Paneth cell-derived growth factors support tumorigenesis in the small intestine.

Qing Chen,Kohei Suzuki,Bujun Ge,Igor Dozmorov,Jie Song,Purva Gopal,Luis Sifuentes-Dominguez,Ezra Burstein,Adam Lopez,Petro Starokadomskyy,Shuai Tan,Naoteru Miyata

doi:10.26508/lsa.202000934

Abstract

Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit. PC depletion in Apc Min mice impaired adenoma development in the small intestine and led to decreased Wnt3 expression in small bowel adenomas. To determine if PC-derived Wnt3 was required for adenoma development, we examined tumor formation after PC-specific ablation of Wnt3 We found that this was sufficient to decrease small intestinal adenoma formation; moreover, organoids derived from these tumors displayed slower growth capacity. Overall, we report that PC-derived Wnt3 is required to sustain early tumorigenesis in the small bowel and identify a clear role for PC-derived Wnt production in intestinal pathology.

Highlights

Colorectal adenocarcinoma is an important cancer site worldwide, and is the second most common cause of cancer death in men and women in the United States, with a lifetime risk of ~6% (Brenner et al, 2014; Mattiuzzi et al, 2019)
Germline mutations in APC result in familial adenomatous polyposis (FAP) in humans, which is characterized by intestinal polyposis that affects both the colon and small intestine
Cells of Paneth cells (PCs) lineage are present in intestinal adenomas

Summary

Introduction

Colorectal adenocarcinoma is an important cancer site worldwide, and is the second most common cause of cancer death in men and women in the United States, with a lifetime risk of ~6% (Brenner et al, 2014; Mattiuzzi et al, 2019) This tumor originates from premalignant neoplastic lesions, known as adenomas, which are typically initiated by mutations in the Wnt pathway, a key regulator of stem cell growth (Koch, 2017; Nusse & Clevers, 2017). Subsequent studies identified specialized mesenchymal cells called “telocytes,” which form a pericryptal sheath at the base of the crypt, as the critical stromal source for Wnt in the intestine (Shoshkes-Carmel et al, 2018) It remains unclear what is physiologic or pathologic role for PCderived Wnt production. We examined the potential role of PCs and their secretion of Wnt in intestinal tumorigenesis

Results

Discussion

Materials and Methods

Data and code availability