Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis

López-Arribillaga, Erika; Yan, Bing; Lobo-Jarne, Teresa; Guillén, Yolanda; Menéndez, Sílvia; Andreu, Montserrat; Bigas, Anna; Iglesias, Mar; Espinosa, Lluís

doi:10.3390/cells10112928

Cited by 6 publications

(3 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S4A). Indeed, the occurrence of metaplastic Paneth cells has been widely documented in inflammation and also in cancer of the colon 23,24 .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment

Wei,

Blanc,

Peidli

et al. 2024

Preprint

View full text Add to dashboard Cite

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could potentially adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer epithelial cells in single-cell data. In colorectal cancer datasets, we find that our method and others based on gene expression or allelic imbalances identify overlapping sets of cancer versus normal epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.

show abstract

“…S4A). Indeed, the occurrence of metaplastic Paneth cells has been widely documented in inflammation and also in cancer of the colon 23,24 .…”

Section: Resultsmentioning

confidence: 99%

“…S4A). Indeed, the occurrence of metaplastic Paneth cells has been widely documented in inflammation and also in cancer of the colon 23,24 . The CRC microenvironment modulates epithelial cell states and developmental trajectories…”

Section: Consensus Cell Identity Leads To Higher Homogeneity Of Trans...mentioning

confidence: 99%

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment

Wei,

Blanc,

Peidli

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…A recent study has shown an association between Paneth cell-containing adenomas, male gender and increased adenoma burden (102). In addition, recent research has shown that the accumulation of Paneth cells in early colorectal adenomas is related to catenin signaling, suggesting that Paneth cells may form a stem cell niche for adenoma cells, which could have therapeutic implications (103).…”

Section: Expression Of Defa6-icre In Colorectal Tumors and Its Use In...mentioning

confidence: 99%

The fate of secretory cells during intestinal homeostasis, regeneration, and tumor formation is regulated by Tcf4

Janeckova,

Stastna,

Hrckulak

et al. 2024

Preprint

View full text Add to dashboard Cite

The single-layer epithelium of the gastrointestinal tract is a dynamically renewing tissue that ensures nutrient absorption, secretory and barrier functions and is involved in immune responses. The basis for this homeostatic renewal is the Wnt signaling pathway. Blocking this pathway can lead to epithelial damage, while its abnormal activation can result in the development of intestinal tumors. In this study, we investigated the dynamics of intestinal epithelial cells and tumorigenesis using a conditional mouse model. Using single-cell and bulk RNA sequencing and histological analysis, we elucidated the cellular responses following the loss of specific cell types. We focused on the fate of cells in the lower parts of the intestinal crypts and the development of colon adenomas. By partially inactivating the transcription factor Tcf4, a key effector of the Wnt signaling pathway, we analyzed the regeneration of isolated hyperproliferative foci (crypts). Our results suggest that the damaged epithelium is not restored by a specific regeneration program associated with oncofetal gene production, but rather by a standard homeostatic renewal pathway. Moreover, disruption of Tcf4 in secretory progenitors resulted in a significant shift in the cell lineage from Paneth cells to goblet cells, characterized by morphological changes and loss of Paneth cell-specific genes. We also found that hyperactivation of the Wnt signaling pathway in colonic adenomas correlated with the upregulation of genes typical of Paneth cells in the intestine, followed by the emergence of secretory tumor cells producing the Wnt3 ligand. The absence of Tcf4 led to a phenotypic shift of the tumor cells towards goblet cells. Our study presents a new model of epithelial regeneration based on the genetically driven partial elimination of intestinal crypts. We highlight the critical role of Tcf4 in the control of cell lineage decisions in the intestinal epithelium and colon tumors.

show abstract

High‐confidence calling of normal epithelial cells allows identification of a novel stem‐like cell state in the colorectal cancer microenvironment

Wei,

Blanc,

Peidli

et al. 2024

Intl Journal of Cancer

View full text Add to dashboard Cite

Single‐cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non‐cancer cells in single‐cell data. We find that our method and others based on gene expression or allelic imbalances identify overlapping sets of colorectal cancer versus normal colon epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem‐like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo‐time range of normal colon stem‐like cells in a cancer context. We identify cancer‐associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.

show abstract

Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis

Cited by 6 publications

References 31 publications

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment

The fate of secretory cells during intestinal homeostasis, regeneration, and tumor formation is regulated by Tcf4

High‐confidence calling of normal epithelial cells allows identification of a novel stem‐like cell state in the colorectal cancer microenvironment

Contact Info

Product

Resources

About