Specific Extracellular Matrix Remodeling Signature of Colon Hepatic Metastases

Rio, Maguy Del; Mollévi, Caroline; Vezzio-Vié, Nadia; Bibeau, Frédéric; Ychou, Marc; Martineau, Pierre

doi:10.1371/journal.pone.0074599

Cited by 49 publications

(45 citation statements)

References 44 publications

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“…For published microarray (GSE41258 34 , GSE49355 35 , GSE6919 36 , GSE32269 37 , GSE85258 38 and GSE59000 39 ) and RNA-seq dataset (GSE50760 40 ), we downloaded the normalized expression values directly from Gene Expression Omnibus (GEO) database.…”

Section: Methodsmentioning

confidence: 99%

“…Genes defined as tissue-specific needed to meet two criteria: 1) ranked in the top 5 among all tissue and cell types and 2) also highly expressed (∼90th percentile of all genes) in particular tissues and cell types. The log2 ratios were computed for several datasets from normalized expression data, including the primary versus liver metastatic tumor samples from GSE41258 34 , GSE49355 35 , GSE50760 40 , GSE6919 36 , GSE32269 37 , GSE85258 38 and GSE59000 39 datasets, and the DMSO versus JQ1 treatment on SW620 cells. Then, the pre-ranked Gene Set Enrichment Analysis 17 was performed with tissue-associated gene sets and dataset with default parameters.…”

Section: Methodsmentioning

confidence: 99%

“…normal liver tissue) in the metastasis samples. We adapted a published method 35 to remove ambiguous probes/genes. Because hepatic metastasis (HM) sample may be contaminated by certain normal hepatic tissue (HN), the measured expression value of HM for each probe/gene, mHM , is different from the real expression value: where λ is the ratio of HN contamination in HM.…”

Section: Methodsmentioning

confidence: 99%

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Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis

Teng

Yang

et al. 2017

Preprint

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13Tumor metastasis is the cause of death for 90% of cancer patients, and no 14 currently-available therapies target this multi-step process in which cancer cells 15 spread from the local tissue of a primary tumor to distant organs where they 16 establish secondary tumors 1 . Although epithelial-to-mesenchymal transition 2 , 17 tumor-secreted exosomes 3 , epigenetic regulators as well as other genes 4-8 have 18 been implicated in metastasis, little is known about how cells adapt to and 19 colonize new tissue environments. Here, we show that the epigenetics-mediated 20reprogramming of tissue-specific gene transcription in cancer cells promotes 21 metastasis. Using colorectal cancer (CRC) as a model, we found in both clinical 22 3 reprogramming in several cohorts of clinical CRC tumor samples and in multiple 33 other forms of metastatic cancers, indicate that this reprogramming may be a 34 common feature of metastasis in multiple cancers and suggest the targeted 35 disruption of this epigenetic reprogramming as a strategy for the development of 36 therapies to treat metastasis, the leading cause of cancer-related mortality. 37 MAIN 39Tumor metastasis refers to the movement of tumor cells from a primary site 40to distant organs that they progressively colonize 9 . More than 100 years ago, 41Paget suggested the idea of metastasis as the interaction of "seeds" and "soil" 10 , 42 but subsequent research has yielded only a limited understanding of the 43 mechanism(s) through which metastatic cancer cells ("seeds") adapt to and 44 colonize a new tissue environment ("soil"), the crucial steps of the metastasis 45 process 11 . 46It has been reported that the expression of tissue-specific or cell-lineage 47 7 the genome regions around loci encoding up-regulated liver-specific genes had 113 enriched H3K27ac (P value = 2.2e-16, by t-test) and H3K4me2 (P value = 2.2e-16, 114 by t-test) deposition (Fig. 2c). 115So-called super-enhancers are a small fraction of total enhancers and 116 encompass broad chromatin domains with H3K27ac deposition near genes 117 essential for defining cell identity 20,21 . By identifying super-enhancers in SW480 118 and SW620 cells based on our H3K27ac ChIP-seq datasets, we found that in 119 addition to the 264 super-enhancers common to both cell lines, there are 280 and 120 215 unique super-enhancers in SW620 and SW480 cells, respectively (Extended 121 Data Fig. 4d). Comparison between our ChIP-seq and RNA-seq data revealed a 122 high Pearson correlation coefficient (R = 0.807, P value < 2.2e-16) between the 123 genome-wide distribution of super-enhancers and the expression levels of the 124 nearest genes in these two cell lines ( Fig. 2d and Extended Data Fig. 4e). Notably, 125 many of the liver-specific genes in SW620 cells were found near SW620-unique 126 super-enhancers; while the colon-specific genes in SW480 cells were found close 127 to SW480-unique super-enhancers ( Fig. 2e and Extended Data Fig. 4f, g). Our 128 epigenetic and transcriptomics experiments demonstrate that reshaped enhancer 129 ...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis

