Optimized protocol for stable isotope tracing and steady-state metabolomics in mouse HER2+ breast cancer brain metastasis

Parida, Pravat Kumar; Marquez-Palencia, Mauricio; Kaushik, Akash; Kim, Kangsan; Nair, Vidhya R.; Sudderth, Jessica; Vu, Hieu; Zacharias, Lauren G.; DeBerardinis, Ralph J.; Malladi, Srinivas

doi:10.1016/j.xpro.2022.101345

Cited by 1 publication

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“…This experiment was performed as described before 6 , 23 , 24 . Briefly, 5 × 10 4 cells were resuspended in 100 μl 1× PBS were intracardially injected into the left ventricle of mice with the help of 26 G tuberculin syringe.…”

Section: Methodsmentioning

confidence: 99%

Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases

et al. 2023

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Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.

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Section: Methodsmentioning

confidence: 99%