EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer

Liu, Xia; Adorno-Cruz, Valery; Jia, Yuzhi; Kawaguchi, Masashi; Dashzeveg, Nurmaa K.; Taftaf, Rokana; Ramos, Erika K.; Schuster, Emma J.; El-Shennawy, Lamiaa; Patel, Dhwani; Zhang, Youbin; Cristofanilli, Massimo; Liu, Huiping

doi:10.7150/thno.57706

Cited by 52 publications

(54 citation statements)

References 49 publications

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“…Furthermore, the kinase reactome analyses identified the phosphoproteome kinase networks shared between CD81 and CD44 regulation, including PAK2, one of our previously identified targets of CD44 in tumor cluster formation (36) ( Supplementary Figure S4, Excel Data 4 ). These data are consistent with our previous discoveries on EGFR and PAK2 which are two representative components of the CD44 signaling and functional regulation in tumor cell clustering and metastasis (36, 61).…”

Section: Resultssupporting

confidence: 93%

“…Our previous work demonstrated that CD44 mediates tumor cell aggregation and CTC cluster formation that promotes metastasis (36, 61), and is associated with reduced progression-free survival (34, 35). To determine if CD81 regulates breast cancer metastasis like CD44, we assessed the clinical relevance of CD81 expression in human breast tumors and CTCs.…”

Section: Resultsmentioning

confidence: 99%

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CD81 partners with CD44 in promoting exosome biogenesis, tumor cluster formation, and lung metastasis in triple negative breast cancer

Ramos

Tsai

Dashzeveg

et al. 2022

Preprint

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Tumor-initiating cells with reprogramming plasticity are thought to be essential for cancer development and metastatic regeneration in many cancers; however, the molecular mechanisms are not fully understood. This study reports that CD81, a tetraspanin protein marker of small extracellular vesicles (exosomes), functions as a binding partner of CD44 and facilitates self-renewal of tumor initiating cells. Using machine learning-assisted protein structure modeling, co-immunoprecipitation, and mutagenesis approaches, we further demonstrate that CD81 interacts with CD44 on the cellular membrane through their extracellular regions. In-depth global and phosphoproteomic analyses of clustering tumor cells unveils endocytosis-related signature pathways of proteins and phosphorylation patterns regulated by CD81 and CD44 specifically or shared between two. Notably, CRISPR Cas9-mediated depletion of either CD44 or CD81 results in loss of both proteins in cancer cell-secreted exosomes, a state which abolishes exosome-induced self-renewal of recipient cells for mammosphere formation. CD81 is expressed in >80% of human circulating tumor cells (CTCs) and specifically enriched in clustered CTCs along with CD44 isolated from breast cancer patients. Mimicking the phenotypes of CD44 deficiency, loss of CD81 also inhibits tumor cluster aggregation, tumorigenesis, and lung metastasis of triple negative breast cancer (TNBC), supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights the novel role of CD81 and its partnership with CD44 in cancer exosomes, self-renewal, CTC clustering, and metastasis initiation of TNBC.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

CD81 partners with CD44 in promoting exosome biogenesis, tumor cluster formation, and lung metastasis in triple negative breast cancer

Ramos

Tsai

Dashzeveg

et al. 2022

Preprint

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“…Two recently developed, unbiased methods to detect putative CTCs in singles and clusters are (i) immunohistochemical staining to detect vascular CTCs in situ and (ii) flow cytometry of blood-derived CTCs with filtering based on cell/cluster sizes (side scatter and forward scatter channels) as well as molecular markers recognized by antibodies and/or binding ligands [ 11 , 36 , 37 ]. Although blood processing has the caveat of potentially introducing artificial effects on CTCs and cell clustering, the histology-based detection of vascular CTCs in tumor sections can certainly outperform and/or complement the other existing detection technologies in terms of specificity.…”

Section: Ctc Cluster Detection – Various Technologies With Different Advantagesmentioning

confidence: 99%

“…In breast cancer, homotypic clustering of CTCs can be directed by CD44 homophilic interactions that upregulate OCT4, epidermal growth factor receptor (EGFR), and p21-activated kinase 2 (PAK2)/focal adhesion kinase (FAK) signaling pathways [ 11 , 37 ] and also by a newly identified stemness-promoting adhesion molecule, intercellular adhesion molecule 1 (ICAM1) [ 45 ] ( Figure 1 ). Other studies characterizing CTC clusters have shown that intratumor hypoxia can trigger cluster formation and that the cell junction protein plakoglobin is overexpressed in CTC clusters compared with single CTCs in breast cancer [ 3 , 46 ] ( Figure 1 ).…”

