![[Art_Cellular_Banner.JPEG|Center|700]] # [[2.0 DSRCT Basics|DSRCT Basics]] [[2.0 DSRCT Basics|Overview - DSRCT Basics]] DNA: Chromosomal Translocation - EWSR1-WT1 Fusion Transcription Factor Proteins - General Overview EWSR1 Gene: Chromosome 22 WT1 Gene: Chromosome 11 Chimeric Fusion Protein: EWS-WT1 +- KTS Alternate Splicing Phase transition properties Gene Access # [[Fundamentals - Holistic Theories and Frameworks|Science Fundamentals and Principles of Thought]] Holistic Theories & Frameworks. Metaphors Evolutionary and Ecological principles Evidence Level Cascade - Evidence Based Medicine [[Different Preclinical Research Models in the lab and their consequences]] DSRCT and Sarcoma established models [[Timeline of DSRCT research|Timeline of published DSRCT and Ewing's Sarcoma research]] # [[DSRCT and Sarcoma established models]] ## DSRCT Biological Models DSRCT In Vitro models DSRCT Xenografts / PDX In Vitro Cytotoxicity Testing In Silico DSRCT Prediction Targets and Compounds #### Ewings Sarcoma Ewings Cell Models Ewings PDX # Targets: [[Index - DSRCT Targets]] ## DSRCT Relevant Targets [[VEGF Vascular Endothelial Growth Factor]] IGF PDGFa EGFR Epidermal Growth Factor Receptor NTRK3 / TRKc ## Heterogenous / Requires testing [[FGFR4]] - Tissue / Gene expression High | Low [[LSD1]] Lysine Specific Demethylase 1 - ## Location Based Target Overview ### Cell Surface NTRK3 / TRKc ### Cytoplasm ### Nucleus ## Cancer Hallmarks in DSRCT - Canonical [![[Avoiding Immune Destruction.png|240]]](Avoiding%20Immune%20Destruction.md) [![[nonmutational epigenetic reprogramming.png|240]]](Nonmutational%20Epigenetic%20Reprogramming.md) [![[Unlocking Phenotypic Plasticity.png|240]]](<Unlocking Phenotypic Plasticity.md>) [![[resisting cell death.png|240]]](Resisting%20Cell%20Death.md) [![[Sustaining Proliferative Signaling.png|240]]](Sustaining%20Proliferative%20Signaling.md) [![[Evading Growth Suppressors.png|240]]](<Evading Growth Suppressors.md>) [![[replicative immortality.png|240]]](<Enabling Replicative Immortality.md>) [![[Senescent Cells.png|240]]](<Senescent Cells.md>) [![[Inducing or Accessing Vasculature (Angiogenesis).png|240]]](Angiogenesis%20In%20DSRCT.md) [![[Tumor-promoting Inflammation.png|240]]](<Tumor-Promoting Inflammation.md>) [![[Images Repository/Deregulating Cellular Metabolism.png|240]]](<Deregulated Cellular Metabolism.md>) [![[Activating Invasion & Metastasis.png|240]]](<Activating Invasion & Metastasis.md>) [![[Polymorphic Microbiomes.png|240]]](<Polymorphic Microbiomes.md>) ## [[Overview - Epigenetic Aspects]] [[HDAC, Methylation]] [[SWI SNF Chromatin Remodelling Complex]] [[PRC2 & EZH2]] [[LSD1]] [[NurRD Nucleosome Remodeling Deacetylase Complex]] PVRL2 CD112? [[E2F Family Transcription Network]] Physical Structure considerations (gene access etc) [[FOXM1]] [[mRNA's, miRNA, circRNA, RISC’s]] ## Established DSRCT Models Overview / Table Cell Models Xenograft / PDX In Vitro Cytotoxicity Testing In Silico DSRCT Prediction Targets and Compounds ## Visuals, Models, Illustrations ## Potential Biomarkers in DSRCT ### Peripheral Blood TGFb Neuron Specific Enolase (NSE) IGF IGFBPx Cytokines? VEGF? EWS-WT1 Fusion DNA in blood ## Molecular Heterogeneity - Principles and Models Post Translational Modifications Transcription, Transcription Factors Isoforms of the Fusion Protein +-KTS https://www.pnas.org/doi/10.1073/pnas.1519210113 ## Cell Structure Disorder Differentiation - Undifferentiated cellular state Cancer Stem Cells - SOX2, NANOG, EMT/MeRT ## [[Tumour Microenvironment (TME)]] Acidic TME Angiogenesis VEGF/VEGF-A Hypoxia HIF-1a Physical diffusion - Positive pressure and drug penetration, immune infiltration. ## Altered Metabolism Arginine / ASS1 Gene Immune System Metabolic Dynamics - Antagonistic Metabolism Tumour Cell - Disorded Metabolism ENT4 / PMAT ## Resistance of Cell Death 1.       [**Fundamentals and Principles of Thought**](#_Fundamentals_and_Principles) (‘Philosophy of Science’, Epistemology) **2.