Abstract
The metastatic potential of tumors depends in part on their response to growth factors available in the tumor microenvironment. We addressed how micro-environmental cues control tumor cell ...invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that pharmacological blockade of FGFR represses brain tissue infiltration in vivo. TGF-ß regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-ß pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-ß counters inactivation of FRS2 and restores pro-invasive signaling 1. These findings pinpoint coincidence detection of bFGF and TGF-ß signaling by FRS2 as a mechanism that controls tumor cell invasion and identified targeting of FRS2 as a rational strategy to abrogate aberrant FGFR signaling independent of kinase inhibition. Using computer-assisted compound discovery, we screened chemical libraries for potential small molecule inhibitors of the interaction between FGFR and FRS2. Using functional testing, we selected potential hits that block invasion comparable to current small molecule FGFR kinase inhibitors and that bind FRS2 in the relevant domain. Thus, our study provides first evidence of rationally discovered, precisely acting small molecule interaction inhibitors with the potential to effectively target pro-invasive signaling in MB and other FGFR-driven cancers. 1. Santhana Kumar K et al. Cell Rep. 2018; 23: 3798–812
Abstract
Aberrant activation of the sonic hedgehog (SHH) pathway is one of the key drivers of tumorigenesis in aggressive pediatric brain tumors. However, SHH pathway inhibitors for the treatment of ...brain tumors demonstrated only limited responses in clinical trials indicating that a better understanding of the human SHH pathway is needed. Using an integrative transcriptomic analysis of several thousand normal and neoplastic tissues with and without SHH activation, we identified HHIP-AS1 as an important long non-coding RNA that is strongly associated with SHH signaling in pediatric brain tumors. HHIP-AS1 expression was significantly up- and downregulated upon SHH activation or inhibition, respectively. We also revealed that HHIP-AS1 shares a bidirectional promoter with HHIP and that common transcription factors control both expressions. Transient and stable HHIP-AS1 knockdown (KD) led to a significant less aggressive phenotype of medulloblastoma and ATRT in vitro and in vivo (in cell lines, patient-derived primary cultures and in orthotopic mouse models). In detail, we observed a significant reduction of proliferation, cell viability, clonogenicity, and an induction of cell cycle arrest with a mitotic arrest upon HHIP-AS1 KD. Additionally, RNA sequencing and proteomic analysis unraveled cytoplasmic dynein complex 1 intermediate chain 2 (DYNC1I2), which is a key mitosis regulator, as a target of HHIP-AS1. Further investigations revealed that HHIP-AS1 stabilizes DYNC1I2 via RNA–RNA interaction and that DYNC1I2 overexpression rescued the observed phenotypes. Taken together, our analysis demonstrates that HHIP-AS1 promotes tumorigenesis in SHH-driven brain tumors and identify a novel lncRNA as a component in the human SHH signaling pathway.
STEM CELLS
Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker ...of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca
-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.
Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell-based immunotherapies. Evidence suggests that activation of stimulator of interferon ...genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell-based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of
and
genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell-based immunotherapies.
Osteogenesis is an important developmental event that results in bone formation. Bone forming cells or osteoblasts develop from mesenchymal stem cells (MSCs) through a highly controlled process ...regulated by several signaling pathways. The osteogenic lineage commitment of MSCs is controlled by cell–cell interactions, paracrine factors, mechanical signals, hormones, and cytokines present in their niche, which activate a plethora of signaling molecules belonging to bone morphogenetic proteins, Wnt, Hedgehog, and Notch signaling. These signaling pathways individually as well as in coordination with other signaling molecules, regulate the osteogenic lineage commitment of MSCs by activating several osteo-lineage specific transcription factors. Here, we discuss the key signaling pathways that regulate osteogenic differentiation of MSCs and the cross-talk between them during osteogenic differentiation. We also discuss how these signaling pathways can be modified for therapy for bone repair and regeneration.
