0000000000300290
AUTHOR
Caterina Vitali
Stromal niche communalities underscore the contribution of the matricellular protein SPARC to B-cell development and lymphoid malignancies
Neoplastic B-cell clones commonly arise within secondary lymphoid organs (SLO). However, during disease progression, lymphomatous cells may also colonize the bone marrow (BM), where they localize within specialized stromal niches, namely the osteoblastic and the vascular niche, according to their germinal center-or extra-follicular-derivation, respectively. We hypothesized the existence of common stromal motifs in BM and SLO B-cell lymphoid niches involved in licensing normal B-cell development as well as in fostering transformed B lymphoid cells. Thus, we tested the expression of prototypical mesenchymal stromal cell (MSC) markers and regulatory matricellular proteins in human BM and SLO u…
Osteopontin shapes immunosuppression in the metastatic niche.
Abstract The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1−/− mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, wherea…
SOCS2 controls proliferation and stemness of hematopoietic cells under stress conditions and its deregulation marks unfavorable acute leukemias
Abstract Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, replenishing bone marrow–derived circulating populations, while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK–STAT pathways, is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro, sustaining STAT5 phosphorylation in response to IL3, thrombopoietin, and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil (5-FU) and, in turn, induces exhaustion of long-term HSC function along serial bone marro…
Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity.
AbstractAntineutrophil cytoplasmic antibodies (ANCAs) target proteins normally retained within neutrophils, indicating that cell death is involved in the autoimmunity process. Still, ANCA pathogenesis remains obscure. ANCAs activate neutrophils inducing their respiratory burst and a peculiar form of cell death, named NETosis, characterized by formation of neutrophil extracellular traps (NETs), decondensed chromatin threads decorated with cytoplasmic proteins endorsed with antimicrobial activity. NETs have been consistently detected in ANCA-associated small-vessel vasculitis, and this association prompted us to test whether the peculiar structure of NET favors neutrophil proteins uploading i…
MEF2C and SOCS2 in stemness regulation
The physiologic stemness of hematopoietic stem cells (HSC) relies on mechanisms constitutively active under steady state and is fundamental to maintain a lifelong HSC reservoir. On the other side, similar stemness features sustained by partially overlapping molecular circuits, which have recently come into focus, confer aggressive aggressiveness in leukemia clones. Suppressor of Cytokine Signalling 2 (SOCS2) belongs to the SOCS family, comprising eight members (SOCS1–7 and CIS) with similar structures, which are induced upon JAK/STAT activation and function as negative regulators. Recent evidences have demonstrated that SOCS2 is endowed with immunological functions in differentiated cells b…
The matricellular protein SPARC supports follicular dendritic cell networking toward Th17 responses.
Abstract Lymphnode swelling during immune responses is a transient, finely regulated tissue rearrangement, accomplished with the participation of the extracellular matrix. Here we show that murine and human reactive lymph nodes express SPARC in the germinal centres. Defective follicular dendritic cell networking in SPARC-deficient mice is accompanied by a severe delay in the arrangement of germinal centres and development of humoral autoimmunity, events that are linked to Th17 development. SPARC is required for the optimal and rapid differentiation of Th17 cells, accordingly we show delayed development of experimental autoimmune encephalomyelitis whose pathogenesis involves Th17. Not only h…
Defective stromal remodeling and neutrophil extracellular traps in lymphoid tissues favor the transition from autoimmunity to lymphoma
Abstract Altered expression of matricellular proteins can become pathogenic in the presence of persistent perturbations in tissue homeostasis. Here, we show that autoimmunity associated with Fas mutation was exacerbated and transitioned to lymphomagenesis in the absence of SPARC (secreted protein acidic rich in cysteine). The absence of SPARC resulted in defective collagen assembly, with uneven compartmentalization of lymphoid and myeloid populations within secondary lymphoid organs (SLO), and faulty delivery of inhibitory signals from the extracellular matrix. These conditions promoted aberrant interactions between neutrophil extracellular traps and CD5+ B cells, which underwent malignant …