ASCL1 expression activates an EMT transcriptional program in permissive cellular contexts. Expression of individual EMT marker genes in mutant EGFR lung cancer cell lines and PDXs with or without ASCL1 overexpression.

Permissive

Osimertinib

10.1158/0008-5472.25607385.v1

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Figure S4 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts

Bomiao Hu Marc Wiesehöfer Fernando J. de Miguel Zongzhi Liu Lok-Hei Chan

Expression of signature genes in residual disease in PDXs.

Osimertinib

Permissive

10.1158/0008-5472.25603600.v1

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Figure S1 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts

Bomiao Hu Marc Wiesehöfer Fernando J. de Miguel Zongzhi Liu Lok-Hei Chan

Effects of erlotinib and TKI withdrawal on PDX growth.

Osimertinib

Permissive

Erlotinib Hydrochloride

10.1158/0008-5472.25603609

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Supplementary Table S2 from Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases

Laura E. Stevens William K.C. Cheung Sally J. Adua Anna Arnal Estape Minghui Zhao

Predicted HMMR targeting miRNAs. Results are from the combined Cbio and MIRANDA correlation analysis. Provided as Excel file.

Table (database)

10.1158/0008-5472.22415598.v1

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Supplementary Table 2 from Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells

Alexandra E. Albert Sally J. Adua Wesley L. Cai Anna Arnal Estape Gary W. Cline

Supplementary Table 2 shows differential gene expression in LUAD cells treated with ISRIB during asparagine deprivation.

Table (database)

Asparagine synthetase

10.1158/1541-7786.22513179

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Sympathetic neural regulation of angiogenesis through Adrb2 in prostate cancer: A novel therapeutic target.

Journal of Clinical Oncology (2016)

Ali H. Zahalka Anna Arnal Estape Maria Maryanovich Fumio Nakahara Paul S. Frenette

11524 Background: The sympathetic nervous system (SNS) has been implicated in the pathogenesis of epithelial malignancies. Clinical studies have shown that elevated SNS activity is associated with increased prostate cancer risk and mortality, whereas use of sympathetic β-adrenergic receptor (bAR) blockers reduces the risk. The prostate stroma is highly innervated by the SNS, and depletion of bARs (Adrb2 + Adrb3) in this compartment inhibits tumor growth. We aim to identify the stromal populations that mediate SNS signaling in the tumor microenvironment, and elucidate the mechanism by which loss of bAR signaling inhibits prostate cancer progression. Methods: In vivo xenograft tumor growth was measured in Adrb2-/-; Adrb3-/- mice using an orthotopic PC3-luciferase model. Cancer progression in the transgenic HI-myc model was assessed after conditional Adrb2 deletion in stromal populations by intercrossing Adrb2fl/fl line to stromal Cre lines: endothelial Cdh5CreERT2, myeloid Csf1riCre, and pericyte NG2CreERTM. A novel prostate-specific collagen matrix transplantation assay was employed to assess angiogenesis. Results: Deletion of the SNS bAR neural receptors Adrb2 and Adrb3 in the microenvironment synergized to arrest tumor growth. Imaging the tumor vasculature revealed a defect in vessel branching, suggesting altered angiogenesis in the absence of bAR stimulation. Histology revealed that vascular innervation was greatest during the pre-neoplastic PIN stage, and that conditional Adrb2 deletion in endothelial cells, but not myeloid cells or pericytes, reduced progression to high-grade PIN, and maintained inhibition of disease progression throughout all histopathological cancer stages. In the orthotopic matrix assay, endothelial deletion of Adrb2 was confirmed to inhibit angiogenesis as did sympathetic denervation. Conclusions: The SNS mediates a pro-angiogenic switch during the early stages of prostate carcinogenesis. We identified endothelial cells as the stromal targets of the SNS, and that abrogation of bAR signaling in the vasculature inhibits angiogenesis and delays prostate cancer progression, suggesting a novel therapeutic avenue for prostate cancer treatment.

