Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging

Abstract

SummaryAdult stem cells may acquire mutations that modify cellular behavior, leading to functional declines in homeostasis or providing a competitive advantage resulting in premalignancy. However, the frequency, phenotypic impact, and mechanisms underlying spontaneous mutagenesis during aging are unclear. Here, we report two mechanisms of genome instability in adult Drosophila intestinal stem cells (ISCs) that cause phenotypic alterations in the aging intestine. First, we found frequent loss of heterozygosity arising from mitotic homologous recombination in ISCs that results in genetic mosaicism. Second, somatic deletion of DNA sequences and large structural rearrangements, resembling those described in cancers and congenital diseases, frequently result in gene inactivation. Such modifications induced somatic inactivation of the X-linked tumor suppressor Notch in ISCs, leading to spontaneous neoplasias in wild-type males. Together, our findings reveal frequent genomic modification in adult stem cells and show that somatic genetic mosaicism has important functional consequences on aging tissues.

Intrinsic regulation of enteroendocrine fate by Numb

“…We hypothesize that Notch activity is inhibited by Numb in the two daughter cells maintaining them in a plastic state capable of ISC and EE fate. The concept of ISC/EE plasticity in conditions of low Notch is supported by the phenotype detected upon Notch inactivation in ISCs, which results in the accumulation of clusters of ISC-like and EE-like cells (Micchelli & Perrimon, 2006;Ohlstein & Spradling, 2006), and can arise from a single Notch mutant stem cell (Siudeja et al, 2015). Our genetic data suggest that Numb inhibits Notch through its interaction with the AP-2 complex.…”

Intestinal stem cell response to injury: lessons from Drosophila

“…Loss of N signaling leads to symmetric ISC divisions and the formation of intestinal tumors consisting of large clusters of ISC and EE-like cells [2, 3, 21]. Indeed the same neoplasia occurs spontaneously in aging guts due to frequent somatic mutations that inactivate N in ISCs [22]. On the contrary, activating the N pathway induces ectopic differentiation of midgut progenitors into mature ECs, resulting in their rapid loss from the midgut [3, 8, 23].…”

JNK-dependent intestinal barrier failure disrupts host-microbe homeostasis during tumorigenesis

“…Recent studies have investigated tumors that arise by loss of differentiation, accumulation of differentiating stem cell or stem cell hyperproliferation in adult Drosophila intestine (Guo et al, 2013;Patel et al, 2015;Ragab et al, 2011;Suijkerbuijk et al, 2016;Zhai et al, 2015;Cordero et al, 2012;Parvy et al, 2018;Siudeja et al, 2015;Kwon et al, 2015). Loss-of BMP signaling through mutation in SMAD4 or BMPR1A is a known cause of gastrointestinal cancers in man (Hardwick et al, 2008).…”

“…EBs differentiate into either enterocytes (ECs) or enteroendocrine cells (EEs) to ensure homeostatic turnover of the tissue (reviewed in Miguel-Aliaga et al, 2018). Several well conserved signaling pathways, including Notch, BMP, Wnt, JAK/STAT and Ras, are required for maintaining intestinal homeostasis and their dysregulation can lead to tumor formation in the Drosophila intestine (Guo et al, 2013;Patel et al, 2015;Ragab et al, 2011;Suijkerbuijk et al, 2016;Zhai et al, 2015;Cordero et al, 2012;Parvy et al, 2018;Siudeja et al, 2015).…”