Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Abstract

Hereditary mixed polyposis syndrome (HMPS) is characterised by the development of mixed morphology colorectal tumours and is caused by a 40 kb duplication that results in aberrant epithelial expression of the mesenchymal Bone Morphogenetic Protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell-fate, that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem-cell properties in Lgr5 negative (non-expressing) progenitor cells that have exited the stem-cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem-cell is not the sole cell-of-origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic pre-malignant lesions with a hitherto unknown pathogenesis and these lesions can be considered the sporadic equivalents of HMPS polyps.

GREM1 and POLE variants in hereditary colorectal cancer syndromes

“…The GREM1 duplication also confirms that alterations of regions giving rise to amplifications and up‐regulation of expression can have an effect on tumor initiation also in germ‐line cells. The genotype, phenotype, and also the increased expression levels of GREM1 in our family give further support to the suggested role of activation of GREM1 as a cause of initiation and development of colorectal tumors (Jaeger et al, 2012; Davis et al, 2015). …”

“…In our study an activating 16 kb duplication was found upstream of GREM1 . A duplication of approximately 40 kb of an upstream region containing parts of the SCG5 gene and also a region between, but not the GREM1 gene itself, has recently been shown to over express GREM1 in colorectal epithelium (Jaeger et al, 2012; Davis et al, 2015). The GREM1 gene encodes the secreted BMP antagonist Gremlin.…”

CD34 + mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury

“…We further show that inhibition of Grem1 significantly reduces the generation of CD34 + CSC-induced spheroids, indicating that secretion of Grem1 by CD34 + CSCs plays a predominant role in maintenance of IESCs. Consistent with this hypothesis, forced expression of Grem1 in epithelial cells is sufficient to disrupt intestinal morphogenic gradients, promoting the persistence or reacquisition of stem cells properties by differentiated epithelial cells (35). The massive epithelial proliferation observed in CD34…”

Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models

“…Importantly they also observed that deletion of Apc in differentiated enterocytes (using low levels of recombination in AhCre Apc fl/fl mice) caused the formation of small lesions that rarely went on to form tumours (or if they did it was at long latency), thus demonstrating that Lgr5 + stem cells were indeed efficient cells of origin for intestinal cancer (162). This paper seemed to have settled the debate in favour of the bottom-up model, however, two papers then discovered that transformation could occur in Lgr5-negative cells outside of the crypt base stem cell niche, ether in cells with Apc and Kras mutations (163), or those expressing the BMP antagonist Gremlin (164). More recently, the development of a new Cre (carbonic anhydrase), which does not induce in colonic stem cells but only in more differentiated cells, confirmed these results in the colon (165).…”