Integrative multi-omics analysis of a colon cancer cell line with heterogeneous Wnt activity revealed RUNX2 as an epigenetic regulator of EMT

Yi, Hongyang; Li, Guipeng; Long, Yongkang; Liang, Weizheng; Cui, Huanhuan; Zhang, Bin; Tan, Ying; Li, Yunfei; Shen, Luochen; Deng, Daqi; Tang, Yisen; Mao, Chenyu; Tian, Shuye; Cai, Yuyan; Zhu, Qionghua; Hu, Yuhui; Chen, Wei; Fang, Liang

doi:10.1038/s41388-020-1351-z

Cited by 38 publications

(40 citation statements)

References 64 publications

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“…More than 1000 cells were analyzed from each subpopulation and sequenced to a depth of approximately 50,000 reads each with the MiSeq System (Illumina). After dimension reduction with tSNE, the EpCAM lo and EpCAM hi cells clustered in separate groups in HCT116 ( Figure 5A ), whereas the SW480 cells showed a partial overlap between the two subpopulations and a distinct EpCAM hi cluster, identified as the non-adherent subpopulation within the SW480 cell line (‘spheres’) ( Hirsch et al, 2014 ; Yi et al, 2020 ; Figure 5—figure supplement 1A ). Substantial overlap between the EpCAM hi/lo subpopulations was retained upon subsequent exclusion of the non-adherent cells in SW480, attributed to additional variance in genes independent of EpCAM hi/lo differences ( Figure 5—figure supplement 1B ).…”

Section: Resultsmentioning

confidence: 99%

Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Sacchetti

Teeuwssen

Verhagen

et al. 2021

eLife

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Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphologic and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated 1. enhanced Wnt/b-catenin signaling, 2. a broad spectrum of degrees of EMT activation including hybrid E/M states (partial EMT) with highly plastic features, and 3. high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and b-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically-distinct cellular states, and to underlie the phenotypic plasticity of colon cancer cells.

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Section: Resultsmentioning

confidence: 99%

Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Sacchetti

Teeuwssen

Verhagen

et al. 2021

eLife

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show abstract

“…After dimension reduction with tSNE, the EpCAM lo and EpCAM hi cells clustered in separate groups in HCT116 (Fig. 5A), whereas the SW480 cells showed a partial overlap between the two subpopulations and a distinct EpCAM hi cluster, identified as the non-adherent subpopulation within the SW480 cell line (“spheres”) 30, 31 (Fig. S5-1A).…”

Section: Resultsmentioning

confidence: 99%

Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Sacchetti

Teeuwssen

Verhagen

et al. 2020

Preprint

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Phenotypic plasticity represents the most relevant hallmark of the metastasizing carcinoma cell as it bestows it with the capacity of altering its own cellular identity when exposed to different environments along the invasion-metastasis cascade. However, the study of the mechanisms underlying phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental study models. Here, we identified a subpopulation of colon cancer cells endowed with phenotypic plasticity: CD44hi/EpCAMlo cells are highly motile, invasive, chemoresistant, and metastatic both in vitro and in vivo. Bulk and single-cell RNAseq analysis indicated that they encompass a broad spectrum of degrees of EMT activation, together with stem/progenitor-like feature, enhanced Wnt/β-catenin signaling, and a high correlation with the CMS4 subtype, accounting for ∼25% of colon cancer cases with poor prognosis. Enhanced Wnt and the downstream upregulation of EMT transcription factors such as ZEB1 represent key events in eliciting phenotypic plasticity to cancer cells along the invasive front of primary colon carcinomas. Of note, different combinations of distinct sets of epithelial and mesenchymal genes define alternative transcriptional trajectories through which state transitions arise. Hybrid E/M stages are predicted to represent the origin of these differentiation routes through biologically-distinct cellular states and as such to underlie the phenotypic plasticity of colon cancer cells.

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“…More recently, it has been demonstrated that RUNX2 could interact with BRG1 to target CD44 for promoting invasion and migration of colorectal cancer cells [22]. It has been also recently reported that Integrative multi-omics analysis of a colon cancer cells with heterogeneous Wnt activity reveals RUNX2 as an epigenetic regulator of Epithelial-mesenchymal transition (EMT), the critical process which promotes cancer metastasis, stemness and resistance to treatment [23].…”

Section: Runx2 and Skeletal Development Runx2 Promotes Osteoblast Differentiation Via Several Signaling Pathways Runx2 Directly Acts On Omentioning

confidence: 99%

Role of RUNX2 in Melanoma: A New Player in Tumor Progression and Resistance to Therapy

Pulica¹,

Solal²,

Lasfar³

2021

Melanoma

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RUNX2, a transcription factor, initially known for its indispensable role in skeletal development. RUNX2 is essential for osteoblast differentiation and the maintain of the osteocyte balance. RUNX2 acts directly on osteoblasts via Fgf pathway or on mesenchymal progenitors through Hedgehog, Wnt, Pthlh and DLX5. Currently, many reports point its critical role in the progression and metastasis of several cancer types. RUNX2 is involved in EMT process, invasion and metastasis through the modulation of important oncogenic pathways, including Wnt, FAK/PTK and AKT. In melanoma, RUNX2 is a key player in mediating intrinsic RTK-associated pro-oncogenic properties. We have showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL, in melanoma cells rendered resistant to BRAF mutant inhibitors. Approximately half of melanomas carry BRAF mutations which enhance tumor invasion and metastasis. In this chapter, we describe the potential mechanisms, leading to the upregulation of RUNX2 in melanoma with BRAF mutations. We also highlight the critical role of PI3K/AKT in the expression and activation of RUNX2, and its consequences on the regulation of many critical factors, controlling cancer invasion and metastasis.

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Integrative multi-omics analysis of a colon cancer cell line with heterogeneous Wnt activity revealed RUNX2 as an epigenetic regulator of EMT

Cited by 38 publications

References 64 publications

Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Role of RUNX2 in Melanoma: A New Player in Tumor Progression and Resistance to Therapy

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