Tumor progression

10.1200/jco.2016.34.15_suppl.11524

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Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain

BMC Medical Genomics (2020)

Wesley L. Cai Celeste B. Greer Jocelyn F. Chen Anna Arnal Estape Jian Cao

Abstract Background Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2. Using ATAC-seq, we identified a metastasis open-chromatin signature that is elevated in basal-like and HER2-enriched breast cancer subtypes and associates with worse prognosis in human samples. We further uncovered TFs associated with the open chromatin landscapes of metastatic cells and whose expression correlates with risk for metastasis. While some of these TFs are associated with primary breast tumor subtypes, others more specifically correlate with lung or brain metastasis. Conclusions We identify distinctive epigenomic properties of breast cancer cells that metastasize to the lung and brain. We also demonstrate that signatures of active chromatin sites are partially linked to human breast cancer subtypes with poor prognosis, and that specific TFs can independently distinguish lung and brain relapse.

Epigenomics

Chromatin immunoprecipitation

ChIP-sequencing

Chromosome conformation capture

10.1186/s12920-020-0695-0

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BSLM-10 MOLECULAR AND HISTOLOGICAL CHARACTERIZATION OF NSCLC PROGRESSION TO LEPTOMENINGEAL METASTASIS WITH COMORBID INTRAPARENCHYMAL DISEASE

Neuro-Oncology Advances (2024)

Savannah E. Kandigian Sampada Puranik Darin Dolezal Tang Tang D. Wang

Abstract Leptomeningeal disease (LMD) is a rare form of central nervous system (CNS) metastasis wherein tumor cells invade the cerebrospinal fluid (CSF) filled space that surrounds the brain and spinal cord. For patients with LMD, prognosis is extremely poor even with aggressive treatment. The mechanisms of progression to LMD and the adaptations tumor cells make to survive in this metabolically sparse microenvironment are poorly understood. As 60% of patients with LMD have concurrent or prior parenchymal metastases, our laboratory examined our established murine models of parenchymal metastases for signs of leptomeningeal infiltration. We identify two xenograft non-small cell lung cancer (NSCLC) models of intraparenchymal metastasis following intra-arterial injection that show progression to LMD in a subset of cases. In the H2030-BrM3 model, this occurs de novo, whereas the EGFR-mutant PC9-R2 model progresses to LMD only following onset of resistance to tyrosine kinase inhibitor treatment. Subsequent in vivo passaging of the H2030-BrM3 line through the cerebral lateral ventricles resulted in the H2030-LMD2 cell line, which has high affinity for leptomeningeal metastases and shows extensive perivascular invasion within the brain parenchyma. In vitro, the H2030-LMD2 line shows altered clustering behavior and increased survival when cultured in suspension. RNA-sequencing of this cell line across adherent and suspension culture conditions shows multiple biological processes upregulated in the LMD-tropic line, including chemotaxis, apical junction formation, and TGF-β signaling. Targetable pathways emerging from this analysis will be functionally investigated for their role in promoting progression to LMD, including through validation in the syngeneic KPN1-BrM line which has been selected for its CNS affinity and shows progression to LMD. Spatial sequencing and multiplexed immunofluorescence will furthermore investigate the tumor microenvironment in the perivascular niche and subarachnoid spaces. These findings will be clinically corroborated with molecular characterization of the CSF of patients with leptomeningeal metastases.

10.1093/noajnl/vdae090.020

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Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

Cell Reports (2019)

Emily Wingrove Zongzhi Liu Kiran D. Patel Anna Arnal Estape Wesley L. Cai

The brain is a major site of relapse for several cancers, yet deciphering the mechanisms of brain metastasis remains a challenge because of the complexity of the brain tumor microenvironment (TME). To define the molecular landscape of brain metastasis from intact tissue in vivo, we employ an RNA-sequencing-based approach, which leverages the transcriptome of xenografts and distinguishes tumor cell and stromal gene expression with improved sensitivity and accuracy. Our data reveal shifts in epithelial and neuronal-like lineage programs in malignant cells as they adapt to the brain TME and the reciprocal neuroinflammatory response of the stroma. We identify several transcriptional hallmarks of metastasis that are specific to particular regions of the brain, induced across multiple tumor types, and confirmed in syngeneic models and patient biopsies. These data may serve as a resource for exploring mechanisms of TME co-adaptation within, as well as across, different subtypes of brain metastasis.

Brain tumor

10.1016/j.celrep.2019.03.085

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Citations (58)