ADAMTS1 protease is required for a balanced immune cell repertoire and tumour inflammatory response

Abstract

Recent advances have emphasized the relevance of studying the extracellular microenvironment given its main contribution to tissue homeostasis and disease. Within this complex scenario, we have studied the extracellular protease ADAMTS1 (a disintegrin and metalloprotease with thrombospondin motif 1), implicated in vascularization and development, with reported anti- and pro-tumorigenic activities. In this work we performed a detailed study of the vasculature and substrates in adult organs of wild type and Adamts1-deficient mice. In addition to the expected alterations of organs like kidney, heart and aorta, we found that the lack of ADAMTS1 differently affects lymphocyte and myeloid populations in the spleen and bone marrow. The study of the substrate versican also revealed its alteration in the absence of the protease. With such premises, we challenged our mice with subcutaneous B16F1 syngeneic tumours and closely evaluated the immune repertoire in the tumours but also in the distant spleen and bone marrow. Our results confirmed a pro-inflammatory landscape in the absence of ADAMTS1, correlating with tumour blockade, supporting its novel role as a modulator of the immune cell response.

Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells

“…Indeed, our data with SwN mice disclosed a complete halt using ATS1-KO cells, which was partially overcome using an NSG model. Importantly, the immune system of NSG mice displays a stronger defect than SwN, so the distinct ability of ATS1-KO cells to initiate tumor progression in these two models could be related with an immunomodulatory role already attributed to ADAMTS1 [11]. Certainly, these results encourage further studies to unveil the impact of this ECM-modifying enzyme on the immune system, although distinct models must be considered.…”

“…All these data confirmed the relevance of ADAMTS1 for tumor development. Since previous findings already remarked its effect on the vasculature [9,11,24], we analyzed it in our NSG samples. Endomucin (EMCN) IF revealed an increased vessel density but a reduction in perimeter in tumors derived from ATS1-KO cells (Figure 3e,f), resulting in a lack of significant differences in terms of total vessel area between WT and ATS1-KO tumors (Figure 3f), as previously described in other tumor studies [6,9].…”

“…Animals were monitored every two days after cell injection until final time point, when they were sacrificed and tumors were dissected for further analyses. Tumor volume was calculated as: in progress tumor volume = (π × length × width 2 )/6, and final tumor volume = (π × length × width × height)/6) [11].…”

“…In fact, proteolytic activity has been widely acknowledged in different tumor types [3]. Among these proteases, studies on ADAMTS1, first member of the ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin motifs) family [4], underlined its tumor suppressive [5,6] but also its protumorigenic properties [7][8][9], including its key contribution for the acquisition of an endothelial-like (EL) phenotype [10] or its competences to modulate the immune response [11]. Likewise, similar attributes have been reported to further ADAMTS members [12], recognizing the necessary commitment to know better the nature of ADAMTS-mediated actions that concern the modulation of phenotypic properties of cancer cells.…”

Identification of prognosis-related genes in the tumor microenvironment of stomach adenocarcinoma by TCGA and GEO datasets

“…ADAMTS1 expression was dysregulated in primary gastric cancer and paired lymph node metastasis [38]. Recent study found that ADAMTS1 was required for a balanced immune cell repertoire and tumor inflammatory response via affecting lymphocyte and myeloid populations in the spleen and bone marrow [39]. In the present study, we analyzed the correlations between OGN, JAM2, RERG, OLFML2B, and ADAMTS1 expressions and clinical characteristics (clinical stage, grade, N stage, T stage, and H. polyri infection) (Supplementary Figure S1).…”