A core program of gene expression characterizes cancer metastases

Hartung, Franz; Wang, Yunguan; Aronow, Bruce J.; Weber, Georg F.

doi:10.18632/oncotarget.22240

Cited by 21 publications

(35 citation statements)

References 57 publications

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“…Our study is in line with these previous studies and potentially uncovers gene expression signatures between for example primary melanoma and melanoma skin metastasis ( Figure 6C, the signature shows a perfect example of anti-parallel gene expression pattern which in our study suggests being a perfect biomarker to tailor the anti-PD1 immunotherapy). Our study also supports the notion of changes in gene expression signatures that appear to facilitate primary cells to disseminate and metastasize (15).…”

Section: Discussionsupporting

confidence: 87%

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A Transcriptomic Meta-Analysis Identifies Differentially Expressed Genes across Different Types of Cancer and Their Association with Checkpoint Inhibitor Immunotherapy

Al-Khudhair

Dar

Imam

et al. 2019

Preprint

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Background Checkpoint inhibitor, anti-Programmed cell death protein1/Ligand (PD1 / PDL1) immunotherapy achieved great success in modulating the immune system to reinvigorate targeted immune fight against several types of cancer. However, patients’ clinical response to this cancer immunotherapy varies widely. Biomarkers that can predict the greatest response to the anti-PD1 immunotherapy could help to personalize the maximum benefit for the right patient.Results This study explored transcriptomic biomarkers that were associated with the response (or no-response) to the anti-PD1/PDL1 immunotherapy in seven types of cancer [Malignant Pleural Mesothelioma (n=8), Head and Neck cancer (n=3), Lung Non-Squamous cancer (n=15), Squamous Lung cancer (n=8), Melanoma (n=23), Melanoma Skin Metastasis (n=10), and Renal Cell Carcinoma (n=11)]. The most common differentially expressed genes (105 genes) were between melanoma skin metastasis and renal cell carcinoma; followed by malignant pleural mesothelioma and renal cell carcinoma, which had 79 common differentially expressed genes; then malignant pleural mesothelioma and melanoma skin metastasis, which had 46 differentially expressed genes in common. Many similar (parallel) and dissimilar (anti-parallel) gene expression signatures were identified in this study. Parallel signature Differentially Expressed Genes (DEGs) are genes up-regulated together in either response or no-response group of different types of cancer, while the anti-parallel DEGs show up-regulation in the response group of one type of cancer while same genes are up-regulated in the no-response group of another different type of cancers. Target of Myb1 like 1 Membrane Trafficking Protein gene (TOM1L1) was found to be common among malignant pleural mesothelioma, melanoma skin metastasis, and renal cell carcinoma and was up-regulated in the cancer patients’ samples that did not respond to the anti-PD1/PDL1 immunotherapy. This study also found that differentially expressed Plasminogen Activator, Urokinase Receptor gene (PLAUR), was common among squamous lung cancer, melanoma and melanoma skin metastasis, and was up-regulated in the patients’ samples that responded to the anti-PD1/PDL1 immunotherapy.Conclusion In summary, this study identified DEGs biomarkers that can predict the response or no-response to the anti-PD1 immunotherapy across seven types of cancer. It also affirms the attention to important genes like TOM1L1 and PLAUR for their potential function in the cancer dissemination and metastasis.

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Section: Discussionsupporting

confidence: 87%

“…Cancer studies suggest that cancer invasiveness and metastatic ability are driven through changes of many gene expression signatures within the tumor cells (15). Many of these studies highlighted signatures that are associated either with the primary or metastatic cancer to improve prognosis (16).…”

Section: Discussionmentioning

confidence: 99%

A Transcriptomic Meta-Analysis Identifies Differentially Expressed Genes across Different Types of Cancer and Their Association with Checkpoint Inhibitor Immunotherapy

Al-Khudhair

Dar

Imam

et al. 2019

Preprint

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“…However, this is limited by the need for biopsies of normal host organ tissue where metastases are located such that the transcriptomic profiles of metastases can be normalized (7,8). One interesting survey evaluated primary versus metastatic sites and found that expression studies of metastases obtain signatures that partially reflect the host tissue but have additional signatures (9). This finding highlights the need for considering the metastatic site during analyses.…”

