Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Sacchetti, Andrea; Teeuwssen, Miriam; Verhagen, Mathijs; Joosten, Rosalie; Xu, Tong; Stabile, Roberto; Steen, Berdine van der; Watson, Martin M.; Gusinac, Alem; Kim, Won Kyu; Ubink, Inge; Werken, Harmen J.G. van de; Fumagalli, Arianna; Paauwe, Madelon; Rheenen, Jacco van; Sansom, Owen J.; Kranenburg, Onno; Fodde, Riccardo

doi:10.7554/elife.61461

Cited by 52 publications

(49 citation statements)

References 64 publications

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“…For each cell, an epithelial (E) and mesenchymal (M) score was calculated using two gene sets containing 65 epithelial and 115 mesenchymal genes ( Cesano 2015 ). Following the approach of Sacchetti et al (2021) , we subtracted the E score from the M score to define a single EMT score for each cell (EMT = M – E). Cells in the outer layer had significantly higher EMT scores than cells in the center (Kruskal-Wallis test, p = .0017; Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

“…To calculate the level of EMT in each cell, we followed the approach of Sacchetti et al (2021) Gene Set Variation analysis was performed using the GSVA package ( Hänzelmann et al, 2013 ), where we used a set of EMT markers that is publicly available from the Nanostring nCounter PanCancer Progression Panel ( Cesano 2015 ). This gene set contained 65 epithelial (E) and 115 mesenchymal (M) genes ( Supplementary Table S1 ).…”

Section: Methodsmentioning

confidence: 99%

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Spatially Annotated Single Cell Sequencing for Unraveling Intratumor Heterogeneity

Smit

Feller

et al. 2022

Front. Bioeng. Biotechnol.

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Intratumor heterogeneity is a major obstacle to effective cancer treatment. Current methods to study intratumor heterogeneity using single-cell RNA sequencing (scRNA-seq) lack information on the spatial organization of cells. While state-of-the art spatial transcriptomics methods capture the spatial distribution, they either lack single cell resolution or have relatively low transcript counts. Here, we introduce spatially annotated single cell sequencing, based on the previously developed functional single cell sequencing (FUNseq) technique, to spatially profile tumor cells with deep scRNA-seq and single cell resolution. Using our approach, we profiled cells located at different distances from the center of a 2D epithelial cell mass. By profiling the cell patch in concentric bands of varying width, we showed that cells at the outermost edge of the patch responded strongest to their local microenvironment, behaved most invasively, and activated the process of epithelial-to-mesenchymal transition (EMT) to migrate to low-confluence areas. We inferred cell-cell communication networks and demonstrated that cells in the outermost ∼10 cell wide band, which we termed the invasive edge, induced similar phenotypic plasticity in neighboring regions. Applying FUNseq to spatially annotate and profile tumor cells enables deep characterization of tumor subpopulations, thereby unraveling the mechanistic basis for intratumor heterogeneity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Spatially Annotated Single Cell Sequencing for Unraveling Intratumor Heterogeneity

Smit

Feller

et al. 2022

Front. Bioeng. Biotechnol.

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“…Despite tremendous advances in high-throughput single-cell sequencing in the last decade, no unique mutational signature has yet been identified for metastasis (Celià-Terrassa and Kang, 2016;Welch and Hurst, 2019). Instead, cellular or phenotypic plasticity -the ability of cells to reversibly switch their phenotypes -has been proposed as a hallmark of metastasis (Bhatia et al, 2020;Biswas and De, 2021;Sacchetti et al, 2021). One of the key axes of phenotypic plasticity during metastasis is epithelial-mesenchymal plasticity (EMP), where cells can transition among a range of phenotypes spread over a spectrum ranging from more epithelial (usually more adhesive and less invasive) to more mesenchymal (usually more invasive and having reduced cell-cell adhesion) (Gupta et al, 2019;Pastushenko and Blanpain, 2019).…”

Section: Are Mutations Necessary For Cancer Progression?mentioning

confidence: 99%

Cancer: More Than a Geneticist’s Pandora’s Box

Saxena¹,

Subbalakshmi²,

Kulkarni³

et al. 2021

Preprint

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Despite identical genetic constitution, a cancer cell population can exhibit phenotypic variations termed as non-genetic/non-mutational heterogeneity. Such heterogeneity – a ubiquitous nature of biological systems – has been implicated in metastasis, therapy resistance and tumour relapse. Here, we review the evidence for existence, sources and implications of non-genetic heterogeneity in multiple cancer types. Stochasticity/ noise in transcription, protein conformation and/or external microenvironment can underlie such heterogeneity. Moreover, the existence of multiple possible cell states (phenotypes) as a consequence of the emergent dynamics of gene regulatory networks may enable reversible cell-state transitions (phenotypic plasticity) that can facilitate adaptive drug resistance and higher metastatic fitness. Finally, we highlight how computational and mathematical models can drive a better understanding of non-genetic heterogeneity and how a systems-level approach integrating mathematical modelling and in vitro/in vivo experiments can map the diverse phenotypic repertoire, and identify therapeutic vulnerabilities of an otherwise clonal cell population.

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“…Recently, we identified and thoroughly characterized subpopulations of CD44 hi /EpCAM lo colon cancer cells (here referred to as EpCAM lo ) that coexist with their epithelial counterparts (CD44 hi /EpCAM hi ; for brevity EpCAM hi ) through stochastic state transitions governed by phenotypic plasticity and pEMT 17 . Accordingly, EpCAM lo cells feature highly invasive and metastatic capacities.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer

Fodde

2022

Preprint

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Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial to mesenchymal (EMT) and mesenchymal to epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in colon cancer. By taking advantage of the identification of a subpopulation of quasi-mesenchymal and highly metastatic EpCAMlo colon cancer cells, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1, alters the AS pattern of a broad spectrum of targets including CD44 and NUMB, thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in colon cancer and in other malignancies, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets.

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Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

Cited by 52 publications

References 64 publications

Spatially Annotated Single Cell Sequencing for Unraveling Intratumor Heterogeneity

Spatially Annotated Single Cell Sequencing for Unraveling Intratumor Heterogeneity

Cancer: More Than a Geneticist’s Pandora’s Box

Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer

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