Nature's three publications provide new prevention strategies for high-risk groups of colorectal cancer

Author | Lemon Tree Editor | Qi About 80% of patients with colorectal cancer (CRC) have mutations in the tumor suppressor gene Apc.

Apc mutation promotes proliferation, inhibits cell death, and blocks differentiation in the intestine, which may help improve the relative fitness of cells [1, 2].

Existing studies have shown that Apc mutations in intestinal stem cells can negatively regulate WNT signal transduction by guiding the phosphorylation and degradation of β-catenin [3], thereby uncontrollably breaking the gap between WNT agonists and antagonists Balance [4, 5], this phenomenon often induces early colorectal cancer.

 So far, due to the difficulties of directly targeting WNT signals, these studies have not promoted more effective treatments or new CRC prevention strategies.

However, the molecular mechanism of Apc-deficient cells competing with wild-type cells has great potential in promoting the discovery of new chemical methods to inhibit the formation of colorectal cancer.

 On June 2, 2021, Nature magazine published three back-to-back publications from the Owen J.
Sansom team from the Bison Cancer Institute in the United Kingdom, together with the Pekka Katajisto team from the University of Helsinki in Finland, and the Benjamin D.
Simons team from the University of Cambridge, United Kingdom, and the University of Cambridge, United Kingdom.
The work of Bon-Kyoung Koo's team and Louis Vermeulen's team at the University of Amsterdam Medical Center in the Netherlands explored that intestinal stem cells can restore the competitiveness of wild-type cells by inhibiting Apc mutations, thereby improving the health of normal cells and limiting the proliferation and expansion of precancerous clones.
, To provide prevention strategies for high-risk groups of colorectal cancer.

 In the first study titled "NOTUM from Apc-mutant cells biases clonal competition to initiate cancer", the authors found that the NOTUM gene is a key mediator in the early stages of Apc mutation.

NOTUM can disable the WNT pathway by removing palmitate-modified carboxylesterase on WNT or inhibiting the binding of WNT to its receptor.

The author found through in vitro experiments and in vivo experiments in mice that NOTUM preferentially inhibits the growth of wild-type cells rather than Apc mutant cells.
As a key paracrine negative factor for Apc mutant cells to regulate WNT signaling, it can inhibit the function of wild-type intestinal stem cells (Figure 1).

At the same time, NOTUM is the main medium that drives the fixation of Apc mutant clones, is necessary for tumor formation, and can be positioned as a therapeutic target for intestinal tumors driven by Apc.

Existing studies have shown that according to the expression of WNT target genes, human colorectal cancer can be divided into ligand-dependent (RSPO-fusion / RNF43-mutant) and ligand-independent (APC-mutant) subtypes, which activate the WNT signaling pathway.
Different mutation methods (APC vs RSPO or RNF43) will achieve mutation clone fixation through corresponding molecular mechanisms, and ligand-dependent colorectal cancer is not regulated by NOTUM.

Figure 1.
NOTUM inhibits cell proliferation and promotes the differentiation of wild-type intestinal stem cells.
In the second study titled "Tracing oncogene-driven remodelling of the intestinal stem cell niche", the author constructed a way to allow the same in the small intestine.
Mutant and wild-type cells in the tissues are differentially tracked, and the oncogene-related multicolor reporter mouse model-Red2Onco system (Figure 2).

The tumor immune microenvironment is closely related to the early formation of colorectal cancer.

Based on the Red2Onco system, research combined with single-cell analysis found that the paracrine remodeling driven by mutations of KRAS and PI3K or Apc deletion creates a niche environment, promotes oncogenic cloning, changes the function of WNT signaling, and makes it easier to induce colorectal.
cancer.

In short, niche remodeling may be a common feature of tumorigenic mutants.

Figure 2.
Red2Onco system-oncogene-related multicolor report.
In the third study titled "Apc-mutant cells act as supercompetitors in intestinal tumour initiation", the author first found Apc mutations through organoids and in vivo experiments in mice Type exhibits the characteristics of a super competitor and will actively inhibit the growth of neighboring cells and even induce apoptosis of wild-type intestinal stem cells.

Secondly, the authors detected in Drosophila that Apc mutant cells induce the differentiation of wild-type intestinal stem cells by secreting a variety of WNT antagonists.

Notum, as a WNT antagonist, was found to be the main driving factor for the competition of Drosophila wing adult disc cells.

At the same time, the authors confirmed that the pharmacological inhibition of NOTUM in epithelial granular cells in the crypts of the small intestine can enhance the function and restore vitality of stem cells in the aging intestine.

Finally, the authors detected the overexpression of WNT antagonists NOTUM, DKK1, SFRP5 and WIF1 in human cells with Apc mutations (Figure 3).

In short, although the method for pharmacological activation of the ligand receptor level of the WNT pathway cannot inhibit the growth of tumors, it can prevent the occurrence of tumors.

 In summary, the above three studies unanimously show that Apc mutation may act as a super competitor, inhibiting the activity of wild-type, while regulating the balance of WNT pathway agonists and antagonists, and induce the formation of early intestinal cancer.

Identifying and inhibiting the malignant pre-clone signal that produces a super-competitive phenotype may be a new strategy to prevent cancer.

Original link: https://doi.
org/10.
1038/s41586-021-03525-zhttps://doi.
org/10.
1038/s41586-021-03605-0https://doi.
org/10.
1038/s41586-021-03558 -4 Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated.

References 1.
Morin, PJ, Vogelstein, B.
& Kinzler, KW Apoptosis and APC in colorectal tumorigenesis.
Proc.
Natl Acad.
Sci.
USA 93, 7950-7954 (1996) 2.
Fevr, T.
, Robine, S .
, Louvard, D.
& Huelsken, J.
WNT/β-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells.
Mol.
Cell.
Biol.
27, 7551-7559 (2007) 3.
Morin, PJ et al .
Activation of β-catenin–Tcf signaling in colon cancer by mutations in β-catenin or APC.
Science 275, 1787–1790 (1997).
4.
Powell, SM et al.
APC mutations occur early during colorectal tumorigenesis.
Nature 359, 235–237 (1992) 5.
Fearon, ER & Vogelstein, B.
A genetic model for colorectal tumorigenesis.
Cell 61, 759–767 (1990).