Abstract 4434: Cancer cell-derived adrenomedullin downregulates Zeb1 in adipocytes to induce adipolysis and promote breast cancer progression

Abstract

Abstract Background: Once breast carcinoma in situ breaks through the basement membrane, it preferentially invades the lipid-rich microenvironment around the mammary gland, which indicates a poor prognosis. However, the detailed mechanisms of this interaction remain elusive. Here, we describe bidirectional communication between breast cancer cells and cancer-associated adipocytes (CAAs). Different from the common hormone-driven mechanism of lipolysis of adipocytes, we found that CAAs perform a unique lipolysis program, and Zeb1 plays an important role in this lipolysis process. Methods: Fabp4-cre;Zeb1-/- as adipose tissue-specific Zeb1 gene knockout homozygous mice and Fabp4-cre;Zeb1 tg as adipose tissue-specific Zeb1 gene overexpression mice were constructed to study mammary gland development and perform orthotopic tumor transplantation experiments. Tetracycline-induced Zeb1-overexpressing stable cells were constructed from mouse preadipocytes 3T3-L1 to study phenotypes of lipolysis. Single-cell sequencing, targeted lipidomics, and RNA sequencing analysis were used to investigate the interaction between cancer cells and adipocytes. Western blotting and immunohistochemical staining assays were used to detect the expression Zeb1 at the cellular level, in mouse models and in patient tissue samples. Results: Our results indicated that breast cancer cell-derived adrenomedullin (ADM) significantly down-regulates Zeb1 expression in adipocytes, which drives downstream gene expression of Pnpla2/HSL/SCD1 and induces adipocyte lipolysis into CAA, a process that results in the release of excess palmitoleic acid. Consequently, we proved that palmitoleic acid could replace arachidonic acid (ARA) in the phospholipid sn-2 position of breast cell membrane, which enhances the fluidity and invasiveness of cancer cells. In addition, overexpression of Zeb1 in adipocytes reduces the ability of cancer cells to induce adipolysis and inhibits the malignant progression of cancer cells. Conclusion: These results indicate that Zeb1 plays a pivotal role as core transcriptional factor in CAA lipolysis. The interaction between breast cancer cells and adipocytes leads to the reprogramming of metabolism within their tumor microenvironment, which may become a new target for breast cancer treatment. Citation Format: Lixia Cao, Xiao Chen, Yi Shi, Shuang Yang. Cancer cell-derived adrenomedullin downregulates Zeb1 in adipocytes to induce adipolysis and promote breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4434.