Cancer Cells Retrace a Stepwise Differentiation Program during Malignant Progression.

Details

Serval ID
serval:BIB_E3BABADE6621
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cancer Cells Retrace a Stepwise Differentiation Program during Malignant Progression.
Journal
Cancer discovery
Author(s)
Saghafinia S., Homicsko K., Di Domenico A., Wullschleger S., Perren A., Marinoni I., Ciriello G., Michael I.P., Hanahan D.
ISSN
2159-8290 (Electronic)
ISSN-L
2159-8274
Publication state
Published
Issued date
10/2021
Peer-reviewed
Oui
Volume
11
Number
10
Pages
2638-2657
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Pancreatic neuroendocrine tumors (PanNET) comprise two molecular subtypes, relatively benign islet tumors (IT) and invasive, metastasis-like primary (MLP) tumors. Until now, the origin of aggressive MLP tumors has been obscure. Herein, using multi-omics approaches, we revealed that MLP tumors arise from IT via dedifferentiation following a reverse trajectory along the developmental pathway of islet β cells, which results in the acquisition of a progenitor-like molecular phenotype. Functionally, the miR-181cd cluster induces the IT-to-MLP transition by suppressing expression of the Meis2 transcription factor, leading to upregulation of a developmental transcription factor, Hmgb3. Notably, the IT-to-MLP transition constitutes a distinct step of tumorigenesis and is separable from the classic proliferation-associated hallmark, temporally preceding accelerated proliferation of cancer cells. Furthermore, patients with PanNET with elevated HMGB3 expression and an MLP transcriptional signature are associated with higher-grade tumors and worse survival. Overall, our results unveil a new mechanism that modulates cancer cell plasticity to enable malignant progression. SIGNIFICANCE: Dedifferentiation has long been observed as a histopathologic characteristic of many cancers, albeit inseparable from concurrent increases in cell proliferation. Herein, we demonstrate that dedifferentiation is a mechanistically and temporally separable step in the multistage tumorigenesis of pancreatic islet cells, retracing the developmental lineage of islet β cells.This article is highlighted in the In This Issue feature, p. 2355.
Keywords
Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Gene Expression Regulation, Mice, Neuroendocrine Tumors/genetics, Neuroendocrine Tumors/pathology, Pancreatic Neoplasms/genetics, Pancreatic Neoplasms/pathology
Pubmed
Web of science
Open Access
Yes
Create date
19/05/2021 14:08
Last modification date
09/04/2022 6:33
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