Section: Homotypic and Heterotypic Ctc Clustersmentioning

confidence: 99%

Better together: circulating tumor cell clustering in metastatic cancer

et al. 2021

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Circulating tumor cells (CTCs) are vital components of liquid biopsies for diagnosis of residual cancer, monitoring of therapy response, and prognosis of recurrence. Scientific dogma focuses on metastasis mediated by single CTCs, but advancement of CTC detection technologies has elucidated multicellular CTC clusters, which are associated with unfavorable clinical outcomes and a 20-to 100-fold greater metastatic potential than single CTCs. While the mechanistic understanding of CTC cluster formation is still in its infancy, multiple cell adhesion molecules and tight junction proteins have been identified that underlie the outperforming attributes of homotypic and heterotypic CTC clusters, such as cell survival, cancer stemness, and immune evasion. Future directions include high-resolution characterization of CTCs at multiomic levels for diagnostic/prognostic evaluations and targeted therapies. Circulating tumor cells form clusters that enhance breast cancer metastasisAlthough metastasis accounts for 90% of solid tumor-related mortality, it currently evades targeted treatments and demands a better understanding. Metastasis is a multistep process during which cancer cells spread from the primary tumor site to distant organs, starting with the primary tumor formation, where tumor cells gradually expand and locally invade the surrounding stroma and tissues, including the blood and lymphatic vessels. At this point, the intravasated tumor cells, now called 'circulating tumor cells' (CTCs) and a vital component of liquid biopsy [1,2], develop adaptive mechanisms that favor their survival in the harsh microenvironment of the circulatory system. CTCs may disseminate to distant parts of the body before they finally extravasate or get trapped within the capillaries in certain organs, form metastatic niches, and regenerate secondary tumors [3][4][5].The presence of CTCs in the blood of patients with cancer was first detected in 1869 by Thomas Ashworth [6], but, because of advances in technology, CTCs have only recently attracted great attention for their key role in tumor metastasis [6,7]. Many studies have shown that CTCs may be used to predict disease progression and prognosis in patients with metastatic cancer [4]. In metastatic cancers such as breast cancer, the currently accepted level of CTCs that correlates with worse overall survival and progression-free survival is five or more CTCs in 7.5 mL of blood [8]. CTC enumeration can be used to better stratify patients with stage IV breast cancer as stage IV aggressive, with more than five CTCs, and stage IV indolent, with fewer than five CTCs [8]. Stage IV indolent disease is associated with significantly longer overall survival, regardless of disease subtype and prior treatment [8]. The presence of CTCs in early breast cancer was also demonstrated to have prognostic impact [9,10]. Thus, CTC analysis in patients with cancer is a minimally invasive, clinically informative method of predicting disease stage and survival that is not dependent on cancer subtype or previous trea...

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“…Another cell adhesion protein, CD44, is regulated by EGFR and drives the aggregation of triple-negative breast cancer cells. EGFR inhibition effectively blocks cell aggregation in vitro and reduces lung metastasis in vivo [110].…”

Section: Disaggregation Of Ctc Clustersmentioning

confidence: 99%

Metastasis Prevention: Focus on Metastatic Circulating Tumor Cells

et al. 2021

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Metastasis is the main cause of cancer death. Metastatic foci are derived from tumor cells that detach from the primary tumor and then enter the circulation. Circulating tumor cells (CTCs) are generally associated with a high probability of distant metastasis and a negative prognosis. Most CTCs die in the bloodstream, and only a few cells form metastases. Such metastatic CTCs have a stem-like and hybrid epithelial-mesenchymal phenotype, can avoid immune surveillance, and show increased therapy resistance. Targeting metastatic CTCs and their progenitors in primary tumors and their descendants, particularly disseminated tumor cells, represents an attractive strategy for metastasis prevention. However, current therapeutic strategies mainly target the primary tumor and only indirectly affect metastasis-initiating cells. Here, we consider potential methods for preventing metastasis based on targeting molecular and cellular features of metastatic CTCs, including CTC clusters. Also, we emphasize current knowledge gaps in CTC biology that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

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EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer

Cited by 52 publications

References 49 publications

CD81 partners with CD44 in promoting exosome biogenesis, tumor cluster formation, and lung metastasis in triple negative breast cancer

CD81 partners with CD44 in promoting exosome biogenesis, tumor cluster formation, and lung metastasis in triple negative breast cancer

Better together: circulating tumor cell clustering in metastatic cancer

Metastasis Prevention: Focus on Metastatic Circulating Tumor Cells

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