Biology subjects

Miles, B.

Publications and source records attributed to Miles, B..

3 recordsLinked to original sources

bioRxiv2021

MacroH2A impedes metastatic growth by enforcing a discrete dormancy program in disseminated cancer cells

AO_SCPLOWBSTRACTC_SCPLOWMacroH2A variants have been associated with tumor suppression through inhibition of proliferation and metastasis, as well as their role in cellular senescence. However, their role in regulating the dormant state of disseminated cancer cells (DCCs) remains unclear. Here we reveal that solitary dormant DCCs display increased levels of macroH2A variants in head and neck squamous cell carcinoma PDX models and patient samples compared to proliferating primary or metastatic lesions. We further demonstrate that microenvironmental and stress adaptive signals such as TGF{beta}2 and p38/{beta}, which induce DCC dormancy, upregulate macroH2A expression. Functionally, we find that overexpression of macroH2A variants is sufficient to induce tumor cells into dormancy and notably, inducible expression of the macroH2A2 variant suppresses the growth of DCCs into overt metastasis. However, this dormant state does not require well-characterized dormancy factors such as DEC2 and NR2F1, suggesting alternate pathways. Our transcriptomic analyses reveal that macroH2A2 overexpression inhibits E2F, RAS and MYC signaling programs, while upregulating inflammatory cytokines commonly secreted by senescent cells. Taken together, our results demonstrate that macroH2A2 enforces a stable dormant phenotype in DCCs by activating a select subset of dormancy and senescence genes that limit metastasis initiation.

cancer biology↗

bioRxiv2021

A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy

AO_SCPLOWBSTRACTC_SCPLOWDisseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D cultures in vitro and on chicken embryo chorioallantoic membrane (CAM) in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor {beta} (RAR{beta}) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lo phenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.

cancer biology↗

bioRxiv2020

Landscape of oncoviral genotype and co-infection via Human papilloma andHepatitis B viral tumor in-situ profiling

Hepatitis B virus (HBV) and human papillomavirus (HPV) infection are known risk factors for developing several cancers. However, the effect of viral genotype and co-infection in actually driving oncogenesis remains unclear. We have developed and deployed a new scalable, high throughput tool (ViralMine) for sensitive and precise oncoviral genotype deconvolution using tumor RNA sequencing data from 537 virally infected liver, cervical, and head and neck tumors. We provide the first comprehensive integrative landscape of tumor-viral gene expression, viral antigen immunogenicity, patient survival, and mutational profiling organized by tumor onco-viral genotype. We find that HBV and HPV genotype, and surprisingly high rates of multi-genotype co-infection, serve as significant predictors of patient survival, tumor immune responsiveness, and APOBEC activity modulation. Finally, we demonstrate that HPV genotype strongly associates with viral onco-gene expression over cancer type, implying expression may be similar across episomal and stochastic integration-based infections. Significance StatementWe demonstrate that scalable, high-accuracy oncoviral genotyping, gene expression, and co-infection estimation is feasible from legacy tumor RNA-seq data. While HBV and HPV genotype are known risk factors for oncogenesis, viral genotype and co-infection are shown to strongly associate with disease progression, patient survival, mutational signatures, and putative tumor neoantigen immunogenicity, facilitating novel clinical associations with infections.

cancer biology↗