**       [**Holistic Theories and Frameworks**](#_2_Holistic_Theories) <span class="sidenote">This is a sidenote. </span> lorem ipsum sidenote spacing test 2.1     Antifragility & Tinkering framework - Resiliency, Robustness, and Antifragility 2.2     Adaptive Evolutionary Dynamics – Ecological Metaphors <span class="sidenote">This is a longer sidenote. Altered metabolism Arginine / ASS1 Gene Immune System Metabolic Dynamics - Antagonistic Metabolism Tumour Cell - Disorded Metabolism ENT4 / PMAT </span> 2.3     Seed & Soil 2.4     Survivability onion 2.5     Evidence Level Cascade **3.**       [**DSRCT basics**](#_DSRCT_Basics) 3.1     Transcription Factors 3.2     Phase transition properties 3.3     Fusion protein **3.4**     Gene Access **4.**       [**Epigenetic aspects**](#_Epigenetic_Aspects) 4.1     HDAC, Methlyation (2 separate?) 4.2     SWI/SNF chromatin remodelling complex 4.3     PRC2 – EZH2 4.4     LSD1 4.5     PVRL2 / CD112? 4.6     E2F Family Transcription Network 4.7     Physical Structure considerations (gene access etc) 4.8     FOXM1 **5.**       [**Established DSRCT Models**](#_4_Established_DSRCT) 5.1     Cell lines 5.2     Xenografts **6.**       [**Good DSRCT Visuals**](#_Good_DSRCT_Visuals:) **7.**       [**Good Visual General**](#_Good_visuals_general:) **8.**       [**DSRCT Studies index**](#_5_DSRCT_Studies) **9.**       [**Summary tables**](#_6_Summary_Tables) **10.**    [**Oncogenesis – Initiation**](#_7_Oncogenesis_–) 10.1  Cell of Origin & implications **11.**    [**Pathology**](#_10._Pathology) 11.1  Reports & Observations 11.2  Fusion Gene transcripts – FISH 12.    [**Molecular Heterogeneity – Principles & Models**](#_8_Molecular_Heterogeneity,) 12.1  Post-translational modification 12.2  Transcription, transcription factors 12.3  Isoforms of the Fusion Protein +-KTS 13.    Cell Structure Disorder, DSRCT Plasticity etc 13.1  Differentiation – Undifferentiated state 13.2  EMT/MeRT (Sarcoma) (STAT3?) 14.    Metastasis 14.1  Motility, Adhesion 14.2  Invasion 14.3  EMT/MeRT (Sarcoma). STAT3 14.4  EPCAM 14.5  MMP’s? **15.**    [**Tumour Microenvironment (TME)**](#_9_Tumour_Microenvironment) 15.1  Acidic TME 15.2  Angiogenesis 15.3  Hypoxia | HIF-1a 15.4  VEGF/VEGF-A 15.5  Inflammation 15.6  Immune microenvironment (Own topic?) 15.7  IL-2 / IL15Rβ 15.8  TGF-β 16.    DSRCT Microenvironment & Immune Evasion 16.1  Desmoplasia, Stroma 16.1.1         PDGFa 16.2  Fibrosis, scarring 16.3  CAFs, Macrophages and TAMs 16.4  IL-6 16.5  Immune Checkpoints DSRCT 16.5.1         B7H3 / CD276 (Checkpoint)   16.5.2         PD-1 (T cells, not tumor) **17.**    [**Altered Metabolism – DSRCT & TME**](#_12_Altered_Metabolism) 17.1  Arginine / ASS1 gene 17.2  Immune system antagonistic metabolism 17.3  Tumor Cell Metabolism 17.4   ENT4 Equilibrative Nucleoside Transp. / PMAT **18.**    [**Resistance of cell death**](#_14_Resistance_of) 18.1  Evasion of apoptosis 18.2  DNA Damage Repair (DDR, Replication Stress) 18.3  CHK1 Checkpoint Kinase 1, CCND1 18.4  BCL2 (PARPi relevance) 18.5  DR4/DR5 Death receptor? 18.6  Senesensce **19.**    [**Growth, Proliferation**](#_11_Growth,_Proliferation) 19.1  Growth factors, protein kinases, cell signalling 19.2  DHT 19.3  IGF/IGF-1 19.4  AR Androgen Receptor 19.4.1         FOXM1 19.5  mTOR 19.6  PDGF-A / PDGFR-A 19.7  PI3K/Akt/mTOR pathway 19.8  MAPK 20.    Cell Surface – Recptors, RTKs 20.1  NTRK3 / TrkC 21.    Autophagy - Contextual 22.    Immune system (large topic, perhaps separate?) 22.1  Immune metabolism considerations / similarity to cancer metabolism – care 22.2  STAT3 23.    NTRK3 / TRKc 23.1  BAIAP3? 23.2  ERBB/HER2 24.    Cancer Stem Cells (CSC) 25.    Circadian rhythm system disruptions 26.    Other targets of investigation 26.1  LIF 26.1.1         LIF & miRNA-21. IL-6 rel? 26.2  MLF-1 26.3  EGR-1 / ZNF268 / NGFI-A 26.4  ETS Transcription Factor 26.5  FGFR4 26.6  SLFN11 Schlafen-11 26.7  SIK1 Salt Inducible Kinase 26.8  mRNA, MiRNA, RISCs. circRNA’s 26.9  p53