype

Wimmer

Zauner

Ablinger

et al. 2020

Preprint

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AbstractBackgroundCutaneous squamous cell carcinomas (cSCC) are the primary cause of premature deaths in patients suffering from the rare skin-fragility disorder recessive dystrophic epidermolysis bullosa, which is in marked contrast to the rarely metastasizing nature of these carcinomas in the general population. This remarkable difference is attributed to the frequent development of chronic wounds caused by an impaired skin integrity. However, the specific molecular and cellular changes to malignancy, and whether there are common players in different types of aggressive cSCCs, remain relatively undefined.MethodsMiRNA expression profiling was performed across various cell types isolated from skin and cSCCs. Microarray results were confirmed by qPCR and by an optimized in situ hybridization protocol. Functional impact of overexpression of a dysregulated miRNA was assessed in migration and 3D spheroid assays. Sample-matched transcriptome data was generated to support the identification of disease relevant miRNA targets.ResultsSeveral miRNAs were identified as dysregulated in cSCCs as compared to controls. These included the metastasis-linked miR-10b, which was significantly upregulated in primary cell cultures and in archival biopsies. At the functional level, overexpression of miR-10b conferred the stem cell-characteristic of 3D-spheroid formation capacity to keratinocytes, and impaired their mobility. Analysis of miR-10b downstream effects identified a novel putative target of miR-10b, the actin- and tubulin cytoskeleton-associated protein DIAPH2.ConclusionThe discovery that miR-10b confers an aspect of cancer stemness – that of enhanced tumor cell adhesion, known to facilitate metastatic colonization - provides an important avenue for future development of novel therapies targeting this metastasis-linked miRNA.

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Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models

Cited by 276 publications

References 65 publications

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

ITGA2is a target of miR-206 promoting cancer stemness and lung metastasis through enhancedACLYandCCND1expression in triple negative breast cancer

MiRNA-10b marks aggressive squamous cell carcinomas, and confers a cancer stem cell-like phenotype

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