Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases

Stevens, Laura E.; Cheung, William K.C.; Adua, Sally J.; Arnal-Estapé, Anna; Zhao, Minghui; Liu, Zongzhi; Brewer, Kelly K.; Herbst, Roy S.; Nguyen, Don X.

doi:10.1158/0008-5472.can-16-1978

Cited by 58 publications

(50 citation statements)

References 49 publications

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“…H2030-BrM3 cells also encode few additional exonic mutations as compared with the H2030 parental line despite significant transcriptomic alterations (Jacob et al, 2015; Nguyen et al, 2009). When injected into the arterial circulation of athymic mice, H2030-BrM3 cells extravasate into the brain within 7 days, with perivascular micrometastasis (defined here as clusters <100 cells) detected between 7 and 21 days, and expansion as macrometastasis observed for up to 49 days (Stevens et al, 2017; Valiente et al, 2014). …”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

et al. 2019

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SUMMARY 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.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

et al. 2019

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“…EMT, which is marked by the loss of epithelial markers and the acquisition of mesenchymal markers, correlates with higher properties of stemness and has been recently found to play a critical role in the development of chemoresistance in various cancers (11,12,44). Intriguingly, previous studies uncovered that HMMR is robustly increased in the EMT-related wound repair and cancer diseases, regulating the cell motility and rendering aggressive phenotypes to promote cancer metastasis (31)(32)(33)46). On the other hand, HMMR is expressed and required for the maintenance of stemness by up-regulating several pluripotency markers in hESC and mammary and glioblastoma stem-like cells (34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan‐mediated motility receptor confers resistance to chemotherapy via TGFβ/Smad2‐induced epithelial‐mesenchymal transition in gastric cancer

et al. 2019

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Chemotherapy is one of the vital treatments for gastric cancer (GC) patients, especially those suffering advanced stages. Chemoresistance results in tumor relapse, leading to poor prognosis in GC patients; thus, identifying key regulators in this process might provide novel clues for GC therapy. Herein, we identify hyaluronan‐mediated motility receptor (HMMR) as a key regulator of chemoresistance in GC. HMMR was found to be substantially up‐regulated in 5‐fluorouracil (5‐Fu)–resistant GC biopsies and cell lines. High expression of HMMR significantly correlates with tumor relapse and predicts poorer prognosis in GC patients. Moreover, we observed that HMMR induced epithelial‐mesenchymal transition and increased the cancer stem cell properties of GC, thus rendering resistance to chemotherapy. Importantly, silencing of HMMR effectively increased the susceptibility to 5‐Fu therapy both in vitro and in vivo. Furthermore, we demonstrated that HMMR activates the TGF‐β/Smad2 signaling pathway, which was required for the HMMR‐mediated oncogenic effects and exhibited significant clinical relevance with HMMR expression. These findings reveal a critical role for HMMR in the chemoresistance of GC and suggest that HMMR might be a potential prognostic marker or therapeutic target against the disease.—Zhang, H., Ren, L., Ding, Y., Li, F., Chen, X., Ouyang, Y., Zhang, Y., Zhang, D. Hyaluronan‐mediated motility receptor confers resistance to chemotherapy via TGFβ/Smad2‐induced epithelial‐mesenchymal transition in gastric cancer. FASEB J. 33, 6365–6377 (2019). http://www.fasebj.org

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“…We and others have previously identified different molecular subtypes of LUAD, which have distinct developmental gene expression profiles [14,27,28]. High GATA6 expression in particular may be a context-dependent marker of KRAS mutant tumors that express markers of the distal airways [12] and committed alveolar cells (alveolarlike or alveolar-high tumors) [14,29]. NKX2-1 and HOPX can inhibit LUAD progression [14,30], and their expression was partially inversely correlated with GATA6 in "alveolarhigh" tumors but less so in other LUAD subtypes (Supplementary Fig.…”

Section: Suppressing Gata6 Reprograms Chromatin At Distal Enhancersmentioning

confidence: 99%

Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

et al. 2020

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Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent with undefined epigenetic mechanisms of action. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 in lung adenocarcinoma (LUAD) progression. Impairing Gata6 in genetically engineered mouse models reduces the proliferation and increases the differentiation of Kras mutant LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation and genetic context of Krasmediated tumor initiation. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in lung development, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse transcriptional programs associated with bone morphogenetic protein signaling, alveolar specification, and tumor suppression. These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their proliferation and divergent lineage dependencies during tumor progression.

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Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases

Cited by 58 publications

References 49 publications

Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

Hyaluronan‐mediated motility receptor confers resistance to chemotherapy via TGFβ/Smad2‐induced epithelial‐mesenchymal transition in gastric cancer

Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

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