The Drosophila functional Smad suppressing element fuss, a homologue of the human Skor genes, retains pro-oncogenic properties of the Ski/Sno family

Over the years Ski and Sno have been found to be involved in cancer progression e.g. in oesophageal squamous cell carcinoma, melanoma, oestrogen receptor-positive breast carcinoma, colorectal carcinoma, and leukaemia. Often, their prooncogenic features have been linked to their ability of inhibiting the anti-proliferative action of TGF-ß signalling. Recently, not only pro-oncogenic but also anti-oncogenic functions of Ski/Sno proteins have been revealed. Besides Ski and Sno, which are ubiquitously expressed other members of Ski/Sno proteins exist which show highly specific neuronal expression, the SKI Family Transcriptional Corepressors (Skor). Among others Skor1 and Skor2 are involved in the development of Purkinje neurons and a mutation of Skor1 has been found to be associated with restless legs syndrome. But neither Skor1 nor Skor2 have been reported to be involved in cancer progression. Using overexpression studies in the Drosophila eye imaginal disc, we analysed if the Drosophila Skor homologue Fuss has retained the potential to inhibit differentiation and induce increased proliferation. Fuss expressed in cells posterior to the morphogenetic furrow, impairs photoreceptor axon pathfinding and inhibits differentiation of accessory cells. However, if its expression is induced prior to eye differentiation, Fuss might inhibit the differentiating function of Dpp signalling and might maintain proliferative action of Wg signalling, which is reminiscent of the Ski/Sno protein function in cancer.

Exploring the Pathways to Chronic Lymphocytic Leukemia

In chronic lymphocytic leukemia (CLL), increasing knowledge of the biology of the tumor cells has led to transformative improvements in our capacity to assess and treat patients. The dependence of tumor cells on surface immunoglobulin (Ig) receptor signaling, on survival pathways, and on accessory cells within the microenvironment has led to a successful double-barrelled attack with designer drugs. Studies have revealed that CLL should be classified based on the mutational status of the expressed IGHV sequences into two diseases, either unmutated (U) or mutated (M)-CLL, each with a distinctive cellular origin, biology, epigenetics/genetics, and clinical behavior. The origin of U-CLL lies among the natural antibody repertoire and dominance of IGHV1-69 reveals a superantigenic driver. In both U-CLL and M-CLL, a calibrated stimulation of tumor cells by self-antigens apparently generates a dynamic reiterative cycle as cells, protected from apoptosis, transit between blood and tissue sites. But there are differences in outcome, with the balance between proliferation and anergy favoring anergy in M-CLL. Responses are modulated by an array of microenvironmental interactions. Availability of T-cell help is a likely determinant of cell fate, the dependency on which varies between U-CLL and M-CLL, reflecting the different cells of origin, and affecting clinical behavior. Despite such advances, cell-escape strategies, Richter transformation, and immunosuppression remain as challenges, which only may be met by continued research into the biology of CLL.

Signaling Pathway Mediating Myeloma Cell Growth and Survival

The multiple myeloma (MM) bone marrow (BM) microenvironment consists of different types of accessory cells. Both soluble factors (i.e., cytokines) secreted from these cells and adhesion of MM cells to these cells play crucial roles in activation of intracellular signaling pathways mediating MM cell growth, survival, migration, and drug resistance. Importantly, there is crosstalk between the signaling pathways, increasing the complexity of signal transduction networks in MM cells in the BM microenvironment, highlighting the requirement for combination treatment strategies to blocking multiple signaling pathways.

Role of Chronic Lymphocytic Leukemia (CLL)-Derived Exosomes in Tumor Progression and Survival

Chronic lymphocytic leukemia (CLL) is a B-lymphoproliferative disease, which consists of the abnormal proliferation of CD19/CD5/CD20/CD23 positive lymphocytes in blood and lymphoid organs, such as bone marrow, lymph nodes and spleen. The neoplastic transformation and expansion of tumor B cells are commonly recognized as antigen-driven processes, mediated by the interaction of antigens with the B cell receptor (BCR) expressed on the surface of B-lymphocytes. The survival and progression of CLL cells largely depend on the direct interaction of CLL cells with receptors of accessory cells of tumor microenvironment. Recently, much interest has been focused on the role of tumor release of small extracellular vesicles (EVs), named exosomes, which incorporate a wide range of biologically active molecules, particularly microRNAs and proteins, which sustain the tumor growth. Here, we will review the role of CLL-derived exosomes as diagnostic and prognostic biomarkers of the disease.

Neutrophils as Sentinel Cells of the Immune System: A Role of the MPO-halide-system in Innate and Adaptive Immunity

: For decades, neutrophils were generally regarded as the cells of innate immunity with proinflammatory and phagocytic properties involved in a dual activity, beneficial (antimicrobial) and detrimental (tissue damage). Importantly, until the discovery of toll-like receptors (TLRs), a role of neutrophils in adaptive immunity was limited to the effector stage of humoral response and phagocytosis of opsonized antigens. Moreover, in common opinion, neutrophils, as well as the entire innate immune system, were not functionally associated with adaptive immunity. At the time we demonstrated protein chlorination by HOCl, the major product of neutrophil MPO-halide system enhances protein immunogenicity. Based on this discovery, we proposed, as the first, a new role for neutrophils as APC-accessory cells involved in the induction stage of adaptive immunity. Thereafter, we developed our theory concerning the role of neutrophils as the cells which link innate and adaptive immunity. We proposed that protein modification by HOCl may act as a neutrophildependent molecular tagging system, by which sentinel dendritic cells can faster recognise pathogen- derived antigens. Contemporaneously, it was demonstrated that taurine, the most abundant free amino acid in neutrophil cytosol and the major scavenger of HOCl, is a part of the oxidantantioxidant network and is responsible for the regulation and termination of acute inflammation. Moreover, it has been described, that taurine chloramine (TauCl), the physiological products of the reaction of HOCl with taurine, show anti-microbial and anti-inflammatory properties. : In this review, the role of HOCl, taurine and TauCl in innate and adaptive immunity will be discussed.

