Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

Arianna Fumagalli; Koen C. Oost; Lennart Kester; Jessica Morgner; Laura Bornes; Lotte Bruens; Lisa Spaargaren; Maria Azkanaz; Tim Schelfhorst; Evelyne Beerling; Maria C. Heinz; Daniel Postrach; Danielle Seinstra; Anieta M. Sieuwerts; John W.M. Martens; Stefan van der Elst; Martijn van Baalen; Debajit Bhowmick; Nienke Vrisekoop; Saskia I.J. Ellenbroek; Saskia J.E. Suijkerbuijk; Hugo J. Snippert; Jacco van Rheenen

doi:10.1016/j.stem.2020.02.008

Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

Arianna Fumagalli, Koen C. Oost, Lennart Kester, Jessica Morgner, Laura Bornes, Lotte Bruens, Lisa Spaargaren, Maria Azkanaz, Tim Schelfhorst, Evelyne Beerling, Maria C. Heinz, Daniel Postrach, Danielle Seinstra, Anieta M. Sieuwerts, John W.M. Martens, Stefan van der Elst, Martijn van Baalen, Debajit Bhowmick, Nienke Vrisekoop, Saskia I.J. EllenbroekSaskia J.E. Suijkerbuijk, Hugo J. Snippert, Jacco van Rheenen

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117 Citations (Scopus)

Abstract

Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5⁻ and formed distant metastases in which Lgr5⁺ CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5⁻ cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors.

Original language	English
Pages (from-to)	569-578.e7
Journal	Cell Stem Cell
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2020.02.008
Publication status	Published - 2 Apr 2020
Externally published	Yes

Keywords

cancer stem cells
circulating tumor cells
colorectal cancer
intravital microscopy
Lgr5
metastasis
microenvironment
plasticity

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10.1016/j.stem.2020.02.008

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Fumagalli, A., Oost, K. C., Kester, L., Morgner, J., Bornes, L., Bruens, L., Spaargaren, L., Azkanaz, M., Schelfhorst, T., Beerling, E., Heinz, M. C., Postrach, D., Seinstra, D., Sieuwerts, A. M., Martens, J. W. M., van der Elst, S., van Baalen, M., Bhowmick, D., Vrisekoop, N., ... van Rheenen, J. (2020). Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer. Cell Stem Cell, 26(4), 569-578.e7. https://doi.org/10.1016/j.stem.2020.02.008

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title = "Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer",

abstract = "Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5− and formed distant metastases in which Lgr5+ CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5− cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors.",

keywords = "cancer stem cells, circulating tumor cells, colorectal cancer, intravital microscopy, Lgr5, metastasis, microenvironment, plasticity",

author = "Arianna Fumagalli and Oost, {Koen C.} and Lennart Kester and Jessica Morgner and Laura Bornes and Lotte Bruens and Lisa Spaargaren and Maria Azkanaz and Tim Schelfhorst and Evelyne Beerling and Heinz, {Maria C.} and Daniel Postrach and Danielle Seinstra and Sieuwerts, {Anieta M.} and Martens, {John W.M.} and {van der Elst}, Stefan and {van Baalen}, Martijn and Debajit Bhowmick and Nienke Vrisekoop and Ellenbroek, {Saskia I.J.} and Suijkerbuijk, {Saskia J.E.} and Snippert, {Hugo J.} and {van Rheenen}, Jacco",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = apr,

day = "2",

doi = "10.1016/j.stem.2020.02.008",

language = "English",

volume = "26",

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Fumagalli, A, Oost, KC, Kester, L, Morgner, J, Bornes, L, Bruens, L, Spaargaren, L, Azkanaz, M, Schelfhorst, T, Beerling, E, Heinz, MC, Postrach, D, Seinstra, D, Sieuwerts, AM, Martens, JWM, van der Elst, S, van Baalen, M, Bhowmick, D, Vrisekoop, N, Ellenbroek, SIJ, Suijkerbuijk, SJE, Snippert, HJ & van Rheenen, J 2020, 'Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer', Cell Stem Cell, vol. 26, no. 4, pp. 569-578.e7. https://doi.org/10.1016/j.stem.2020.02.008

TY - JOUR

T1 - Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

AU - Fumagalli, Arianna

AU - Oost, Koen C.

AU - Kester, Lennart

AU - Morgner, Jessica

AU - Bornes, Laura

AU - Bruens, Lotte

AU - Spaargaren, Lisa

AU - Azkanaz, Maria

AU - Schelfhorst, Tim

AU - Beerling, Evelyne

AU - Heinz, Maria C.

AU - Postrach, Daniel

AU - Seinstra, Danielle

AU - Sieuwerts, Anieta M.

AU - Martens, John W.M.

AU - van der Elst, Stefan

AU - van Baalen, Martijn

AU - Bhowmick, Debajit

AU - Vrisekoop, Nienke

AU - Ellenbroek, Saskia I.J.

AU - Suijkerbuijk, Saskia J.E.

AU - Snippert, Hugo J.

AU - van Rheenen, Jacco

PY - 2020/4/2

Y1 - 2020/4/2

N2 - Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5− and formed distant metastases in which Lgr5+ CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5− cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors.

AB - Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5− and formed distant metastases in which Lgr5+ CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5− cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors.

KW - cancer stem cells

KW - circulating tumor cells

KW - colorectal cancer

KW - intravital microscopy

KW - Lgr5

KW - metastasis

KW - microenvironment

KW - plasticity

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U2 - 10.1016/j.stem.2020.02.008

DO - 10.1016/j.stem.2020.02.008

M3 - Article

C2 - 32169167

AN - SCOPUS:85083041283

SN - 1934-5909

VL - 26

SP - 569-578.e7

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

Abstract

Keywords

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