The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer Metastasis.
High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Callie A S
CA
Corsa
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Audrey
A
Brenot
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA; Department of Biochemistry, Washington University, St. Louis, MO 63110, USA.
Whitney R
WR
Grither
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Samantha
S
Van Hove
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA; Department of Computational and Molecular Biophysics, Washington University, St. Louis, MO 63110, USA.
Andrew J
AJ
Loza
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Kun
K
Zhang
Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Suzanne M
SM
Ponik
Laboratory for Optical and Computational Imaging, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Yuming
Y
Liu
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
David G
DG
DeNardo
Laboratory for Optical and Computational Imaging, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Kevin W
KW
Eliceiri
Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA; Laboratory for Optical and Computational Imaging, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Patricia J
PJ
Keely
ICCE Institute, Washington University, St. Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA. Electronic address: glongmore@wustl.edu.
Gregory D
GD
Longmore
D000483:Alleles; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000070820:Discoidin Domain Receptor 2 / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D053547:Keratin-14 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009940:Organoids / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment
D053547:Keratin-14; D000070820:Discoidin Domain Receptor 2