Abstract 836: CRACD/CRAD, a tumor suppressor for gastric cancer development

Abstract

Gastric cancer (GC) is the third most common cancer and the second most common cause of cancer death in Asia. The highest incidence rates are observed in Eastern Asia. To date, the comprehensive mechanism of GC initiation remains elusive. Here, we discovered CRACD (Capping Protein Inhibiting Regulator of Actin Dynamics/CRAD/KIAA1211) as a tumor suppressor, frequently inactivated in GC. To determine the pathologic roles of CRACD, we employed Cracd knock-out (KO) mice and gastric organoids (GOs). Intriguingly, Cracd KO mice and GOs displayed hyperplastic gastric epithelium. Mechanistically, CRACD is essential for stabilizing the cadherin-catenin-actin (CCA) complex. The loss of CRACD leads to the release and nuclear translocation of β-catenin for Wnt target gene transactivation. Indeed, the genetic ablation of Cracd hyperactivated Wnt/β-catenin signaling with the disruption of the CCA complex. The genes encoding the Receptor Tyrosine Kinase (RTK)-RAS signaling pathway and the TP53 are genetically altered in 60% and 50% of gastric adenocarcinomas, respectively. To define the genetic interaction of Cracd loss with the RTK-RAS and TP53 signaling, we established genetically engineered GOs models carrying Trp53 deletion and KrasG12D activation in combination with Cracd KO (CKP) or Cracd wild type (KP). Compared to KP, CKP GOs exhibited neoplasia, higher mucin deposition, and increased carcinoma embryonic antigen (CEA) expression, pathologically related to the poor prognosis in GC patients. Meanwhile, loss of Cracd significantly accelerated the growth of CKP GOs with increased stemness. Furthermore, the CKP cell line derived from GOs exhibited relatively poor prognosis features of GC than KP cells in the xenograft models, represented by boosted tumor size and weight, poor differentiation, hyperplasia, increased CEA, and mucin secretion. Together, we identified CRACD as a tumor suppressor, of which inactivation contributes to GC initiation and progression, which may be translated into the development of a biomarker-guided regimen for CRACD mutations-associated GC patients. Citation Format: Gengyi Zou, Yuanjian Huang, Kyung Pil Ko, Shengzhe Zhang, Bong Jun Kim, Jie Zhang, Sohee Jun, Youn-Sang Jung, Biyun Zheng, Jae-Il Park. CRACD/CRAD, a tumor suppressor for gastric cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 836.