TY - JOUR
T1 - Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination
AU - Sharma, Ved P.
AU - Tang, Binwu
AU - Wang, Yarong
AU - Duran, Camille L.
AU - Karagiannis, George S.
AU - Xue, Emily A.
AU - Entenberg, David
AU - Borriello, Lucia
AU - Coste, Anouchka
AU - Eddy, Robert J.
AU - Kim, Gina
AU - Ye, Xianjun
AU - Jones, Joan G.
AU - Grunblatt, Eli
AU - Agi, Nathan
AU - Roy, Sweta
AU - Bandyopadhyaya, Gargi
AU - Adler, Esther
AU - Surve, Chinmay R.
AU - Esposito, Dominic
AU - Goswami, Sumanta
AU - Segall, Jeffrey E.
AU - Guo, Wenjun
AU - Condeelis, John S.
AU - Wakefield, Lalage M.
AU - Oktay, Maja H.
N1 - Funding Information:
We thank the Analytical Imaging Facility at Albert Einstein College of Medicine for microscopy help, particularly Dr. Peng Guo for help with Imaris 3D reconstructions; Yu Lin for help with TMEM staining; members of the Condeelis, Oktay, Segall, Cox, Entenberg, and Hodgson laboratories for helpful discussions, and Jen Mehalko for cloning expertise. This research was supported in part by CA150344, CA100324, CA216248, CA255153, F32 CA243350, an IRACDA fellowship, K12 GM102779, the Gruss Lipper Biophotonics Center and its associated Integrated Imaging Program, and SIG #1S10OD019961-01 and P30CA013330 (Flow Cytometry Core Facility). The research was supported in part by the Intramural Research Program of the NIH grant ZIA BC 005785 to L.M.W. This research was supported by Jane A. and Myles P. Dempsey.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.
AB - Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites.
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U2 - 10.1038/s41467-021-27308-2
DO - 10.1038/s41467-021-27308-2
M3 - Article
C2 - 34911937
AN - SCOPUS:85121357051
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7300
ER -
