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1.
bioRxiv ; 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38617347

ABSTRACT

Therapeutic resistance to immune checkpoint blockade has been commonly linked to the process of mesenchymal transformation (MT) and remains a prevalent obstacle across many cancer types. An improved mechanistic understanding for MT-mediated immune evasion promises to lead to more effective combination therapeutic regimens. Herein, we identify the Hedgehog transcription factor, Gli2, as a key node of tumor-mediated immune evasion and immunotherapy resistance during MT. Mechanistic studies reveal that Gli2 generates an immunotolerant tumor microenvironment through the upregulation of Wnt ligand production and increased prostaglandin synthesis. This pathway drives the recruitment, viability, and function of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) while also impairing type I conventional dendritic cell, CD8 + T cell, and NK cell functionality. Pharmacologic EP2/EP4 prostaglandin receptor inhibition and Wnt ligand inhibition each reverses a subset of these effects, while preventing primary and adaptive resistance to anti-PD-1 immunotherapy, respectively. A transcriptional Gli2 signature correlates with resistance to anti-PD-1 immunotherapy in stage IV melanoma patients, providing a translational roadmap to direct combination immunotherapeutics in the clinic. SIGNIFICANCE: Gli2-induced EMT promotes immune evasion and immunotherapeutic resistance via coordinated prostaglandin and Wnt signaling.

2.
J Clin Invest ; 134(6)2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38319732

ABSTRACT

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.


Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Metformin , Humans , Mice , Animals , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Phosphatidylinositol 3-Kinases/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , TOR Serine-Threonine Kinases/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Glucose , Metformin/pharmacology , Tumor Microenvironment
3.
bioRxiv ; 2023 Oct 20.
Article in English | MEDLINE | ID: mdl-37904990

ABSTRACT

Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, which presents therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Genetic or pharmacologic disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (ATM) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models with different p53 mutations to identify transactivation-independent p53 activity as a key mediator of such radiosensitivity. These studies deeply profile a genetically faithful and versatile model of a lethal brain tumor to identify resistance mechanisms for a therapeutic strategy currently in clinical trials.

4.
Trends Mol Med ; 27(4): 365-378, 2021 04.
Article in English | MEDLINE | ID: mdl-33573910

ABSTRACT

Retinal congenital malformations known as microphthalmia, anophthalmia, and coloboma (MAC) are associated with alterations in genes encoding epigenetic proteins that modify chromatin. We review newly discovered functions of such chromatin modifiers in retinal development and discuss the role of epigenetics in MAC in humans and animal models. Further, we highlight how advances in epigenomic technologies provide foundational and regenerative medicine-related insights into blinding disorders. Combining knowledge of epigenetics and pluripotent stem cells (PSCs) is a promising avenue because epigenetic factors cooperate with eye field transcription factors (EFTFs) to direct PSC fate - a foundation for congenital retinal disease modeling and cell therapy.


Subject(s)
Cell- and Tissue-Based Therapy , Chromatin/pathology , Retinal Diseases/genetics , Transcription Factors , Animals , Anophthalmos/genetics , Anophthalmos/therapy , Blindness/etiology , Blindness/genetics , Blindness/therapy , Cell- and Tissue-Based Therapy/methods , Cell- and Tissue-Based Therapy/trends , Coloboma/genetics , Coloboma/therapy , Congenital Abnormalities/genetics , Congenital Abnormalities/therapy , Disease Models, Animal , Epigenomics , Humans , Microphthalmos/genetics , Microphthalmos/therapy , Pluripotent Stem Cells , Regenerative Medicine/methods , Regenerative Medicine/trends , Retina/cytology , Retina/pathology , Retinal Diseases/therapy , Transcription Factors/genetics , Transcription Factors/metabolism
5.
Stem Cell Reports ; 16(11): 2642-2658, 2021 11 09.
Article in English | MEDLINE | ID: mdl-34715053

ABSTRACT

p53 alterations occur during culture of pluripotent stem cells (PSCs), but the significance of these events on epigenetic control of PSC fate determination remains poorly understood. Wdr5 deletion in p53-null (DKO) mouse ESCs (mESCs) leads to impaired self-renewal, defective retinal neuroectoderm differentiation, and de-repression of germ cell/meiosis (GCM)-specific genes. Re-introduction of a WDR5 mutant with defective H3K4 methylation activity into DKO ESCs restored self-renewal and suppressed GCM gene expression but failed to induce retinal neuroectoderm differentiation. Mechanistically, mutant WDR5 targets chromatin that is largely devoid of H3K4me3 and regulates gene expression in p53-null mESCs. Furthermore, MAX and WDR5 co-target lineage-specifying chromatin and regulate chromatin accessibility of GCM-related genes. Importantly, MAX and WDR5 are core subunits of a non-canonical polycomb repressor complex 1 responsible for gene silencing. This function, together with canonical, pro-transcriptional WDR5-dependent MLL complex H3K4 methyltransferase activity, highlight how WDR5 mediates crosstalk between transcription and repression during mESC fate choice.


Subject(s)
Cell Differentiation/genetics , Cell Self Renewal/genetics , Histones/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Mouse Embryonic Stem Cells/metabolism , Pluripotent Stem Cells/metabolism , Tumor Suppressor Protein p53/genetics , Animals , Cell Line , Chromatin/genetics , Chromatin/metabolism , Chromatin Immunoprecipitation Sequencing/methods , Gene Expression Profiling/methods , Intracellular Signaling Peptides and Proteins/metabolism , Methylation , Mice , Mice, Knockout , Mice, Transgenic , RNA-Seq/methods , Tumor Suppressor Protein p53/metabolism
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