Teng

Yang

et al. 2017

Preprint

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“…It is more frequent among the elderly; nearly 60% of incident cases are diagnosed in patients aged 65 years or over . Moreover, approximately 40% will at one point have metastatic disease (mCRC) . In the last 10 years, targeted therapies have become available and recommended for the first‐line treatment of mCRC in combination with chemotherapy .…”

Section: Introductionmentioning

confidence: 99%

How are elderly patients treated after a diagnosis of metastatic colorectal cancer in real‐life practice? A study in a French teaching hospital

Gouverneur

Rouyer

Grelaud

et al. 2016

Fundamemntal Clinical Pharma

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Metastatic colorectal cancer (mCRC) is frequent among elderly patients. However, in the era of new targeted therapies, little is known about real-life mCRC treatment in this population. This study aimed to describe elderly mCRC patients and the current real-life treatment practices. mCRC patients aged ≥65 years were identified using the registry of multidisciplinary team meetings, mandatory for all cancer patients, held between January 1, 2013 and June 30, 2014 at the Bordeaux University Hospital. Data were collected from medical records using a standardized questionnaire. Treatment type was defined as follows: at least one anticancer medication administered vs. best supportive care (BSC). A total of 78 patients were included; median age was 74 years and the M/F sex ratio 1.6. Eleven patients (14.1%) were referred to a geriatric oncology consultation. One patient died before treatment initiation, 28 (35.9%) had BSC, and 49 (62.8%) were treated with anticancer medications: 20 (25.6%) had chemotherapy combined with a targeted therapy, and 28 (35.9%) chemotherapy alone (one missing data for treatment). Compared to patients treated with anticancer medications, BSC patients were older (P < 0.0001) and had more often metachronous metastases (P = 0.01), more comorbidities (P = 0.05), and a greater number of concomitant medications (P = 0.004). This study is one of the rare investigations providing insight to treatment practices in all elderly mCRC patients, not just those who receive anticancer medications. Our results suggest that efforts must be pursued to better integrate geriatric oncology in daily clinical practice.

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“…Nearly 60% of incident cases are diagnosed in patients 65 years and older . At diagnosis, 20% of patients have at least one metastatic site, and approximately 40% will at one point have metastatic colorectal cancer (mCRC) …”

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confidence: 99%

Treatment Modalities and Survival in Older Adults with Metastatic Colorectal Cancer in Real Life

Gouverneur

Bezin

Jové

et al. 2019

J American Geriatrics Society

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OBJECTIVES Metastatic colorectal cancer (mCRC) is increasingly treated with targeted therapies, but little is known about real‐life mCRC treatment in older adults. The aims were to describe the real‐life first‐line treatment modalities in older adult mCRC patients, to identify factors associated with treatment modalities, and to evaluate survival with regard to treatment modalities. PATIENTS AND METHODS A cohort of mCRC patients aged 65 years and older at diagnosis was identified between 2009 and 2013 using French national healthcare insurance system claims data. Treatment modalities were: treatment with one or more anticancer medication vs best supportive care and, among treated patients, treatment with targeted therapy vs conventional chemotherapy alone. Multivariate logistic regression was used to identify factors associated with treatment by anticancer medication and by targeted therapy. Cox proportional hazards models were used to assess the independent effect of treatment modalities on overall survival while adjusting for baseline covariates identified with logistic regression. RESULTS A total of 503 patients were included with a median age of 78 years (54% were men). Of these, 299 (59%) were treated with anticancer medications. Among treated patients, 131 (44%) received targeted therapy. In multivariate analysis, age 75 years or older, renal failure, malnutrition, and five or more concomitant medications were associated with a lower likelihood of treatment with anticancer medications. Among treated patients, age 75 years or older, history of cancer, lymph node metastases, and a single metastatic site were associated with a lower likelihood of treatment with targeted therapy. Multivariate Cox proportional hazards models found that treatment with any anticancer medication tended to be associated with a lower risk of death; treatment with targeted therapy was not significantly associated. CONCLUSION A more appropriate prescription of anticancer medications in the older adult will require the definition of more explicit criteria to avoid undertreatment. The real benefit of targeted therapies vs conventional chemotherapy alone needs to be confirmed in this population. J Am Geriatr Soc 67:913–919, 2019.

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Specific Extracellular Matrix Remodeling Signature of Colon Hepatic Metastases

Cited by 49 publications

References 44 publications

Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis

Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis

How are elderly patients treated after a diagnosis of metastatic colorectal cancer in real‐life practice? A study in a French teaching hospital

Treatment Modalities and Survival in Older Adults with Metastatic Colorectal Cancer in Real Life

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