Accumulation of CD38 in Hybrid Epithelial/Mesenchymal Cells Promotes Immune Remodeling and Metastasis in Breast Cancer

Authors

Tanvi H Visal
Recep Bayraktar
Petra den Hollander
Michael A Attathikhun
Tieling Zhou
Jing Wang
Li Shen
Corina-Elena Minciuna
Meng Chen
Elizve Barrientos-Toro
Harsh Batra
Maria Gabriela Raso
Fei Yang
Edwin R Parra
Aysegul A Sahin
George A Calin
Sendurai A Mani

Publication Date

3-3-2025

Journal

Cancer Research

Abstract

Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer. The epithelial-to-mesenchymal transition is a nonbinary process in the metastatic cascade that generates tumor cells with both epithelial and mesenchymal traits known as hybrid EM cells. Recent studies have elucidated the enhanced metastatic potential of cancers featuring the hybrid EM phenotype, highlighting the need to uncover molecular drivers and targetable vulnerabilities of the hybrid EM state. Here, we discovered that hybrid EM breast tumors are enriched in CD38, an immunosuppressive molecule associated with worse clinical outcomes in liquid malignancies. Altering CD38 expression in tumor cell impacted migratory, invasive, and metastatic capabilities of hybrid EM cells. Abrogation of CD38 expression stimulated an antitumor immune response, thereby preventing the generation of an immunosuppressive microenvironment in hybrid EM tumors. CD38 levels positively correlated with PD-L1 expression in samples from patients with TNBC. Moreover, targeting CD38 potentiated the activity of anti-PD-L1, eliciting strong antitumor immunity, with reduced tumor growth in hybrid EM models. Overall, this research exposes upregulation of CD38 as a specific survival strategy utilized by hybrid EM breast tumors to suppress immune cell activity and sustain metastasis, with strong implications in other carcinomas that have hybrid EM properties. Significance: Hybrid cells co-featuring epithelial and mesenchymal traits in triple-negative breast cancer express elevated levels of CD38 to induce immunosuppression and metastasis, indicating CD38 inhibition as potential strategy for treating breast cancer.

Keywords

ADP-ribosyl Cyclase 1, Humans, Female, Epithelial-Mesenchymal Transition, Triple Negative Breast Neoplasms, Mice, Animals, Tumor Microenvironment, Membrane Glycoproteins, Cell Line, Tumor, Neoplasm Metastasis, B7-H1 Antigen, Xenograft Model Antitumor Assays

DOI

10.1158/0008-5472.CAN-24-0400

PMID

39853244

PMCID

PMC11873730

PubMedCentral® Posted Date

1-24-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes