Abstract 7587: Fascin1 might be a promising molecular target for colorectal cancer patients at advanced stage

Abstract

Abstract Background: Colorectal cancers (CRC) show high morbidity and mortality. Especially, the consensus molecular subtypes 4 (CMS4)-CRC shows extremely poor prognosis and high chemo-resistance rate, in compared with the other types of CRC. CMS4-CRC is histologically characteristic for the extensive stromal infiltration with poorly differentiated cancer cells in the tumor microenvironment. Several studies have reported that sessile serrated adenomas, which is characterized by disorganized crypt architecture and irregular serrations with high malignant potential such as epithelial-mesenchymal transition and TGFβ signaling, might be closely associated with CMS4-CRC. Fascin-1 is an actin-binding protein supposed to be associated with sessile serrated adenomas. However, the expression and clinical significance of fascin-1 in CMS4 CRC remains to be unclear. Aim: The aim of this study was to clarify the clinic-pathological significance of fascin-1 in colorectal cancer, and to evaluate the effects of fascin-1 inhibitors on the invasion and migration ability of CMS4 cancer cell lines. Materials and Methods: We conducted an immunohistochemical study on 351 colorectal cancer patients, where we examined the expression levels of Fascin-1 and analyzed their correlation with the patients’ clinicopathologic features. Using two human CMS4-CRC cell lines, SW480 and HCT116, we investigated the effects of the fascin-1 inhibitors, NP-G2-044 and BDP-13176, on the proliferation and the migration activity of CMS4-CRC cells via MTT assay and a wound-healing assay. Results: Fascin-1 is expressed both on cancer cells and on stromal cells, but mainly expressed on cancer cells. Significance of fascin-1 expression on cancer cells was evaluated in this study. Fascin-1 expression is significantly associated with histologically poorly differentiation (p < 0.001), deeper T invasion (p = 0.003), and proximal colon cancer (p < 0.001). High fascin-1 expression is significantly associated with worse prognosis (p = 0.0085, log-rank) and higher recurrence rates (p = 0.018). Univariate analysis demonstrated that overall survival of patients was significantly associated with Fascin1 expression in cancer cells, age ≥65 years old, poor histological type, lymphatic invasion, lymph node metastasis, and venous invasion. Multivariate analysis revealed that fascin1 expression (p = 0.037), poor histological type (p = 0.022), venous invasion (p = 0.078), and lymph node metastasis (p = 0.009) were significantly correlated with the overall survival rate of CRC patients. Both fascin-1 inhibitors significantly reduced the invasion and migration of colorectal cancer cells at the concentration of 100 nM. Conclusions: Fascin-1 is one of key molecules for the development of CRC. Fascin-1 might be a promising molecular target for CMS4-CRC patients at advanced stage. Citation Format: Canfeng Fan, Qiang Wang, Rika Aoyama, Hinano Nishikubo, Kyouka Kawabata, Imanishi Daiki, Takashi Sakuma, Koji Maruo, Gen Tsujio, Yurie Yamamoto, Tatsunari Fukuoka, Masakazu Yashiro. Fascin1 might be a promising molecular target for colorectal cancer patients at advanced stage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7587.