Potential Perturbations of Critical Cancer-regulatory Genes in Triple-Negative Breast Cancer Cells Within the Humanized Microenvironment of Patient-derived Xenograft Models

Yujeong Her; Jihui Yun; Hye-Youn Son; Woohang Heo; Jong-Il Kim; Hyeong-Gon Moon

doi:10.4048/jbc.2023.0177

Potential Perturbations of Critical Cancer-regulatory Genes in Triple-Negative Breast Cancer Cells Within the Humanized Microenvironment of Patient-derived Xenograft Models

J Breast Cancer. 2024 Feb;27(1):37-53. doi: 10.4048/jbc.2023.0177. Epub 2024 Jan 15.

Authors

Yujeong Her¹, Jihui Yun^{2

3}, Hye-Youn Son⁴, Woohang Heo⁴, Jong-Il Kim^{2

3

5

6}, Hyeong-Gon Moon^{2

5

7

8}

Affiliations

¹ Interdisciplinary Graduate Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
² Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
³ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
⁴ Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
⁵ Cancer Research Institute, Seoul National University, Seoul, Korea.
⁶ Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
⁷ Department of Surgery, Seoul National University Hospital, Seoul, Korea.
⁸ Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. moonhg74@snu.ar.kr.

Abstract

Purpose: In this study, we aimed to establish humanized patient-derived xenograft (PDX) models for triple-negative breast cancer (TNBC) using cord blood (CB) hematopoietic stem cells (HSCs). Additionally, we attempted to characterize the immune microenvironment of the humanized PDX model to understand the potential implications of altered tumor-immune interactions in the humanized PDX model on the behavior of TNBC cells.

Methods: To establish a humanized mouse model, high-purity CD34⁺ HSCs from CB were transplanted into immunodeficient NOD scid γ mice. Peripheral and intratumoral immune cell compositions of humanized and non-humanized mice were compared. Additionally, RNA sequencing of the tumor tissues was performed to characterize the gene expression features associated with humanization.

Results: After transplanting the CD34⁺ HSCs, CD45⁺ human immune cells appeared within five weeks. A humanized mouse model showed viable human immune cells in the peripheral blood, lymphoid organs, and in the tumor microenvironment. Humanized TNBC PDX models showed varying rates of tumor growth compared to that of non-humanized mice. RNA sequencing of the tumor tissue showed significant alterations in tumor tissues from the humanized models. tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) is a shared downregulated gene in tumor tissues from humanized models. Silencing of TNFRSF11B in TNBC cell lines significantly reduced cell proliferation, migration, and invasion in vitro. Additionally, TNFRSF11B silenced cells showed decreased tumorigenicity and metastatic capacity in vivo.

Conclusion: Humanized PDX models successfully recreated tumor-immune interactions in TNBC. TNFRSF11B, a commonly downregulated gene in humanized PDX models, may play a key role in tumor growth and metastasis. Differential tumor growth rates and gene expression patterns highlighted the complexities of the immune response in the tumor microenvironment of humanized PDX models.

Keywords: Disease Models, Animal; Humans; Osteoprotegerin; Triple Negative Breast Neoplasms.

Abstract

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