Pericyte-fibroblast transition promotes tumor growth and metastasis.
Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte-fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB-activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB-induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB-promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
Kayoko
K
Hosaka
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Key Laboratory of International Collaborations, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China;
Yunlong
Y
Yang
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
Takahiro
T
Seki
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
Carina
C
Fischer
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
Olivier
O
Dubey
Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden;
Erik
E
Fredlund
Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden;
Johan
J
Hartman
Center for Molecular Medicine, Department of Medicine, Solna, Karolinska Institute, 171 76 Stockholm, Sweden;
Piotr
P
Religa
Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden;
Hiromasa
0000-0002-6793-5885
H
Morikawa
Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan;
Yoko
Y
Ishii
Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan;
Masakiyo
M
Sasahara
Department of Oncology-Pathology, Karolinska Institute, 171 77 Stockholm, Sweden;
Ola
O
Larsson
Department of Cell and Developmental Biology, University College London, London WC1E 6DE, United Kingdom;
Giulio
G
Cossu
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
Renhai
R
Cao
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
Sharon
S
Lim
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Key Laboratory of International Collaborations, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China; Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE1 7RH, United Kingdom yihai.cao@ki.se.
Yihai
Y
Cao
D000818:Animals; D000077214:Becaplermin; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta
PDGF; fibroblast; mesenchymal cell; metastasis; pericyte