NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

Chrispus Ngule; Ruyi Shi; Xingcong Ren; Hongyan Jia; Felix Oyelami; Dong Li; Younhee Park; Jinhwan Kim; Hami Hemati; Yi Zhang; Xiaofang Xiong; Andrew Shinkle; Nathan L. Vanderford; Sara Bachert; Binhua P. Zhou; Jianlong Wang; Jianxun Song; Xia Liu; Jin Ming Yang

doi:10.1186/s12943-024-02102-y

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

Chrispus Ngule, Ruyi Shi, Xingcong Ren, Hongyan Jia, Felix Oyelami, Dong Li, Younhee Park, Jinhwan Kim, Hami Hemati, Yi Zhang, Xiaofang Xiong, Andrew Shinkle, Nathan L. Vanderford, Sara Bachert, Binhua P. Zhou, Jianlong Wang, Jianxun Song, Xia Liu, Jin Ming Yang

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Original language	English
Article number	188
Journal	Molecular Cancer
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12943-024-02102-y
State	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

This work was supported by the National Cancer Institute Grant R01CA221867 to J. Y. and J.S., start-up funds from the Markey Cancer Center and College of Medicine, University of Kentucky, to J. Y., and Susan G. Komen Foundation CCR18548501 and NIH grant P20GM121327 to X.L. We thank the Shared Resource Facility of the University of Kentucky and Markey Cancer Center (P30CA177558), the Imaging Core Facility of the Center for Cancer Metabolism COBRE (P20 GM121327), and UK histology core (ADC grant P30 AG072946) for technical support and assistance. We also thank Prof. Christine Brainson for her assistance with the artificial intelligence analysis, Mr. Leif Magnuson for his help with confocal microscopy imaging, and Dr. Sara Bachert and Ms. Dana Napier for their support in clinical sample identification and tissue slide processing.

Funders	Funder number
University of Kentucky College of Medicine
University of Kentucky Markey Comprehensive Cancer Center	P30CA177558
Susan G Komen Foundation	CCR18548501
National Childhood Cancer Registry – National Cancer Institute	R01CA221867
Center for Cancer Metabolism COBRE	P20 GM121327, P30 AG072946
National Institutes of Health (NIH)	P20GM121327

Keywords

Cancer stem cells
MDSCs
NAC1
NK cells
TME
TNBC

ASJC Scopus subject areas

Molecular Medicine
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s12943-024-02102-y

Cite this

Ngule, C., Shi, R., Ren, X., Jia, H., Oyelami, F., Li, D., Park, Y., Kim, J., Hemati, H., Zhang, Y., Xiong, X., Shinkle, A., Vanderford, N. L., Bachert, S., Zhou, B. P., Wang, J., Song, J., Liu, X., & Yang, J. M. (2024). NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer. Molecular Cancer, 23(1), Article 188. https://doi.org/10.1186/s12943-024-02102-y

@article{51d218a3333b41e4b4531d7786f6a733,

title = "NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer",

abstract = "Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.",

keywords = "Cancer stem cells, MDSCs, NAC1, NK cells, TME, TNBC",

author = "Chrispus Ngule and Ruyi Shi and Xingcong Ren and Hongyan Jia and Felix Oyelami and Dong Li and Younhee Park and Jinhwan Kim and Hami Hemati and Yi Zhang and Xiaofang Xiong and Andrew Shinkle and Vanderford, \{Nathan L.\} and Sara Bachert and Zhou, \{Binhua P.\} and Jianlong Wang and Jianxun Song and Xia Liu and Yang, \{Jin Ming\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s12943-024-02102-y",

language = "English",

volume = "23",

number = "1",

}

Ngule, C, Shi, R, Ren, X, Jia, H, Oyelami, F, Li, D, Park, Y, Kim, J, Hemati, H, Zhang, Y, Xiong, X, Shinkle, A, Vanderford, NL, Bachert, S, Zhou, BP, Wang, J, Song, J, Liu, X & Yang, JM 2024, 'NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer', Molecular Cancer, vol. 23, no. 1, 188. https://doi.org/10.1186/s12943-024-02102-y

TY - JOUR

T1 - NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

AU - Ngule, Chrispus

AU - Shi, Ruyi

AU - Ren, Xingcong

AU - Jia, Hongyan

AU - Oyelami, Felix

AU - Li, Dong

AU - Park, Younhee

AU - Kim, Jinhwan

AU - Hemati, Hami

AU - Zhang, Yi

AU - Xiong, Xiaofang

AU - Shinkle, Andrew

AU - Vanderford, Nathan L.

AU - Bachert, Sara

AU - Zhou, Binhua P.

AU - Wang, Jianlong

AU - Song, Jianxun

AU - Liu, Xia

AU - Yang, Jin Ming

PY - 2024/12

Y1 - 2024/12

N2 - Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

AB - Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

KW - Cancer stem cells

KW - MDSCs

KW - NAC1

KW - NK cells

KW - TME

KW - TNBC

UR - https://www.scopus.com/pages/publications/85203272916

UR - https://www.scopus.com/inward/citedby.url?scp=85203272916&partnerID=8YFLogxK

U2 - 10.1186/s12943-024-02102-y

DO - 10.1186/s12943-024-02102-y

M3 - Article

C2 - 39243032

AN - SCOPUS:85203272916

SN - 1476-4598

VL - 23

JO - Molecular Cancer

JF - Molecular Cancer

IS - 1

M1 - 188

ER -

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this