The Na+-K+-ATPase is needed in glia of touch receptors for responses to touch in C. elegans

Increasing evidences support that accessory cells in mechanosensors regulate neuronal output; however, the glial molecular mechanisms that control this regulation are not fully understood. We show here in Caenorhabditis elegans that specific glial Na+-K+-ATPase genes are needed for nose touch-avoidance behavior. Our data support the requirement of these Na+-K+-ATPases for homeostasis of Na+ and K+ in nose touch receptors. Our data add to our understanding of glial regulation of mechanosensors.

Regulatory T Cells in Cancer

The immune system has evolved complex effector mechanisms to protect the host against a diversity of pathogenic organisms and regulatory adaptations that can curtail pathological sequelae of inflammatory events, prevent autoimmunity, and assist in tissue repair. Cancers, by virtue of their local manifestations of tissue dysfunction and destruction, inflammation, and genomic instability, can evoke these protective mechanisms, which support the progression of tumors and prevent their immune eradication. Central to these processes is a subset of CD4+ T cells, known as regulatory T (Treg) cells, that express the X chromosome–linked transcription factor FOXP3. In addition to their critical role in controlling autoimmunity and suppressing inflammatory responses in diverse biological settings, Treg cells are ubiquitously present in the tumor microenvironment where they promote tumor development and progression by dampening antitumor immune responses. Furthermore, Treg cells can directly support the survival of transformed cells through the elaboration of growth factors and interacting with accessory cells in tumors such as fibroblasts and endothelial cells. Current insights into the biology of tumor-associated Treg cells have opened up opportunities for their selective targeting in cancer, with the goal of alleviating their suppression of antitumor immune responses while maintaining overall immune homeostasis.

Wnt5a Induces ROR1-Dependent Upregulation of MMP9 and Enhanced Invasiveness in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) cells recirculate between blood and lymphoid tissue compartments, where they receive growth/survival signals from accessory cells within the lymphoid-tissue microenvironment. Such trafficking requires leukemia cells to pass through endothelial barriers and to transverse the extracellular matrix (EM), a process that is facilitated by matrix metallopeptidases (MMP). We co-cultured CLL cells with marrow mesenchymal stromal cells (MSCs) at a physiologic oxygen tension (e.g., 5% O2 in N2). Under such conditions we found that MSCs could enhance leukemia-cell expression of MMP9, a 92 kDa type IV collagenase and key MMP involved in EM degradation. Unexpectedly, however, we found circulating CLL cells with high-level expression of the onco-embryonic protein, ROR1 (designated ROR1Pos), also had high-level expression of MMP9 despite not having immediate contact with such accessory cells. Moreover, we found that circulating ROR1Pos CLL (N = 12) had significantly greater levels of MMP9 than blood CLL cells with low-to-negligible levels of ROR1 (ROR1Neg CLL, N = 10) (P < 0.001). Short-term culture of ROR1Pos CLL in serum-free media significantly reduced their expressed levels of MMP9, unless we added exogenous Wnt5a, a non-canonical Wnt factor and ligand for ROR1 that we found expressed at significantly higher levels in the plasma of patients with CLL than in age-matched adults (Yu et al., J Clin Invest, 2015). Treatment of ROR1Pos CLL cells with Wnt5a enhanced their expression and release of MMP9 and their capacity to invade Matrigel in a Boyden-Chamber Assay; such effects could not be inhibited by inhibitors of B-cell receptor/chemokine signaling (e.g. Ibrutinib), but could be blocked by cirmtuzumab, a humanized mAb specific for ROR1 that can inhibit leukemia-cell ROR1-signaling in patients with CLL (Choi et al., Cell Stem Cell, 2018). Silencing expression of MMP9 with siRNA or treatment with a MMP9-specific inhibitor (CAS 1177749-58-4) could inhibit the capacity of Wnt5a to enhance the invasive capability of CLL cells, indicating that MMP9 plays a major role in facilitating CLL-cell invasiveness. Targeted siRNA-mediated silencing of cytoskeletal proteins HS1/cortactin, which complex with ROR1 in response to Wnt5a (Hasan et al., Leukemia, 2018; Hasan et al., Leukemia, 2017), also impaired the capacity of Wnt5a to enhance expression and release of MMP9 in ROR1Pos CLL. Collectively, these studies indicate that Wnt5a can induce ROR1-signaling leading to enhanced expression of MMP9, which can facilitate invasion of the EM. Moreover, inhibitors of ROR1 signaling, such as cirmtuzumab, can repress Wnt5a-induced CLL-cell expression of MMP9, potentially impairing the homing of ROR1Pos CLL to their protective niches within the lymphoid microenvironment. Disclosures Kipps: AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees.