An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

AbstractMedulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3. Via incremental selection with vincristine, we derived the stably chemoresistant variant, Med8A-R, that exhibited multi-drug resistance, enhanced IL-6 induced pY705-STAT3 levels, and increased IL6R expression. Consequently, abrogation of STAT3 or IL6R expression in Med8A-R led to restored chemosensitivity to vincristine, highlighting a prominent role for canonical IL-6/STAT3 signaling in acquired drug resistance. Furthermore, Med8A-S subjected to conditioning exposure with IL-6, termed Med8A-IL6+ cells, exhibited enhanced vincristine resistance, increased expression of pY705-STAT3 and IL6R, and increased secretion of IL-6. When cocultured with Med8A-IL6+ cells, Med8A-S cells exhibited increased pY705-STAT3 and increased IL-6 secretion, suggesting a cytokine feedback loop responsible for amplifying STAT3 activity. Similar IL-6 induced phenomena were also observed in the Group 3 MB cell lines, D283 and D341, including increased pY705-STAT3, drug resistance, IL-6 secretion and IL6R expression. Our study unveiled autocrine IL-6 as a promoter of STAT3 signaling in development of drug resistance, and suggests therapeutic benefits for targeting the IL-6/STAT3 signaling axis in Group 3 MBs.

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The multi-faceted functioning portrait of LRF/ZBTB7A

Human Genomics ◽

10.1186/s40246-019-0252-0 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Caterina Constantinou ◽

Magda Spella ◽

Vasiliki Chondrou ◽

George P. Patrinos ◽

Adamantia Papachatzopoulou ◽

...

Keyword(s):

Cell Fate ◽

Cellular Response ◽

Molecular Mechanisms ◽

Aerobic Glycolysis ◽

Specific Cell ◽

Regulation Of Transcription ◽

Cancer Type ◽

Cellular Effects ◽

Physiological Processes ◽

Signaling Axis

AbstractTranscription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A’s orchestrated action.

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The association of PSA levels and survival outcomes in patients with chemotherapy-naïve, castration-resistant prostate cancer (CRPC) who were treated with androgen receptor signaling axis targeting agent (ARAT): A Japanese cohort study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.315 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 315-315

Author(s):

Tatsuya Shimomura ◽

Keiichiro Mori ◽

Toshihiro Yamamoto ◽

Hajime Onuma ◽

Hiroyuki Inaba ◽

...

Keyword(s):

Survival Outcome ◽

Castration Resistant Prostate Cancer ◽

Free Survival ◽

Group 4 ◽

Castration Resistant ◽

Signaling Axis ◽

Psa Response ◽

Group 3 ◽

Group 2 ◽

Group 1

315 Background: PSA decline is used as one of the treatment outcome of androgen receptor signaling axis targeting agent (ARAT) in general. However, correlation between PSA decline and survival outcome is not discussed enough. In this study we evaluated how PSA decline influence the survival outcome of ARAT against chemo-naive castration resistant prostate cancer (CRPC). Methods: A total of 200 chemo-naïve CRPC cases treated with ARAT (abiraterone acetate or enzalutamide) were included in this study. We investigated the relationship between PSA response rate and survival outcome (PSA progression free survival (PSA-PFS), Failure free survival (FFS) and overall survival (OS)). Results: PSA response rate correlated with PSA-PFA, TFS and OS significantly (p<0.0001, <0.0001, 0.0009, respectively). And we categorized PSA decline in four groups, group 1: no PSA decline, group 2: 0-50%, group 3: 50%-90%, group 4: over 90%. Median PSA-PFS were 2M (group 1), 4M (group 2), 10M (group 3) and 16M (group 4) (p<0.0001). Median FFS were 3M (group 1), 6M (group 2), 12M (group 3) and 27M (group 4) (p<0.0001). Median OS were 28M (group 1), 36M (group 2), not reached (group 3 and 4) (p=0.0056). In terms of OS, there is a big different between PSA decline <50% and ≥50% in survival curve. And we compare the factors influencing PSA decline ≥50%. PSA and age at initiating ARAT are significant factors predicting PSA decline 50%. Lower PSA and lower age correlated PSA decline ≥50%. Conclusions: PSA decline strongly correlated with PSA-PFS, FFS and OS in this study. It would be a surrogate marker predicting survival outcomes of chemo-naïve CRPC cases treated with ARAT. Further investigation is warranted to confirm these results.

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Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis

10.1101/826917 ◽

2019 ◽

Cited By ~ 3

Author(s):

Timothy J. Aikin ◽

Amy F. Peterson ◽

Michael J. Pokrass ◽

Helen R. Clark ◽

Sergi Regot

Keyword(s):

Cell Fate ◽

Temporal Patterns ◽

Mapk Signaling ◽

Paracrine Signaling ◽

Cell Behaviors ◽

Cell Fate Decisions ◽

Epithelial Tissues ◽

Mapk Activity ◽

Signaling Axis ◽

Quality Control Mechanism

ABSTRACTEpithelial tissues are constantly challenged by individual cell fate decisions while maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their signaling states and cellular behaviors creating competitive interactions that are poorly understood. Here we show that the temporal patterns of MAPK activity are decoded by the ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity coordinates both single and collective cell behaviors to maintain tissue homeostasis.

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PDTM-28. AN OTX2-PAX3 SIGNALLING AXIS REGULATES GROUP 3 MEDULLOBLASTOMA CELL FATE

Neuro-Oncology ◽

10.1093/neuonc/noz175.804 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi193-vi193

Author(s):

Jamie Zagozewski ◽

Ghazaleh Shahriary ◽

Ludivine Morrison ◽

Margaret Stromecki ◽

Agnes Fresnoza ◽

...

Keyword(s):

Cell Fate ◽

Tumor Size ◽

Prolonged Survival ◽

Pax6 Expression ◽

Self Renewal ◽

Cell Fate Decisions ◽

Group 3

Abstract The majority of Group 3 medulloblastomas (MB) exhibit amplification or increased expression of OTX2. OTX2 is primarily known as an oncogenic driver of tumor growth and cell cycle progression in Group 3 MB; however, its role as a repressor of differentiation is poorly characterized. Therefore, we utilized extensive patient data and mapped Group 3 MB chromatin dynamics in stem cell-enriched cultures to evaluate the divergent role of OTX2 in cell fate decisions in Group 3 MB pathogenesis. Several PAX genes were identified as novel OTX2 targets in Group 3 MB. Examination of patient data revealed that PAX3 and PAX6 expression is significantly reduced in Group 3 MB patients and is associated with significantly reduced survival. Functional evaluation of PAX3 and PAX6 expression showed that PAX3 expression significantly reduced self-renewal capacity of Group 3 MB tumorspheres in vitro and significantly prolonged survival and reduced tumor size in orthotopic xenograft models in vivo. RNA-sequencing of PAX3 and PAX6 gain of function (GOF) tumorspheres revealed mTORC1 signalling was specifically downregulated in PAX3 GOF, indicating this pathway may be critical for the survival and self-renewal differences observed between PAX3/PAX6 GOF models. Treatment of Group 3 MB with mTOR inhibitors reduced self-renewal in vitro and significantly prolonged survival and reduced tumor size in vivo. To further evaluate the role for this signalling axis in the Group 3 MB neural lineage hierarchy, we carried out scRNA-sequencing in tumorspheres from 4 Group 3 MB cell lines. Interestingly, a broad range of OTX2 expression was observed across single cell clusters, suggesting distinct OTX2 regulatory hierarchies are present in Group 3 MB. Collectively, our work demonstrates the multifaceted role of OTX2 as a regulator of cell fate decisions in Group 3 MB and identifies a novel role for mTORC1 signalling in Group 3 MB self-renewal and differentiation.

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Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior

10.1101/2021.02.12.431015 ◽

2021 ◽

Cited By ~ 2

Author(s):

Mai T. Ngo ◽

Victoria R. Barnhouse ◽

Aidan E. Gilchrist ◽

Christine J. Hunter ◽

Joy N. Hensold ◽

...

Keyword(s):

Stem Cell ◽

Cell Fate ◽

Three Dimensional ◽

Cell Behavior ◽

Vascular Density ◽

Microfluidic Mixing ◽

Hematopoietic Stem ◽

Stem Cell Fate ◽

Signaling Axis ◽

Dose Dependent

AbstractBiomaterials that replicate patterns of microenvironmental signals from the stem cell niche offer the potential to refine platforms to regulate stem cell behavior. While significant emphasis has been placed on understanding the effects of biophysical and biochemical cues on stem cell fate, vascular-derived or angiocrine cues offer an important alternative signaling axis for biomaterial-based stem cell platforms. Elucidating dose-dependent relationships between angiocrine cues and stem cell fate are largely intractable in animal models and two-dimensional cell culture. In this study, we leverage microfluidic mixing devices to generate three-dimensional hydrogels containing lateral gradients in vascular density alongside murine hematopoietic stem cells (HSCs). Regional differences in vascular density can be generated via embossed gradients in cell, matrix, or growth factor density. HSCs co-cultured alongside vascular gradients reveal spatial patterns of HSC phenotype in response to angiocrine signals. Notably, decreased Akt signaling in high vessel density regions led to increased expansion of lineage-positive hematopoietic cells. This approach offers a combinatorial tool to rapidly screen a continuum of microenvironments with varying vascular, biophysical, and biochemical cues to reveal the influence of local angiocrine signals on HSC fate.

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The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

Stem Cells International ◽

10.1155/2020/8849218 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Qian Gao ◽

Jin Zheng ◽

Zegui Ni ◽

Pengli Sun ◽

Congcong Yang ◽

...

Keyword(s):

Stem Cells ◽

Bladder Cancer ◽

Cancer Stem Cells ◽

Cell Fate ◽

Biological Functions ◽

Aldh Activity ◽

Promoter Regions ◽

Self Renewal ◽

Signaling Axis

The dynamic N6-methyladenosine (m6A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m6A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m6A abundance and the expression of m6A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m6A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCs in vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m6A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC.

