• intestinal cancer

In the Drosophila midgut, differentiation of intestinal stem cells (ISCs) involves an intermediate differentiating cell called the enteroblast (EB). The Drosophila gene Sox21a is expressed primarily in enteroblasts and appears to be required for EBs to become fully differentiated cells. Flies homozygous for amorphic mutations in the Dmel\Sox21a gene are viable, but develop hyperplastic tumors composed of enteroblasts in the adult midgut.

Dmel\Sox21a belongs to the Sox family of transcription factors, which have been studied in multiple organisms and have been shown to regulate cell fate decisions during development and to play roles in adult tissue homeostasis and regeneration. There are 8 identified SOX genes in flies; there are 20 in human. RNAi-targeting constructs, alleles caused by insertional mutagenesis, and alleles created by targeted recombination, including an amorphic alleles, have been generated for Dmel\Sox21a. Physical and genetic interactions have been described; see below and in the Sox21a gene record.

Further characterization of the Sox21a tumors revealed that the mutant enteroblasts themselves are non-mitotic, but are capable of tumor initiation. A feedback loop between the enteroblasts and the progenitor intestinal stem cells was identified that leads to production of additional EBs from ISCs. Activation of this loop is essential for damage-induced intestinal regeneration, however, sustained activation of the feedloop leads to tumorigenesis. Normally, Sox21a suppresses this feedback loop, and following epithelial damage, Sox21a is downregulated in EBs. In the midgut of Sox21a mutant animals, the ISC-EB feedback amplification loop is continuously active, which drives overproduction of differentiation-defective EB cells and tumorigenesis.

See also the human disease model report 'cancer, intestinal stem cell models' (FBhh0000767).

[updated Apr. 2018 by FlyBase; FBrf0222196]