Abstract 2026: Scd1 overexpression in cancer-associated adipocytes drives breast cancer development and metastasis.

Abstract Throughout the course of tumor development in breast cancer (BC), adipocytes within the tumor microenvironment undergo modifiable changes that promote tumor growth and invasive capacity, notably including the upregulation of Scd1, an enzyme integral to lipid metabolism. The timing of this metabolic reprogramming of healthy adipocytes to cancer-associated adipocytes (CAAs), as well as interventions that can reverse this process are poorly understood. To elucidate this progression, we used a polyoma middle T antigen (PyMT) transgenic mouse model that spontaneously develops luminal B-like tumors specific to the mammary fat pad (MFP). Using this model, we performed single-nucleus RNA sequencing (snRNA-seq) and metabolic profiling of MFP from healthy and tumor-bearing PyMT littermates. Among the many differences found when comparing healthy to tumor-bearing tissue at several time points throughout the progression of hyperplasia to invasive carcinoma, we discovered a consistent upregulation of Scd1, a stearoyl-CoA desaturase that performs the rate-limiting step in the conversion of saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), in adipocytes. However, despite the persistent upregulation of Scd1, we noticed an overall depletion of MUFAs in PyMT tumor-bearing tissue, indicating that tumor cells consume MUFAs during their malignant progression to invasive carcinoma and eventual metastasis. First, we recapitulated our snRNA-seq findings from mice in both snRNA-seq and spatial transcriptomics data from human breast tissue through gene signature scoring. We found that our progressive gene signatures accurately map to ductal carcinoma in situ, as well as invasive ductal carcinoma, providing confidence that interventions we establish in our mouse and in vitro models will translate to human BC. Next, to target the malignant transformation observed in our PyMT model, we cultured BC cell lines in adipocyte-conditioned medium, either when adipocyte Scd1 is selectively inhibited (iACM) or when adipocytes are allowed to function normally (ACM). Exposure to ACM alone increased cell viability, spheroid formation, and invasiveness, while iACM led to a marked decrease in all three parameters. Finally, to extend these results back into our mouse model, we injected C57BL/6 mice intracardially with BC cells conditioned in either ACM, iACM, or control media. While ACM led to aggressive metastasis with tropism selective for bone, iACM abolished the tropism and greatly decreased the metastatic capability of the injected cells. Taken together, our data show that the consistent upregulation of Scd1 throughout tumor progression in BC can be inhibited to reduce tumor growth and metastasis, thus identifying Scd1 expression in CAAs as a therapeutic target in BC, both in the early stages of progression and during metastatic spread. Citation Format: Zander Esh, Pascal Naef, Justice Williams, Johnny Le, Gautham Prabhakar, Jacob Insua Rodriguez, Hannah Savage, Ayisha Bushra, Cholsoon Jang, Kai Kessenbrock. Scd1 overexpression in cancer-associated adipocytes drives breast cancer development and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2026.