Cellular plasticity at the nexus of development and disease

Spatz, Lillian B.; Jin, Ramon U.; Mills, Jason C.

doi:10.1242/dev.197392

Cited by 9 publications

(7 citation statements)

References 70 publications

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“…Metaplasia in the stomach is considered to be a response to inflammatory stimuli as well as precancerous lesions [11,12]. Acute inflammatory stimuli caused by DMP-777 or high-dose tamoxifen administration can induce SPEM in mouse models, and the glands immediately recover to normal after removal of stimuli [3,13].…”

Section: Discussionmentioning

confidence: 99%

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma

Kumagai

Shimizu

Nikaido

et al. 2023

The Journal of Pathology

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Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide‐expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71‐year‐old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6‐positive mucous cells, referred to as SPEM, expanded between them. Whole‐exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS‐mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma

Kumagai

Shimizu

Nikaido

et al. 2023

The Journal of Pathology

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“…However, with tools like genetic and chemical lineage tracing and single-cell RNA sequencing (scRNA-seq), and with the advent of cellular reprogramming to generate induced pluripotent stem cells (2,3), it has become clear that cell behavior in tissue can be far more complicated (see, e.g., 4,5). For example, single-cell expression profiling shows that there might not even be clear grooves on the Waddington landscape, but instead, cell identity might be fluid, with the behavior and phenotype of a single differentiated cell being better modeled by a stochastic electron-cloud-like representation (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

Paligenosis: Cellular Remodeling During Tissue Repair

Brown

Cho

Mills

2022

Annu. Rev. Physiol.

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Complex multicellular organisms have evolved specific mechanisms to replenish cells in homeostasis and during repair. Here, we discuss how emerging technologies (e.g., single-cell RNA sequencing) challenge the concept that tissue renewal is fueled by unidirectional differentiation from a resident stem cell. We now understand that cell plasticity, i.e., cells adaptively changing differentiation state or identity, is a central tissue renewal mechanism. For example, mature cells can access an evolutionarily conserved program (paligenosis) to reenter the cell cycle and regenerate damaged tissue. Most tissues lack dedicated stem cells and rely on plasticity to regenerate lost cells. Plasticity benefits multicellular organisms, yet it also carries risks. For one, when long-lived cells undergo paligenotic, cyclical proliferation and redifferentiation, they can accumulate and propagate acquired mutations that activate oncogenes and increase the potential for developing cancer. Lastly, we propose a new framework for classifying patterns of cell proliferation in homeostasis and regeneration, with stem cells representing just one of the diverse methods that adult tissues employ. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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“…To perform specialized functions, distinct cell types must maintain unique identities, including cell type-specific transcriptomes. They also need to adapt to changing environments by deploying plasticity in transcription or even cell identity [31][32][33] . The molecular control of cell identity and plasticity is a fundamental question, with scant mechanistic insights.…”

Section: Discussionmentioning

confidence: 99%

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

Huang

Singh

et al. 2022

Preprint

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Plasticity between cell lineages is a fundamental but poorly understood property of regenerative tissues. In the gut tube, small intestine absorbs nutrients whereas colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screen, we identified MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrain colonic plasticity. MTA2 loss in adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-binds with HNF4A, an activating pan-intestine transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic and gain on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through a HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages; their release unleashes plasticity.

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Cellular plasticity at the nexus of development and disease

Cited by 9 publications

References 70 publications

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma

Paligenosis: Cellular Remodeling During Tissue Repair

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

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