Section: Introductionmentioning

confidence: 99%

“…This finding highlights the need for considering the metastatic site during analyses. Approaches comparing primary tumors and metastatic lesions often fail to address the role of treatment exposure in altering tumor transcriptomic profiles (9,10). This is particularly true for metastases, as biospecimens of metastases obtained in the clinical setting are usually drawn from patients heavily treated with chemotherapy and/or radiation prior to surgical resection (4,11).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Differences between Primary Colorectal Adenocarcinomas and Distant Metastases Reveal Metastatic Colorectal Cancer Subtypes

et al. 2019

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Approximately 20% of colorectal cancer patients with colorectal adenocarcinomas present with metastases at the time of diagnosis, and therapies that specially target these metastases are lacking. We present a novel approach for investigating transcriptomic differences between primary colorectal adenocarcinoma and distant metastases, which may help to identify primary tumors with high risk for future dissemination and to inform the development of metastasis-targeted therapies. To effectively compare the transcriptomes of primary colorectal adenocarcinoma and metastatic lesions at both the gene and pathway levels, we eliminated tissue specificity of the "host" organs where tumors are located and adjusted for confounders such as exposure to chemotherapy and radiation, and identified that metastases were characterized by reduced epithelialmesenchymal transition (EMT) but increased MYC target and DNA-repair pathway activities. FBN2 and MMP3 were the most differentially expressed genes between primary tumors and metastases. The two subtypes of colorectal adenocarcinoma metastases that were identified, EMT inflammatory and proliferative, were distinct from the consensus molecular subtype (CMS) 3, suggesting subtype exclusivity. In summary, this study highlights transcriptomic differences between primary tumors and colorectal adenocarcinoma metastases and delineates pathways that are activated in metastases that could be targeted in colorectal adenocarcinoma patients with metastatic disease. Significance: These findings identify a colorectal adenocarcinoma metastasis-specific gene-expression signature that is free from potentially confounding background signals coming from treatment exposure and the normal host tissue that the metastasis is now situated within.

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“…No obvious changes in HIF-1α protein level after vitamin C treatment indicated that other genes, at least within the transcriptome, could underpin the observed reduced TNBC metastasis. By reviewing the known genes involved in breast cancer metastasis [15][16][17] and our available MDA-MB-231 cell RNA-seq data [4], we identified synaptopodin 2 (SYNPO2), with a known function in metastasis, which showed the highest fold change (2.05-fold increase) in MDA-MB-231 cells after vitamin C treatment. Studies have shown that breast cancer has a reduced amount of SYNPO2, which is associated with higher TNBC metastasis and lower patient survival [18].…”

Section: Vitamin C Increases Synaptopodin 2 Expression In Tnbc Cellsmentioning

confidence: 99%

Vitamin C Inhibits Triple-Negative Breast Cancer Metastasis by Affecting the Expression of YAP1 and Synaptopodin 2

et al. 2019

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Vitamin C supplementation has been shown to decrease triple-negative breast cancer (TNBC) metastasis. However, the molecular mechanism whereby vitamin C inhibits metastasis remains elusive. It has been postulated that vitamin C reduces the levels of HIF-1α, the master regulator of metastasis, by promoting its hydroxylation and degradation. Here, we show that vitamin C at 100 µM, a concentration achievable in the plasma in vivo by oral administration, blocks TNBC cell migration and invasion in vitro. The protein level of HIF-1α remains largely unchanged in cultured TNBC cells and xenografts, partially due to its upregulated transcription by vitamin C, suggesting that HIF-1α unlikely mediates the action of vitamin C on metastasis. Vitamin C treatment upregulates the expression of synaptopodin 2 and downregulates the expression of the transcription coactivator YAP1, both genes in the Hippo pathway. The changes in SYNPO2 and YAP1 expression were subsequently validated at mRNA and protein levels in cultured TNBC cells and xenografts. Further experiments showed that vitamin C treatment inhibits F-actin assembly and lamellipodia formation, which correlates with the changes in SYNPO2 and YAP1 expression. Overall, these results suggest that vitamin C inhibits TNBC metastasis by affecting the expression of SYNPO2 and YAP1. Vitamin C may thus have a potential role in the prevention and treatment of TNBC metastasis.

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A core program of gene expression characterizes cancer metastases

Cited by 21 publications

References 57 publications

A Transcriptomic Meta-Analysis Identifies Differentially Expressed Genes across Different Types of Cancer and Their Association with Checkpoint Inhibitor Immunotherapy

A Transcriptomic Meta-Analysis Identifies Differentially Expressed Genes across Different Types of Cancer and Their Association with Checkpoint Inhibitor Immunotherapy

Transcriptomic Differences between Primary Colorectal Adenocarcinomas and Distant Metastases Reveal Metastatic Colorectal Cancer Subtypes

Vitamin C Inhibits Triple-Negative Breast Cancer Metastasis by Affecting the Expression of YAP1 and Synaptopodin 2

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