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Title: Colonic epithelial adaptation to EGFR-independent growth induces chromosomal instability and is accelerated by prior injury
Authors: Chen, Tiane
Zeineldin, Maged
Johnson, Blake A.
Dong, Yi
Narkar, Akshay
Li, Taibo
Zhu, Jin
Li, Rong 
Larman, Tatianna C.
Keywords: Chromosomal instability
Colorectal cancer
Intestinal organoids
Issue Date: 1-May-2021
Publisher: Elsevier Inc.
Citation: Chen, Tiane, Zeineldin, Maged, Johnson, Blake A., Dong, Yi, Narkar, Akshay, Li, Taibo, Zhu, Jin, Li, Rong, Larman, Tatianna C. (2021-05-01). Colonic epithelial adaptation to EGFR-independent growth induces chromosomal instability and is accelerated by prior injury. Neoplasia (United States) 23 (5) : 488-501. ScholarBank@NUS Repository.
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
Abstract: Although much is known about the gene mutations required to drive colorectal cancer (CRC) initiation, the tissue-specific selective microenvironments in which neoplasia arises remains less characterized. Here, we determined whether modulation of intestinal stem cell niche morphogens alone can exert a neoplasia-relevant selective pressure on normal colonic epithelium. Using adult stem cell-derived murine colonic epithelial organoids (colonoids), we employed a strategy of sustained withdrawal of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) inhibition to select for and expand survivors. EGFR-signaling-independent (iEGFR) colonoids emerged over rounds of selection and expansion. Colonoids derived from a mouse model of chronic mucosal injury showed an enhanced ability to adapt to EGFR inhibition. Whole-exome and transcriptomic analyses of iEGFR colonoids demonstrated acquisition of deleterious mutations and altered expression of genes implicated in EGF signaling, pyroptosis, and CRC. iEGFR colonoids acquired dysplasia-associated cytomorphologic changes, an increased proliferative rate, and the ability to survive independently of other required niche factors. These changes were accompanied by emergence of aneuploidy and chromosomal instability; further, the observed mitotic segregation errors were significantly associated with loss of interkinetic nuclear migration, a fundamental and dynamic process underlying intestinal epithelial homeostasis. This study provides key evidence that chromosomal instability and other phenotypes associated with neoplasia can be induced ex vivo via adaptation to EGF withdrawal in normal and stably euploid colonic epithelium, without introducing cancer-associated driver mutations. In addition, prior mucosal injury accelerates this evolutionary process. © 2021 The Authors
Source Title: Neoplasia (United States)
ISSN: 1522-8002
DOI: 10.1016/j.neo.2021.03.010
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
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