講演情報
[AL-1]2024年奨励賞受賞者 POU5F1発現大腸癌細胞における治療抵抗性系譜の解析と標的化
藤野 志季1,2,3,4, 三吉 範克3,4, 林 理絵3,4, 安井 昌義5, 大植 雅之5, Rita Busuttil2, Alex Boussioutas2, Thang Chien Nguyen1, William Teoh1, 植村 守4, 土岐 祐一郎4, 江口 英利4 (1.Monash Health Dandenong Hospital Colorectal Surgery, 2.Monash University Department of Gastroenterology, 3.大阪国際がんセンターがん医療創生部, 4.大阪大学大学院医学系研究科消化器外科学, 5.大阪国際がんセンター外科)
Recurrence and metastasis after curative treatment remain critical challenges in colorectal cancer（CRC）. Distant metastasis, the spread of cancer cells through the bloodstream to other organs, is a significant barrier to complete cure. Current treatment options for recurrence or metastasis include chemotherapy or radiotherapy, either as a preventive measure for high-risk patients or after confirmation of disease progression. However, providing “optimal treatment” to “patients who will truly relapse”could minimize overtreatment and improve cure rates. Our team has developed a unique patient-derived cancer cell model（isolated tumor-derived cancer cells, iCCs）that preserves cancer heterogeneity and interactions with the tumor microenvironment. Unlike conventional cell lines that lack the complexity of tumor diversity, iCCs exhibit gene expression that closely resembles clinical cancer specimens and recapitulate diverse cell populations. Notably, drug sensitivity assays using iCCs reflect the clinical course of the original patient, demonstrating their potential as a cancer avatar model. These results revealed several molecular mechanisms related to cancer aggressiveness, with POU5F1 emerging as a key gene influencing chemoresistance. Furthermore, POU5F1-positive cells were found to generate diverse cell populations from single cells and resist anticancer treatments, a behavior similar to circulating tumor cells（CTCs）responsible for metastasis. We found that POU5F1-expressing cells are more likely to induce liver metastasis, with POU5F1 being highly expressed in recurrent tumors, which correlates with poor prognosis in CRC patients. Using an EGFP reporter system under the POU5F1 promoter, we successfully isolated POU5F1-positive and -negative cells from the iCCs, overcoming the challenge of targeting a nuclear transcription factor such as POU5F1 in living cells. Single-cell RNA sequencing of the 2DOs revealed heterogeneous populations derived from POU5F1-expressing cells, with significant enrichment of the Wnt signaling pathway in these cells. In addition, these POU5F1-expressing cells show characteristically high expression of CTLA4, and immunocytochemistry confirms the co-expression of POU5F1 and CTLA4. Epigenetic analysis revealed demethylation in some CpG islands at the transcription start sites of both POU5F1 and CTLA4, suggesting an important regulatory mechanism in these metastatic cells.Targeting these pathways, we found that the Wnt/β-catenin inhibitor XAV939 effectively prevented the adhesion and survival of POU5F1-expressing cells in vitro. Importantly, early administration of XAV939 completely inhibited liver metastasis induced by POU5F1-positive cells in vivo. These results highlight the importance of targeting POU5F1-expressing CTCs and provide a promising avenue for novel therapeutic interventions that may prevent metastasis and recurrence.