TY - JOUR
T1 - ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer
AU - Taftaf, Rokana
AU - Liu, Xia
AU - Singh, Salendra
AU - Jia, Yuzhi
AU - Dashzeveg, Nurmaa K.
AU - Hoffmann, Andrew D.
AU - El-Shennawy, Lamiaa
AU - Ramos, Erika K.
AU - Adorno-Cruz, Valery
AU - Schuster, Emma J.
AU - Scholten, David
AU - Patel, Dhwani
AU - Zhang, Youbin
AU - Davis, Andrew A.
AU - Reduzzi, Carolina
AU - Cao, Yue
AU - D’Amico, Paolo
AU - Shen, Yang
AU - Cristofanilli, Massimo
AU - Muller, William A.
AU - Varadan, Vinay
AU - Liu, Huiping
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.
AB - Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.
UR - http://www.scopus.com/inward/record.url?scp=85112249061&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25189-z
DO - 10.1038/s41467-021-25189-z
M3 - Article
C2 - 34381029
AN - SCOPUS:85112249061
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4867
ER -