Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps 1 . Although dissemination of tumour cells seems to be an early and frequent event 2 , the successful initiation of metastatic growth, a process termed 'metastatic colonization', is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites 3,4 . Prevalent target sites are characteristic of many tumour entities 5 , suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.We aimed to explore limiting factors that determine metastatic success using the MMTV-PyMT mouse breast cancer model, which spontaneously metastasizes to the lungs 6 . We reasoned that the recently identified cancer stem cells (CSCs, also called tumour-initiating cells), a subset of cancer cells that allow long-term tumour growth and are thought to be responsible for remissions 7,8 , might also be relevant to the development of metastatic disease ( Supplementary Fig. 1). We measured the relative size of the population of CSCs from primary MMTV-PyMT tumours and their pulmonary metastases using the previously established markers CD90 and CD24, which label a subset of the CD24 1 CD29hi or CD241 CD49f hi population used earlier to isolate CSCs and normal mammary gland stem cells 9-13 (Supplementary Fig. 2). This CSC subset accounts for 3 6 2.1% (s.d.) of all tumour cells from both primary tumours and metastases (Fig. 1a). When CD90 1 CD241 CSCs or CD90 1 CD24 1 -depleted non-CSCs are separately isolated from GFP 1 tumours and directly introduced into mice through tail vein injection (GFP, green fluorescent protein), only the CSC population is able to produce lung metastases (Fig. 1b). Moreover, CD90 1 CD241 cells isolated subsequently from pulmonary metastases are again the only tumour cell population that efficiently initiates secondary metastases (Fig. 1c). This is not due to differences in the extravasation capabilities of CSCs an...

BackgroundObesity is a strong predictor of poor prognosis in breast cancer, especially in postmenopausal women. In particular, tumors in obese patients tend to seed more distant metastases, although the biology behind this observation remains poorly understood.MethodsTo elucidate the effects of the obese microenvironment on metastatic spread, we ovariectomized C57BL/6 J female mice and fed them either a regular diet (RD) or a high-fat diet (HFD) to generate a postmenopausal diet-induced obesity model. We then studied tumor progression to metastasis of Py230 and EO771 grafts. We analyzed and phenotyped the RD and HFD tumors and the surrounding adipose tissue by flow cytometry, qPCR, immunohistochemistry (IHC) and western blot. The influence of the microenvironment on tumor cells was assessed by performing cross-transplantation of RD and HFD tumor cells into other RD and HFD mice. The results were analyzed using the unpaired Student t test when comparing two variables, otherwise we used one-way or two-way analysis of variance. The relationship between two variables was calculated using correlation coefficients.ResultsOur results show that tumors in obese mice grow faster, are also less vascularized, more hypoxic, of higher grade and enriched in CD11b+Ly6G+ neutrophils. Collectively, this favors induction of the epithelial-to-mesenchymal transition and progression to claudin-low breast cancer, a subtype of triple-negative breast cancer that is enriched in cancer stem cells. Interestingly, transplanting HFD-derived tumor cells in RD mice transfers enhanced tumor growth and lung metastasis formation.ConclusionsThese data indicate that a pro-metastatic effect of obesity is acquired by the tumor cells in the primary tumor independently of the microenvironment of the secondary site.Graphical abstractEffects of postmenopausal obesity on primary breast cancer tumoursᅟElectronic supplementary materialThe online version of this article (10.1186/s13058-018-1029-4) contains supplementary material, which is available to authorized users.

Integrins play an important role in haematopoietic stem cell (HSC) maintenance in the bone marrow niche. Here, we demonstrate that Periostin (Postn) via interaction with Integrin-αv (Itgav) regulates HSC proliferation. Systemic deletion of Postn results in peripheral blood (PB) anaemia, myelomonocytosis and lymphopenia, while the number of phenotypic HSCs increases in the bone marrow. Postn−/− mice recover faster from radiation injury with concomitant loss of primitive HSCs. HSCs from Postn−/− mice show accumulation of DNA damage generally associated with aged HSCs. Itgav deletion in the haematopoietic system leads to a similar PB phenotype and HSC-intrinsic repopulation defects. Unaffected by Postn, Vav-Itgav−/− HSCs proliferate faster in vitro, illustrating the importance of Postn-Itgav interaction. Finally, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, leading to increase in p27Kip1 expression resulting in improved maintenance of quiescent HSCs. Together, we demonstrate a role for Itgav-mediated outside-in signalling in regulation of HSC proliferation and stemness.

Breast cancer metastasis is a complex process that depends on intrinsic characteristics of metastatic stem cells, but also on the particular microenvironment that supports their growth and modulates the plasticity of the system. In search for microenvironmental factors supporting cancer stem cell (CSC) growth and tumour progression to metastasis, we here investigated the role of the matricellular protein Transforming Growth Factor Beta Induced (TGFBI) in breast cancer. We crossed the MMTV-PyMT model of mammary gland tumourigenesis with a Tgfbi / mouse, and studied the CSC content of the tumours. We performed RNAseq on wt and ko tumours, and analysed the tumour vasculature and the immune compartment by IHC and FACS. The source of TGFBI expression was determined by qPCR and by bone marrow transplantation experiments. Finally, we performed in silico analyses using the METABRIC cohort to assess the potential prognostic value of TGFBI. We observed that deletion of Tgfbi led to a dramatic decrease in CSC content and lung metastasis. Our results show that lack of TGFBI resulted in tumour vessel normalisation, with improved vessel perfusion and decreased hypoxia, a major factor controlling CSCs and metastasis. Furthermore, human data