The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation
Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

Andersson, PatrikKarolinska Institutet (author)
Hosaka, KayokoKarolinska Institutet (author)
Zhang, YinKarolinska Institute, Sweden (author)
Cao, RenhaiKarolinska Institutet (author)
Iwamoto, HidekiKarolinska Institute, Sweden (author)
Yang, XiaojuanKarolinska Institute, Sweden (author)
Nakamura, MasakiKarolinska Institutet (author)
Wang, JianKarolinska Institute, Sweden (author)
Zhuang, RujieTCM Hospital Zhejiang Prov, Peoples R China (author)
Morikawa, HiromasaKarolinska Institutet (author)
Xue, YuanKarolinska Institute, Sweden; MIT, MA 02139 USA (author)
Braun, HaraldUniversity of Ghent, Belgium; Inflammat Research Centre VIB, Belgium (author)
Beyaert, RudiUniversity of Ghent, Belgium; Inflammat Research Centre VIB, Belgium (author)
Samani, NileshUniversity of Leicester, England; Glenfield Hospital, England (author)
Nakae, SusumuUniversity of Tokyo, Japan (author)
Hams, EmilyUniversity of Dublin Trinity Coll, Ireland (author)
Dissing, SteenUniversity of Copenhagen, Denmark (author)
Fallon, Padraic G.University of Dublin Trinity Coll, Ireland (author)
Langer, RobertKarolinska Inst, Stockholm, Sweden, Univ Leicester, Leicester, England, Glenfield Hosp, Leicester, England (author)
Cao, YihaiLinköpings universitet,Avdelningen för kardiovaskulär medicin,Medicinska fakulteten,Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England(Swepub:liu)yihca64 (author)
Karolinska InstitutetKarolinska Institute, Sweden (creator_code:org_t)

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