Abstract 87: Targeting POU5F1-expressing circulating tumor cells to prevent metastasis and recurrence in colorectal cancer

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Abstract Background: Recurrence and metastasis following curative treatment remain significant challenges in colorectal cancer (CRC). Circulating tumor cells (CTCs) are pivotal in the dissemination of cancer, leading to distant metastases and eventual recurrence. Despite their importance, the cellular lineages driving these processes in CRC remain poorly defined. POU5F1, a transcription factor associated with stemness, is highly expressed in recurrent CRC tumors and is linked to poor prognosis and a high incidence of liver metastasis. Methods: We developed a patient-derived cancer cell model, termed isolated tumor-derived cancer cells, cultured as two-dimensional organoids (2DOs). These 2DOs retain tumor heterogeneity and tumor microenvironment interactions, providing a robust platform for investigating treatment-resistant lineages. Using EGFP-reporter 2DOs, POU5F1-expressing cells were isolated and characterized through drug sensitivity assays, single-cell RNA sequencing, immunocytochemistry, and epigenetic analyses. Therapeutic studies were conducted to evaluate the efficacy of targeting key pathways. Results: POU5F1-expressing cells were highly enriched in blood samples from relapsed CRC patients as CTCs. These cells exhibited cancer stem cell properties, including self-renewal and differentiation, and demonstrated a high capacity for liver metastasis in vivo. Single-cell RNA sequencing revealed that POU5F1-positive cells generate heterogeneous populations enriched in the Wnt signaling pathway. Immunocytochemistry confirmed the co-expression of POU5F1 and CTLA4, with epigenetic analysis showing demethylation at transcriptional start sites of both genes, implicating epigenetic regulation in their aggressiveness. The Wnt/β-catenin pathway inhibitor XAV939 effectively suppressed adhesion and survival of POU5F1-positive cells in vitro. Remarkably, early administration of XAV939 completely inhibited liver metastasis induced by these cells in vivo. Conclusions: POU5F1-expressing cells are critical drivers of CRC metastasis and recurrence, exhibiting stem-like properties and treatment resistance. Their enrichment in Wnt signaling and CTLA4 expression identifies actionable therapeutic targets. Our findings highlight the potential of Wnt/β-catenin inhibitors like XAV939 to prevent CRC metastasis and recurrence, paving the way for improved therapeutic strategies in high-risk patients. Citation Format: Shiki Fujino, Aya Ito, Rie Hayashi, Masayoshi Yasui, Masayuki Ohue, Norikatsu Miyoshi. Targeting POU5F1-expressing circulating tumor cells to prevent metastasis and recurrence in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 87.

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