Abstract 5397: Characteristics of cancer associated fibroblasts isolated from refractory colorectal cancer using RNA sequence

Abstract Primary tumor location of colorectal cancers (CRCs) is emerging as an important prognostic factor owing to distinct biological features. In fact, the patients with right-side CRCs (R-CRCs), in which primary tumors were resected in our department and followed by systemic chemotherapy, have a poorer prognosis in 2-year overall survival and progression-free survival than those with left-side CRCs (L-CRCs). Furthermore, cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. Here, we isolated the CAFs and normal counterparts from 10 CRCs which were performed radical resection, including 5 L-CRCs and 5 R-CRCs, and analyzed transcriptomic profile of CAFs by RNA-sequencing. Gene Set Enrichment Analysis (GSEA) was performed and inflammatory signatures, such as "HALLMARK IL2 STAT5 SIGNALING"(NOM p-value<0.001, FDR q-value=0.146), "HALLMARK IL6 JAK STAT3 SIGNALING"(NOM p-value=0.014, FDR q-value=0.162), "HALLMARK INTERFERON GAMMA RESPONSE"(NOM p-value=0.032, FDR q-value=0.1726), were enriched in the CAFs isolated from R-CRCs (R-CAFs). In addition to sidedness of CRCs, based on gene expression profiles from bulk tumors, CRCs were classified into four consensus molecular subtypes (CMS1-4). Among them, The fibrotic CMS4 subtype portends poor relapse-free survival. We identified 4 CMS4-CRCs, which have the characteristics of stromal activation and the worst prognosis among other CRCs. GSEA showed that the signature of "HALLMARK TNFA_SIGNALING_VIA_NFKB" (NOM p-value=0.023 FDR q-value=0.207), "HALLMARK GLYCOLYSIS" (NOM p-value=0.036 FDR q-value=0.239) were upregulated in the CAFs isolated from CMS4-CRCs. These results indicated that CAFs isolated from refractory CRCs have unique phenotypes and the elucidation of these mechanisms might lead to a promising treatment for refractory CRCs. Citation Format: Hiroaki Kasashima, Yasuhiro Fukui, Ken Yonemitsu, Kisyu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Shigeru Ree, Masakazu Yashiro, Kiyoshi Maeda. Characteristics of cancer associated fibroblasts isolated from refractory colorectal cancer using RNA sequence [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 5397.