Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models

Xia Liu, Rokana Taftaf, Madoka Kawaguchi, Ya Fang Chang, Wenjing Chen, David R. Entenberg, Youbin Zhang, Lorenzo Gerratana, Simo Huang, Dhwani B. Patel, Elizabeth Tsui, Valery Adorno-Cruz, Steven M. Chirieleison, Yue Cao, Allison S. Harney, Shivani Patel, Antonia Patsialou, Yang Shen, Stefanie Avril, Hannah L. GilmoreJustin D. Lathia, Derek W. Abbott, Massimo Cristofanilli, John S. Condeelis, Huiping Liu

Research output: Contribution to journalArticle

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Abstract

Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44–CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44–PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44–PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.

Original languageEnglish (US)
Pages (from-to)96-113
Number of pages18
JournalCancer Discovery
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2019

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Cell Aggregation
Breast Neoplasms
Neoplasm Metastasis
Circulating Neoplastic Cells
Neoplasms
Biomarkers
Triple Negative Breast Neoplasms
Patient Advocacy
Neoplastic Stem Cells
Heterografts
Cell Movement
Seeds
Carcinogenesis
Biopsy

ASJC Scopus subject areas

  • Oncology

Cite this

Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. / Liu, Xia; Taftaf, Rokana; Kawaguchi, Madoka; Chang, Ya Fang; Chen, Wenjing; Entenberg, David R.; Zhang, Youbin; Gerratana, Lorenzo; Huang, Simo; Patel, Dhwani B.; Tsui, Elizabeth; Adorno-Cruz, Valery; Chirieleison, Steven M.; Cao, Yue; Harney, Allison S.; Patel, Shivani; Patsialou, Antonia; Shen, Yang; Avril, Stefanie; Gilmore, Hannah L.; Lathia, Justin D.; Abbott, Derek W.; Cristofanilli, Massimo; Condeelis, John S.; Liu, Huiping.

In: Cancer Discovery, Vol. 9, No. 1, 01.01.2019, p. 96-113.

Research output: Contribution to journalArticle

Liu, X, Taftaf, R, Kawaguchi, M, Chang, YF, Chen, W, Entenberg, DR, Zhang, Y, Gerratana, L, Huang, S, Patel, DB, Tsui, E, Adorno-Cruz, V, Chirieleison, SM, Cao, Y, Harney, AS, Patel, S, Patsialou, A, Shen, Y, Avril, S, Gilmore, HL, Lathia, JD, Abbott, DW, Cristofanilli, M, Condeelis, JS & Liu, H 2019, 'Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models', Cancer Discovery, vol. 9, no. 1, pp. 96-113. https://doi.org/10.1158/2159-8290.CD-18-0065
Liu, Xia ; Taftaf, Rokana ; Kawaguchi, Madoka ; Chang, Ya Fang ; Chen, Wenjing ; Entenberg, David R. ; Zhang, Youbin ; Gerratana, Lorenzo ; Huang, Simo ; Patel, Dhwani B. ; Tsui, Elizabeth ; Adorno-Cruz, Valery ; Chirieleison, Steven M. ; Cao, Yue ; Harney, Allison S. ; Patel, Shivani ; Patsialou, Antonia ; Shen, Yang ; Avril, Stefanie ; Gilmore, Hannah L. ; Lathia, Justin D. ; Abbott, Derek W. ; Cristofanilli, Massimo ; Condeelis, John S. ; Liu, Huiping. / Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. In: Cancer Discovery. 2019 ; Vol. 9, No. 1. pp. 96-113.
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abstract = "Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44–CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44–PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44–PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.",
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AU - Liu, Xia

AU - Taftaf, Rokana

AU - Kawaguchi, Madoka

AU - Chang, Ya Fang

AU - Chen, Wenjing

AU - Entenberg, David R.

AU - Zhang, Youbin

AU - Gerratana, Lorenzo

AU - Huang, Simo

AU - Patel, Dhwani B.

AU - Tsui, Elizabeth

AU - Adorno-Cruz, Valery

AU - Chirieleison, Steven M.

AU - Cao, Yue

AU - Harney, Allison S.

AU - Patel, Shivani

AU - Patsialou, Antonia

AU - Shen, Yang

AU - Avril, Stefanie

AU - Gilmore, Hannah L.

AU - Lathia, Justin D.

AU - Abbott, Derek W.

AU - Cristofanilli, Massimo

AU - Condeelis, John S.

AU - Liu, Huiping

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44–CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44–PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44–PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.

AB - Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44–CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44–PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44+ CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44–PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.

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