Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination

Chih-Wei Chou, Chia-Nung Hung, Cheryl Hsiang-Ling Chiu, Xi Tan, Meizhen Chen, Chien-Chin Chen, Moawiz Saeed, Che-Wei Hsu, Michael A. Liss, Chiou-Miin Wang, Zhao Lai, Nathaniel Alvarez, Pawel A. Osmulski, Maria E. Gaczynska, Li-Ling Lin, Veronica Ortega, Nameer B. Kirma, Kexin Xu, Zhijie Liu, Addanki P. Kumar, Josephine A. Taverna, Gopalrao V. N. Velagaleti, Chun-Liang Chen (), Zhao Zhang () and Tim Hui-Ming Huang ()
Additional contact information
Chih-Wei Chou: University of Texas Health Science Center
Chia-Nung Hung: University of Texas Health Science Center
Cheryl Hsiang-Ling Chiu: University of Texas Health Science Center
Xi Tan: University of Texas Health Science Center
Meizhen Chen: University of Texas Health Science Center
Chien-Chin Chen: Ditmanson Medical Foundation Chia-Yi Christian Hospital
Moawiz Saeed: University of Texas Health Science Center
Che-Wei Hsu: National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University
Michael A. Liss: University of Texas Health Science Center
Chiou-Miin Wang: University of Texas Health Science Center
Zhao Lai: University of Texas Health Science Center
Nathaniel Alvarez: University of Texas Health Science Center
Pawel A. Osmulski: University of Texas Health Science Center
Maria E. Gaczynska: University of Texas Health Science Center
Li-Ling Lin: University of Texas Health Science Center
Veronica Ortega: University of Texas Health Science Center
Nameer B. Kirma: University of Texas Health Science Center
Kexin Xu: University of Texas Health Science Center
Zhijie Liu: University of Texas Health Science Center
Addanki P. Kumar: University of Texas Health Science Center
Josephine A. Taverna: University of Texas Health Science Center
Gopalrao V. N. Velagaleti: University of Texas Health Science Center
Chun-Liang Chen: University of Texas Health Science Center
Zhao Zhang: University of Texas Health Science Center
Tim Hui-Ming Huang: University of Texas Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract While macrophage phagocytosis is an immune defense mechanism against invading cellular organisms, cancer cells expressing the CD47 ligand send forward signals to repel this engulfment. Here we report that the reverse signaling using CD47 as a receptor additionally enhances a pro-survival function of prostate cancer cells under phagocytic attack. Although low CD47-expressing cancer cells still allow phagocytosis, the reverse signaling delays the process, leading to incomplete digestion of the entrapped cells and subsequent tumor hybrid cell (THC) formation. Viable THCs acquire c-Myc from parental cancer cells to upregulate both M1- and M2-like macrophage polarization genes. Consequently, THCs imitating dual macrophage features can confound immunosurveillance, gaining survival advantage in the host. Furthermore, these cells intrinsically express low levels of androgen receptor and its targets, resembling an adenocarcinoma-immune subtype of metastatic castration-resistant prostate cancer. Therefore, phagocytosis-generated THCs may represent a potential target for treating the disease.

Date: 2023
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DOI: 10.1038/s41467-023-42303-5

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