<i>In vivo</i>epigenetic reprogramming of primary human colon cancer cells enhances metastases

Singovski, Grigori; Bernal, Carolina; Kuciak, Monika; Siegl-Cachedenier, Irene; Conod, Arwen; Altaba, Ariel Ruiz i

doi:10.1093/jmcb/mjv034

Cited by 28 publications

(34 citation statements)

References 49 publications

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“…Primary human colon cancer (CC) samples CC36 (TNM3), CC14 (TNM4) and mCC11 (liver metastasis from CC patient) used for this study were as in references [ 10 ], [ 21 ], [ 22 ], [ 23 ]. The human CC HT29 and T84 cell lines, the latter derived from a lung metastasis, were obtained from Cell Line Services.…”

Section: Methodsmentioning

confidence: 99%

Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling

Seth

Altaba

2016

PLoS ONE

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Human colon cancers commonly harbor loss of function mutations in APC, a repressor of the canonical WNT pathway, thus leading to hyperactive WNT-TCF signaling. Re-establishment of Apc function in mice, engineered to conditionally repress Apc through RNAi, resolve the intestinal tumors formed due to hyperactivated Wnt-Tcf signaling. These and other results have prompted the search for specific WNT pathway antagonists as therapeutics for clinically problematic human colon cancers and associated metastases, which remain largely incurable. This widely accepted view seems at odds with a number of findings using patient-derived material: Canonical TCF targets are repressed, instead of being hyperactivated, in advanced colon cancers, and repression of TCF function does not generally result in tumor regression in xenografts. The results of a number of genetic mouse studies have also suggested that canonical WNT-TCF signaling drives metastases, but direct in vivo tests are lacking, and, surprisingly, TCF repression can enhance directly seeded metastatic growth. Here we have addressed the abilities of enhanced and blocked WNT-TCF signaling to alter tumor growth and distant metastases using xenografts of advanced human colon cancers in mice. We find that endogenous WNT-TCF signaling is mostly anti-metastatic since downregulation of TCF function with dnTCF generally enhances metastatic spread. Consistently, elevating the level of WNT signaling, by increasing the levels of WNT ligands, is not generally pro-metastatic. Our present and previous data reveal a heterogeneous response to modulating WNT-TCF signaling in human cancer cells. Nevertheless, the findings that a fraction of colon cancers tested require WNT-TCF signaling for tumor growth but all respond to repressed signaling by increasing metastases beg for a reevaluation of the goal of blocking WNT-TCF signaling to universally treat colon cancers. Our data suggest that WNT-TCF blockade may be effective in inhibiting tumor growth in only a subset of cases but will generally boost metastases.

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Section: Methodsmentioning

confidence: 99%

Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling

Seth

Altaba

2016

PLoS ONE

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“…Visually, this may be akin to punctually sampling overlapping waves of expression that have different periods and amplitudes. It could also explain an increase in VSIG1 levels upon metastatic reprogramming (data not shown; see Singovski et al, 2016), in which it could act as a feedback inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Functional Pro-metastatic Heterogeneity Revealed by Spiked-scRNAseq Is Shaped by Cancer Cell Interactions and Restricted by VSIG1

et al. 2020

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“…The term “epigenetic reprogramming” is commonly used to describe profound alterations in the epigenetic makeup (e.g. [ 57 , 58 ])—and therefore appears to be justified in this context. Addressing the question why those DNA regions showed differences in DNA methylation, we focused on mechanisms known to be involved in regulating DNA methylation dynamics.…”

Section: Discussionmentioning

confidence: 99%

ITIH5 mediates epigenetic reprogramming of breast cancer cells

et al. 2017

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BackgroundExtracellular matrix (ECM) is known to maintain epithelial integrity. In carcinogenesis ECM degradation triggers metastasis by controlling migration and differentiation including cancer stem cell (CSC) characteristics. The ECM-modulator inter- α-trypsin inhibitor heavy chain family member five (ITIH5) was recently identified as tumor suppressor potentially involved in impairing breast cancer progression but molecular mechanisms underlying its function are still elusive.Methods ITIH5 expression was analyzed using the public TCGA portal. ITIH5-overexpressing single-cell clones were established based on T47D and MDA-MB-231 cell lines. Colony formation, growth, apoptosis, migration, matrix adhesion, traction force analyses and polarization of tumor cells were studied in vitro. Tumor-initiating characteristics were analyzed by generating a metastasis mouse model. To identify ITIH5-affected pathways we utilized genome wide gene expression and DNA methylation profiles. RNA-interference targeting the ITIH5-downstream regulated gene DAPK1 was used to confirm functional involvement.Results ITIH5 loss was pronounced in breast cancer subtypes with unfavorable prognosis like basal-type tumors. Functionally, cell and colony formation was impaired after ITIH5 re-expression in both cell lines. In a metastasis mouse model, ITIH5 expressing MDA-MB-231 cells almost completely failed to initiate lung metastases. In these metastatic cells ITIH5 modulated cell-matrix adhesion dynamics and altered biomechanical cues. The profile of integrin receptors was shifted towards β1-integrin accompanied by decreased Rac1 and increased RhoA activity in ITIH5-expressing clones while cell polarization and single-cell migration was impaired. Instead ITIH5 expression triggered the formation of epithelial-like cell clusters that underwent an epigenetic reprogramming. 214 promoter regions potentially marked with either H3K4 and /or H3K27 methylation showed a hyper- or hypomethylated DNA configuration due to ITIH5 expression finally leading to re-expression of the tumor suppressor DAPK1. In turn, RNAi-mediated knockdown of DAPK1 in ITIH5-expressing MDA-MB-231 single-cell clones clearly restored cell motility.ConclusionsOur results provide evidence that ITIH5 triggers a reprogramming of breast cancer cells with known stem CSC properties towards an epithelial-like phenotype through global epigenetic changes effecting known tumor suppressor genes like DAPK1. Therewith, ITIH5 may represent an ECM modulator in epithelial breast tissue mediating suppression of tumor initiating cancer cell characteristics which are thought being responsible for the metastasis of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0610-2) contains supplementary material, which is available to authorized users.

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In vivoepigenetic reprogramming of primary human colon cancer cells enhances metastases

Cited by 28 publications

References 49 publications

Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling

Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling

Functional Pro-metastatic Heterogeneity Revealed by Spiked-scRNAseq Is Shaped by Cancer Cell Interactions and Restricted by VSIG1

ITIH5 mediates epigenetic reprogramming of breast cancer cells

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