Abstract P1-07-29: Single cell RNA sequencing of triple negative breast cancer patient-derived xenograft model identifies AK1 as a key regulator of breast cancer metastasis

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Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer that carries a higher risk of distant metastasis, particularly to the lung and liver. However, cancer cells within a tumor mass are heterogeneous characteristics, with different gene expressions playing various roles in tumor growth and metastasis. This heterogeneity makes it challenging to identify the specific cancer cells and genes that control the metastasis of TNBC. Therefore, we plan to investigate this through single-cell RNA sequencing of PDX models to study the specific cancer cells and genes involved in the metastasis of TNBC. We established PDX models by obtaining tumor tissues from 26 triple-negative breast cancer patients and transplanting them into the mammary fat pads of immunodeficient mice. We classified the 26 TNBC PDX models based on their in vivo metastasis capacity and the clinical outcomes of the corresponding patients. Non-metastatic PDX models were characterized by the lack of distant metastasis development in either mouse experiments or clinical follow-up data (n=5). PDX models were defined as metastatic models when they developed distant metastasis in both mice and humans (n=4). We performed single-cell RNA sequencing on the nine PDX tumors and observed significant differences in gene expression of cancer cells between the metastatic and non-metastatic PDX models. Following the single-cell RNA sequencing data analysis, we identified the relevance between the high expressed genes in cells of the metastatic PDX models and TCGA clinical data. We identified four genes (AK1, HIST1H1C, MUCL1, SCGB2A2) that were significantly upregulated in metastatic PDX tumors and correlated with poor clinical outcomes in TCGA data. We conducted immunohistochemistry on proteins encoded by these genes to validate their effectiveness as metastasis markers at the protein level. We identified that among these four proteins encoded by the genes increased in metastatic PDX tumors, AK1 and HIST1H1C proteins were significantly expressed in metastatic PDX tumor tissues. Because there was no dramatic difference in the expression of the HIST1H1C protein between metastatic and non-metastatic PDX tumors, we focused on AK1 in our study. AK1, adenylate kinase 1, is a major isoform of the AK enzyme that catalyzes the nucleotide phosphoryl exchange reaction 2ADP ↔ ATP+AMP in the cytoplasm. AK is necessary for the functioning of organisms, including growth, differentiation, motility, and metabolism. In breast cancer, however, the role of AK1 in cancer progression and metastasis is unknown. Therefore, we studied the function of AK1 in TNBC using stable AK1 knockdown cell lines and AK1 overexpression cell lines. Surprisingly, we identified the downregulation of cell proliferation in both AK1 knockdown cells and overexpression cells, but trans-well migration and invasion capacity were upregulated in AK1 knockdown cells while AK1 overexpression cells had decreased migration and invasion capacities compared to control cells. In brief, AK1 which was discovered by single cell RNA sequencing of TNBC PDX models is the potential regulator of TNBC metastasis regulating cancer cell migration, invasion and proliferation. Citation Format: Woohang Heo, Sieun Yang, Dakyung Lee, Rokhyun Kim, Jong-Il Kim, Hyeong-Gon Moon. Single cell RNA sequencing of triple negative breast cancer patient-derived xenograft model identifies AK1 as a key regulator of breast cancer metastasis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-29.

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