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Tumour stromal cells support tumourigenesis. We report that Syndecan‐2 (SDC2) is expressed on a nonepithelial, nonhaematopoietic, nonendothelial stromal cell population within breast cancer tissue. In vitro, syndecan‐2 modulated TGFβ signalling (SMAD7, PAI‐1), migration and immunosuppression of patient‐derived tumour‐associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model, overexpression of syndecan‐2 in TASCs significantly enhanced TGFβ signalling (SMAD7, PAI‐1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFβ signalling (SMAD7, PAI‐1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan‐2‐peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFβ‐regulated immunosuppressive genes, such as CXCR4 and PD‐L1. Moreover, using an orthotopic syngeneic breast cancer model, overexpression of syndecan‐2‐peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan‐2 within the TME inhibits tumour growth and metastasis due to decreased TGFβ signalling and increased immune control., What's new? Tumour‐associated stromal cells within the tumour microenvironment play a significant role in promoting tumorigenesis. Current strategies to inhibit tumour‐associated stromal cell function must however reduce the potential side‐effects associated with affecting normal stromal cells. In this study, the authors report that Syndecan‐2 is expressed on a non‐epithelial, non‐haematopoietic, non‐endothelial stromal cell population within breast cancer tissue. Syndecan‐2 contributes to the oncogenic properties of tumour‐associated stromal cells by promoting TGF‐β signalling, tumour growth, metastasis, and immunosuppression. Altogether, the results highlight pro‐tumorigenic, immunosuppressive Syndecan‐2+ stromal cells within the breast tumour microenvironment as a potential therapeutic target.

The marrow microenvironment is a complex and heterogeneous mixture of hematopoietic and stromal progenitors necessary for haematopoiesis. Whilst the hematopoietic progenitors are well described, the stromal cellular composition is not fully elucidated due to the low cells numbers, localisation-distribution-accessibility, and the lack of specific biomarkers. Cellular taxonomy studies have recently identified new populations of stromal subsets with distinct gene signature and regulatory properties of hematopoietic regeneration. Fibroblast activation protein-α (FAP), a stromal cell type first identified in cancer is also rarely found in normal tissues but might play an essential role in tissue homeostasis. Using FAPDM2 transgenic mouse in which FAP-expressing cells can be ablated with Diphtheria Toxin (DTX) FAP+ cells were depleted in healthy mice. Whilst FAP+ cells constituted 5% of all marrow cells; its ablation caused a rapid loss of PDGFR-α, Leptin-R, gp38 and SDC2 stromal cells populations, endothelial cells and vascular disruption. These resulted in anaemia, thrombocytopenia and neutropenia in peripheral blood (PB) and extreme hypo-cellularity in marrow with abnormalities within the hematopoietic progenitors. In an effort to reverse the phenotypes caused by FAP+ cell loss, a single intravenous injection of syngeneic bone marrow-derived stromal cells was administered. In a short-term evaluation, anaemia, thrombocytopenia and neutropenia ameliorated in PB and the numbers of marrow hematopoietic progenitors increased. Our data suggest FAP-expressing cells are a non-redundant component of the marrow microenvironment, necessary for marrow homeostasis and haematopoiesis. These data also provided evidence that stromal cell ablation can be rescued by stromal cell therapy.Significance StatementFAP-expressing cells depletion led to collateral damage in PB and marrow, including haematological defects that can be ameliorated by adoptive transfer of low-dose, ex-vivo expanded FAP-expressing marrow stromal cells. We suggest that stromal cell loss is a feature of severe immune-mediated inflammatory diseases – such as Graft versus Host Disease and sepsis - and that FAPDM2 model represents a novel tool to explore the native function of the recently identified stromal cell sub-populations.