Plant glutamate receptor-like (GLR) genes encode ion channels with demonstrated roles in electrical and calcium (Ca
2+
) signaling. The expansion of the GLR family along the lineage of land plants, ...culminating in the appearance of a multiclade system among flowering plants, has been a topic of interest since their discovery nearly 25 years ago. GLRs are involved in many physiological processes, from wound signaling to transcriptional regulation to sexual reproduction. Emerging evidence supports the notion that their fundamental functions are conserved among different groups of plants as well. In this review, we update the physiological and genetic evidence for GLRs, establishing their role in signaling and cell-cell communication. Special emphasis is given to the recent discussion of GLRs' atomic structures. Along with functional assays, a structural view of GLRs' molecular organization presents a window for novel hypotheses regarding the molecular mechanisms underpinning signaling associated with the ionic fluxes that GLRs regulate. Newly uncovered transcriptional regulations associated with GLRs-which propose the involvement of genes from all clades of
Arabidopsis thaliana
in ways not previously observed-are discussed in the context of the broader impacts of GLR activity. We posit that the functions of GLRs in plant biology are probably much broader than anticipated, but describing their widespread involvement will only be possible with (
a
) a comprehensive understanding of the channel's properties at the molecular and structural levels, including protein-protein interactions, and (
b
) the design of new genetic approaches to explore stress and pathogen responses where precise transcriptional control may result in more precise testable hypotheses to overcome their apparent functional redundancies.
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•The manuscript mainly writes the structure of JAKs and STATs.•The regulation mechanism and negative regulators of JAK/STAT signaling pathway.•Some diseases associated with the ...JAK/STAT pathway and JAKs inhibitors.
The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. It provides a direct mechanism for extracellular factors-regulated gene expression. Current researches on this pathway have been focusing on the inflammatory and neoplastic diseases and related drug.
The mechanism of JAK/STAT signaling is relatively simple. However, the biological consequences of the pathway are complicated due to its crosstalk with other signaling pathways. In addition, there is increasing evidence indicates that the persistent activation of JAK/STAT signaling pathway is closely related to many immune and inflammatory diseases, yet the specific mechanism remains unclear. Therefore, it is necessary to study the detailed mechanisms of JAK/STAT signaling in disease formation to provide critical reference for clinical treatments of the diseases.
In this review, we focus on the structure of JAKs and STATs, the JAK/STAT signaling pathway and its negative regulators, the associated diseases, and the JAK inhibitors for the clinical therapy.
Summary
Diatoms are globally important phytoplankton that dominate coastal and polar‐ice assemblages. These environments exhibit substantial changes in salinity over dynamic spatiotemporal regimes. ...Rapid sensory systems are vital to mitigate the harmful consequences of osmotic stress. Population‐based analyses have suggested that Ca2+ signalling is involved in diatom osmotic sensing. However, mechanistic insight of the role of osmotic Ca2+ signalling is limited.
Here, we show that Phaeodactylum Ca2+ elevations are essential for surviving hypo‐osmotic shock. Moreover, employing novel single‐cell imaging techniques we have characterised real‐time Ca2+ signalling responses in single diatom cells to environmental osmotic perturbations.
We observe that intracellular spatiotemporal patterns of osmotic‐induced Ca2+ elevations encode vital information regarding the nature of the osmotic stimulus. Localised Ca2+ signals evoked by mild or gradual hypo‐osmotic shocks are propagated globally from the apical cell tips, enabling fine‐tuned cell volume regulation across the whole cell.
Finally, we demonstrate that diatoms adopt Ca2+‐independent and dependent mechanisms for osmoregulation. We find that efflux of organic osmolytes occurs in a Ca2+‐independent manner, but this response is insufficient to mitigate cell damage during hypo‐osmotic shock. By comparison, Ca2+‐dependent signalling is necessary to prevent cell bursting via precise coordination of K+ transport, and therefore is likely to underpin survival in dynamic osmotic environments.
Mouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of ...transcription 3 (STAT3).
To investigate the expression of IL6/phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression.
Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically.
Patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p<or=0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens.
The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.
The Wnt signalling pathway is one of the central signalling pathways in bone development, homeostasis and regulation of bone mineral density. It consists of numerous Wnt ligands, receptors and ...co-receptors, which ensure tight spatiotemporal regulation of Wnt signalling pathway activity and thus tight regulation of bone tissue homeostasis. This enables maintenance of optimal mineral density, tissue healing and adaptation to changes in bone loading. While the role of the canonical/β-catenin Wnt signalling pathway in bone homeostasis is relatively well researched, Wnt ligands can also activate several non-canonical, β-catenin independent signalling pathways with important effects on bone tissue. In this review, we will provide a thorough overview of the current knowledge on different non-canonical Wnt signalling pathways involved in bone biology, focusing especially on the pathways that affect bone cell differentiation, maturation and function, processes involved in bone tissue structure regulation. We will describe the role of the two most known non-canonical pathways (Wnt/planar cell polarity pathways and Wnt/Ca
pathway), as well as other signalling pathways with a strong role in bone biology that communicate with the Wnt signalling pathway through non-canonical Wnt signalling. Our goal is to bring additional attention to these still not well researched but important pathways in the regulation of bone biology in the hope of prompting additional research in the area of non-canonical Wnt signalling pathways.
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