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AIBP-CAV1-VEGFR3 axis dictates lymphatic cell fate and controls lymphangiogenesis

10.1101/2020.10.16.342998 ◽

2020 ◽

Author(s):

Xiaojie Yang ◽

Jun-dae Kim ◽

Qilin Gu ◽

Qing Yan ◽

Jonathan Astin ◽

...

Keyword(s):

Cell Fate ◽

Cholesterol Efflux ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Embryonic Stem ◽

Lymphatic Endothelial Cell ◽

Tissue Fluid ◽

Cell Functions ◽

Signaling Axis ◽

And Migration

AbstractThe lymphatics are essential for the maintenance of tissue fluid homeostasis. Accordingly, lymphatic dysfunction contributes to lymphedema. In development, lymphangiogenesis often requires lymphatic endothelial cell (LEC) lineage specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for proper cell functions and organ development, yet the molecular mechanism by which cholesterol metabolism controls lymphangiogenesis is unknown. We show that the secreted protein, ApoA1 binding protein (AIBP), dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the human paralog in zebrafish, impairs LEC progenitor specification and impedes lymphangiogenesis. Mechanistically, we found that caveolin-1 (CAV-1) suppresses VEGFR3 activation in LECs, and that AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. Enhancement of cholesterol efflux with ApoA1 overexpression or inhibition of cholesterol biosynthesis using atorvastatin restores proper lymphangiogenesis in Aibp2 mutant zebrafish. Loss of Cav-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. Recombinant AIBP supplement confers profound LEC fate commitment in the mouse embryonic stem cells (mESC) to LEC differentiation model. Furthermore, enhancement of AIBP-CAV-1-VEGFR3 signaling axis promotes VEGFC-engaged adult lymphangiogenesis in mice. Consistent with these data, AIBP expression is reduced in the epidermis of human lymphedematous skin. These studies identify that AIBP-mediated cholesterol efflux is a critical contributor for lymphangiogenesis. Our studies will provide a new therapeutic avenue for the treatment of lymphatic dysfunctions.One Sentence SummaryOur studies identify that AIBP-CAV-1-VEGFR3 axis enhances VEGFC-elicited lymphangiogenesis, which will guide a new therapeutic strategy for the treatment of lymphatic dysfunctions.

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Notch and TLR signaling coordinate monocyte cell fate and inflammation

eLife ◽

10.7554/elife.57007 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Jaba Gamrekelashvili ◽

Tamar Kapanadze ◽

Stefan Sablotny ◽

Corina Ratiu ◽

Khaled Dastagir ◽

...

Keyword(s):

Cell Fate ◽

Developmental Plasticity ◽

Cell Fates ◽

Tlr Signaling ◽

Tissue Macrophage ◽

Inflammatory Conditions ◽

Conditional Deletion ◽

Signaling Axis ◽

Monocyte Cell ◽

Tlr7 Stimulation

Conventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte development. At the same time, TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes in the blood and ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells, which infiltrate the spleen and major blood vessels and are accompanied by aberrant systemic inflammation. Thus, Notch2 is a master regulator of Ly6Chi monocyte cell fate and inflammation in response to TLR signaling.

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Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00156.2019 ◽

2019 ◽

Vol 317 (4) ◽

pp. L434-L444 ◽

Cited By ~ 3

Author(s):

Aline C. Oliveira ◽

Chunhua Fu ◽

Yuanqing Lu ◽

Mason A. Williams ◽

Liya Pi ◽

...

Keyword(s):

Endothelial Cells ◽

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Myeloid Cells ◽

Suppressor Cells ◽

Pulmonary Vascular Disease ◽

Chronic Lung Diseases ◽

Chemokine Signaling ◽

Signaling Axis ◽

Group 3

Pulmonary hypertension complicates the care of many patients with chronic lung diseases (defined as Group 3 pulmonary hypertension), yet the mechanisms that mediate the development of pulmonary vascular disease are not clearly defined. Despite being the most prevalent form of pulmonary hypertension, to date there is no approved treatment for patients with disease. Myeloid-derived suppressor cells (MDSCs) and endothelial cells in the lung express the chemokine receptor CXCR2, implicated in the evolution of both neoplastic and pulmonary vascular remodeling. However, precise cellular contribution to lung disease is unknown. Therefore, we used mice with tissue-specific deletion of CXCR2 to investigate the role of this receptor in Group 3 pulmonary hypertension. Deletion of CXCR2 in myeloid cells attenuated the recruitment of polymorphonuclear MDSCs to the lungs, inhibited vascular remodeling, and protected against pulmonary hypertension. Conversely, loss of CXCR2 in endothelial cells resulted in worsened vascular remodeling, associated with increased MDSC migratory capacity attributable to increased ligand availability, consistent with analyzed patient sample data. Taken together, these data suggest that CXCR2 regulates MDSC activation, informing potential therapeutic application of MDSC-targeted treatments.

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