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Status |
Public on Jul 08, 2024 |
Title |
Targeting Fatty Acid Oxidation Enhances Response to HER2-targeted Therapy |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Metabolic reprogramming is a hallmark of tumorigenesis and includes alterations in glucose and fatty acid metabolism. In this study, we investigated the role of Carnitine palmitoyl transferase 1A (CPT1A), a key enzyme in fatty acid oxidation (FAO), in the induction of HER2+ (Human Epidermal growth factor 2, ErbB2) breast cancer. Using an ErbB2+ genetically engineered mouse models, we found that ablation of CPT1A delayed tumor onset and reduced tumor growth, angiogenesis, and metastatic capacity. CPT1A-deficient ErbB2+ cells exhibited impaired mitochondrial function, leading to a reliance on the tricarboxylic acid cycle to reduce NAD+/FAD for energy production. Consequently, loss of CPT1A resulted in glucose dependency and an inability to metabolize fats. CPT1A-deficient ErbB2+ tumor cells exhibited increased oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (NRF2) activity. Inhibiting NRF2 or silencing its expression reduced proliferation and glucose consumption in CPT1A-deficient cells. In pre-clinical models of ErbB2+ breast cancer, combining a ketogenic diet with an anti-ErbB2 monoclonal antibody in the context of CPT1A deficiency significantly reduced tumor growth and increased survival. Furthermore, combining the ketogenic diet with CPT1A ablation suppressed tumor growth, enhanced apoptosis, and reduced lung metastasis. Additionally, using an immunocompetent model, we provide evidence that CPT1A inhibition attenuated tumor growth and proliferation by promoting an antitumor immune microenvironment that enhanced the efficacy of ErbB2 targeted therapy. These findings provide insight into the metabolic rewiring in HER2+ breast cancer and highlight the potential of targeting fatty acid oxidation and employing metabolic interventions as a combination therapy strategy for HER2+ breast cancer patients, including those resistant to standard treatment regimes.
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Overall design |
Mammary epithelial cells from transgenic model of breast cancer (MMTV-Neu NDL 2.5-IRES-CRE) were used to study the effects of CPT1A deletion on HER2-driven tumorigenesis. Transcriptomic analysis (RNA-Seq) was performed on cell line preparations from n = two (NIC/wild-type) and n = 4 (NIC/conditional Cpt1a KO) independent tumor-derived cell lines per genotype,
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Contributor(s) |
Nandi I, Ji L, Smith HW, Avizon D, Lavoie C, Papavasiliou V, Attalla S, Muller WJ |
Citation(s) |
39097623 |
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Submission date |
Jan 30, 2024 |
Last update date |
Aug 27, 2024 |
Contact name |
Sherif Samer Attalla |
E-mail(s) |
sherif.attalla@mail.mcgill.ca
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Organization name |
McGill
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Department |
Goodman Cancer Institute
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Lab |
Muller lab
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Street address |
1160 Ave. Pine W
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City |
Montreal |
State/province |
Quebec |
ZIP/Postal code |
H3A1A3 |
Country |
Canada |
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Platforms (1) |
GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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Samples (11)
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GSM8047339 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_1A [KO_1922A_biol rep 1] |
GSM8047340 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_1B [KO_1922B_biol rep 2] |
GSM8047341 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_2A [KO_1925A_biol rep 1] |
GSM8047342 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_2B [KO_1925B_biol rep 2] |
GSM8047343 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_3B [KO_2768B_biol rep 2] |
GSM8047344 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_4A [KO_4258A_biol rep 1] |
GSM8047345 |
Mammary epithelial tumor-derived cells from NIC mice without conditional Cpt1a alleles_4B [KO_4258B_biol rep 2] |
GSM8047346 |
Mammary epithelial tumor-derived cells from wild-type NIC mice with conditional Cpt1a alleles_1A [WT_5257A_biol rep 1] |
GSM8047347 |
Mammary epithelial tumor-derived cells from wild-type NIC mice with conditional Cpt1a alleles_1B [WT_5257B_biol rep 2] |
GSM8047348 |
Mammary epithelial tumor-derived cells from wild-type NIC mice with conditional Cpt1a alleles_2A [WT_8905A_biol rep 1] |
GSM8047349 |
Mammary epithelial tumor-derived cells from wild-type NIC mice with conditional Cpt1a alleles_2B [WT_8905B_biol rep 2] |
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Relations |
BioProject |
PRJNA1071151 |
Supplementary file |
Size |
Download |
File type/resource |
GSE254622_KO_vs_WT_DEG_all.txt.gz |
849.3 Kb |
(ftp)(http) |
TXT |
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