Epigenetic silencing of sonic hedgehog elicits antitumor immune response and suppresses tumor growth by inhibiting the hedgehog signaling pathway in metastatic spine tumors in Sprague‐Dawley rats

Shi, Guang; Zhang, Hong; Yu, Qiong; Jin, Hui; Hu, Chunmei; Li, Shu‐Chun; Ji, Youbo

doi:10.1002/jcb.27277

Cited by 6 publications

(1 citation statement)

References 34 publications

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“…Among the top 30 pathways, we observed a strong impact of CTNNB1 as well as several other pathways described in the literature as influencing anti-tumor immunity such as MYC (Kortlever et al 2017), PPARG (Korpal et al 2017) and SHH (sonic hedgehog) (Shi et al 2018).…”

Section: Activation Of Transcriptional Programs Correlates With the Nmentioning

confidence: 70%

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao

Luke

2019

Preprint

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The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational profile may also dictate response with some oncogenes (i.e. WNT/β-catenin) known to mediate immuno-suppression. Building on these observations we performed a multi-omic analysis of human cancer correlating the T cell-inflamed gene expression signature with the somatic mutanome and transcriptome for different immune phenotypes, by tumor type and across cancers. Strong correlations were noted between mutations in oncogenes and non-T cellinflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c and genes with unknown functions. Conversely, we observe many genes associating with the T cell-inflamed phenotype including VHL and PBRM1, among others.Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion broadly active across cancer types including HIF1A and MYC. Novel examples from specific tumors include sonic hedgehog signaling in ovarian cancer or hormone signaling and novel transcription factors across multiple tumors. Using network analysis, somatic and transcriptomic events were integrated, demonstrating that most non-T cell-inflamed tumors are influenced by multiple pathways. Validating these analyses, we observe significant inverse relationships between protein levels and the T cell-inflamed gene signature with examples including NRF2 in lung, ERBB2 in urothelial and choriogonadotropin in cervical cancer. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms.These results nominate molecular targets and drugs potentially available for immediate translation into clinical trials for patients with cancer.

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Section: Activation Of Transcriptional Programs Correlates With the Nmentioning

confidence: 70%

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao

Luke

2019

Preprint

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Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers

Katoh

2019

Clinical Science

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Hedgehog signals are transduced through Patched receptors to the Smoothened (SMO)-SUFU-GLI and SMO-Gi-RhoA signaling cascades. MTOR-S6K1 and MEK-ERK signals are also transduced to GLI activators through post-translational modifications. The GLI transcription network up-regulates target genes, such as BCL2, FOXA2, FOXE1, FOXF1, FOXL1, FOXM1, GLI1, HHIP, PTCH1 and WNT2B, in a cellular context-dependent manner. Aberrant Hedgehog signaling in tumor cells leads to self-renewal, survival, proliferation and invasion. Paracrine Hedgehog signaling in the tumor microenvironment (TME), which harbors cancer-associated fibroblasts, leads to angiogenesis, fibrosis, immune evasion and neuropathic pain. Hedgehog-related genetic alterations occur frequently in basal cell carcinoma (BCC) (85%) and Sonic Hedgehog (SHH)-subgroup medulloblastoma (87%) and less frequently in breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, non-small-cell lung cancer (NSCLC) and ovarian cancer. Among investigational SMO inhibitors, vismodegib and sonidegib are approved for the treatment of patients with BCC, and glasdegib is approved for the treatment of patients with acute myeloid leukemia (AML). Resistance to SMO inhibitors is caused by acquired SMO mutations, SUFU deletions, GLI2 amplification, other by-passing mechanisms of GLI activation and WNT/β-catenin signaling activation. GLI–DNA-interaction inhibitors (glabrescione B and GANT61), GLI2 destabilizers (arsenic trioxide and pirfenidone) and a GLI-deacetylation inhibitor (4SC-202) were shown to block GLI-dependent transcription and tumorigenesis in preclinical studies. By contrast, SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the immune checkpoint inhibitor pembrolizumab with or without vismodegib in BCC patients is ongoing.

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Anti-hepatoma effect of taccalonolide A through suppression of sonic hedgehog pathway

Tian

2020

Artificial Cells, Nanomedicine, and Biotechnology

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Epigenetic silencing of sonic hedgehog elicits antitumor immune response and suppresses tumor growth by inhibiting the hedgehog signaling pathway in metastatic spine tumors in Sprague‐Dawley rats

Abstract: Our preliminary results indicate that epigenetic silencing of SHH elicits an antitumor immune response and suppresses tumor growth by inhibiting the Hh signaling pathway in metastatic spine tumors.

Cited by 6 publications

References 34 publications

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers

Anti-hepatoma effect of taccalonolide A through suppression of sonic hedgehog pathway

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