TY - JOUR
T1 - A Cdh3-β-catenin-laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration
AU - Hwang, Priscilla Y.
AU - Mathur, Jairaj
AU - Cao, Yanyang
AU - Almeida, Jose
AU - Ye, Jiayu
AU - Morikis, Vasilios
AU - Cornish, Daphne
AU - Clarke, Maria
AU - Stewart-Wigglesworth, Sheila
AU - Pathak, Amit
AU - Longmore, Gregory D.
N1 - Funding Information:
This work was supported by the following funding mechanisms: R01CA223758 and U54CA210173 (G.D.L.), R35GM128764 (A.P.), NSF Center for Engineering MechanoBiology (A.P.), American Cancer Society Postdoctoral Fellowship (PF-17-238-01-CSM) (P.Y.H.). A Centene Corporation contract (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative (G.D.L.). We thank the following people: Ashley C. King, Caleb McCurdy, and Jessanne Y. Lichtenberg for assistance synthesizing the microfluidic systems, Takako Sasaki for the laminin α3 antibody (1110+), Prabhakar Andhey and Maxim Artyomov for bioinformatic assistance, the Washington University Center for Cellular Imaging (WUCCI) and VCU Nanomaterials Core Characterization Facility for imaging assistance, the Flow cytometry and fluorescence-activated cell sorting Core at Washington University, and the McDonnell Genome Institute at Washington University for single-cell sequencing. We would like to thank Cara Gottardi, Northwestern University for assistance in design of β-cat/TCF ChIP experiments. We support inclusive, diverse, and equitable conduct of research. P.Y.H. G.D.L. and A.P. conceived the project, designed experiments, and wrote the manuscript. P.Y.H. D.C. Y.C. M.C. J.Y. S.A.S. V.M. and J.A. performed experiments and, or data analysis. J.M. and A.P. performed computational modeling and wrote corresponding results. The Longmore laboratory receives funding from Pfizer-CTI, San Diego CA and Centene Corporation, St. Louis, MO, USA.
Funding Information:
This work was supported by the following funding mechanisms: R01CA223758 and U54CA210173 (G.D.L.), R35GM128764 (A.P.), NSF Center for Engineering MechanoBiology (A.P.), American Cancer Society Postdoctoral Fellowship ( PF-17-238-01-CSM ) (P.Y.H.). A Centene Corporation contract ( P19-00559 ) for the Washington University-Centene ARCH Personalized Medicine Initiative (G.D.L.). We thank the following people: Ashley C. King, Caleb McCurdy, and Jessanne Y. Lichtenberg for assistance synthesizing the microfluidic systems, Takako Sasaki for the laminin α3 antibody (1110+), Prabhakar Andhey and Maxim Artyomov for bioinformatic assistance, the Washington University Center for Cellular Imaging (WUCCI) and VCU Nanomaterials Core Characterization Facility for imaging assistance, the Flow cytometry and fluorescence-activated cell sorting Core at Washington University, and the McDonnell Genome Institute at Washington University for single-cell sequencing. We would like to thank Cara Gottardi, Northwestern University for assistance in design of β-cat/TCF ChIP experiments. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/9
Y1 - 2023/1/9
N2 - Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration.
AB - Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration.
KW - cadherin-integrin crosstalk
KW - cancer metastasis
KW - cellular protrusion dynamics
KW - collective migration
KW - leader cells
UR - http://www.scopus.com/inward/record.url?scp=85145855179&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2022.12.005
DO - 10.1016/j.devcel.2022.12.005
M3 - Article
C2 - 36626870
AN - SCOPUS:85145855179
SN - 1534-5807
VL - 58
SP - 34-50.e9
JO - Developmental Cell
JF - Developmental Cell
IS - 1
ER -