TY - JOUR
T1 - Spatiotemporal regulation of clonogenicity in colorectal cancer xenografts
AU - van der Heijden, Maartje
AU - Miedema, Daniël M.
AU - Waclaw, Bartlomiej
AU - Veenstra, Veronique L.
AU - Lecca, Maria C.
AU - Nijman, Lisanne E.
AU - van Dijk, Erik
AU - van Neerven, Sanne M.
AU - Lodestijn, Sophie C.
AU - Lenos, Kristiaan J.
AU - de Groot, Nina E.
AU - Prasetyanti, Pramudita R.
AU - Varea, Andrea Arricibita
AU - Winton, Douglas J.
AU - Medema, Jan Paul
AU - Morrissey, Edward
AU - Ylstra, Bauke
AU - Nowak, Martin A.
AU - Bijlsma, Maarten F.
AU - Vermeulen, Louis
N1 - Copyright © 2019 the Author(s). Published by PNAS.
PY - 2019/3/26
Y1 - 2019/3/26
N2 - Cancer evolution is predominantly studied by focusing on differences in the genetic characteristics of malignant cells within tumors. However, the spatiotemporal dynamics of clonal outgrowth that underlie evolutionary trajectories remain largely unresolved. Here, we sought to unravel the clonal dynamics of colorectal cancer (CRC) expansion in space and time by using a color-based clonal tracing method. This method involves lentiviral red-green-blue (RGB) marking of cell populations, which enabled us to track individual cells and their clonal outgrowth during tumor initiation and growth in a xenograft model. We found that clonal expansion largely depends on the location of a clone, as small clones reside in the center and large clones mostly drive tumor growth at the border. These dynamics are recapitulated in a computational model, which confirms that the clone position within a tumor rather than cell-intrinsic features, is crucial for clonal outgrowth. We also found that no significant clonal loss occurs during tumor growth and clonal dispersal is limited in most models. Our results imply that, in addition to molecular features of clones such as (epi-)genetic differences between cells, clone location and the geometry of tumor growth are crucial for clonal expansion. Our findings suggest that either microenvironmental signals on the tumor border or differences in physical properties within the tumor, are major contributors to explain heterogeneous clonal expansion. Thus, this study provides further insights into the dynamics of solid tumor growth and progression, as well as the origins of tumor cell heterogeneity in a relevant model system.
AB - Cancer evolution is predominantly studied by focusing on differences in the genetic characteristics of malignant cells within tumors. However, the spatiotemporal dynamics of clonal outgrowth that underlie evolutionary trajectories remain largely unresolved. Here, we sought to unravel the clonal dynamics of colorectal cancer (CRC) expansion in space and time by using a color-based clonal tracing method. This method involves lentiviral red-green-blue (RGB) marking of cell populations, which enabled us to track individual cells and their clonal outgrowth during tumor initiation and growth in a xenograft model. We found that clonal expansion largely depends on the location of a clone, as small clones reside in the center and large clones mostly drive tumor growth at the border. These dynamics are recapitulated in a computational model, which confirms that the clone position within a tumor rather than cell-intrinsic features, is crucial for clonal outgrowth. We also found that no significant clonal loss occurs during tumor growth and clonal dispersal is limited in most models. Our results imply that, in addition to molecular features of clones such as (epi-)genetic differences between cells, clone location and the geometry of tumor growth are crucial for clonal expansion. Our findings suggest that either microenvironmental signals on the tumor border or differences in physical properties within the tumor, are major contributors to explain heterogeneous clonal expansion. Thus, this study provides further insights into the dynamics of solid tumor growth and progression, as well as the origins of tumor cell heterogeneity in a relevant model system.
KW - Cancer evolution
KW - Cancer stem cells
KW - Colorectal cancer
KW - Intratumor heterogeneity
KW - Tumor growth
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063961772&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30850544
U2 - https://doi.org/10.1073/pnas.1813417116
DO - https://doi.org/10.1073/pnas.1813417116
M3 - Article
C2 - 30850544
SN - 0027-8424
VL - 116
SP - 6140
EP - 6145
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 13
ER -