Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness

Pravat Kumar Parida,Ambar Cajigas,Ralph J Deberardinis,Jessica Sudderth,Carlos L Arteaga,Kangsan Kim,Ariella B Hanker,Prasanna Alluri,Melinda E Sanders,Yan Peng,Sunati Sahoo,Mauricio Marquez-Palencia,Srinivas Malladi,Cheryl Lewis,Vamsidhara Vemireddy,Eduardo Quesada-Diaz,Kenneth E Huffman ,Vidhya R Nair ,Robert Bachoo ,Akash Kaushik ,Bret Mobley ,Paula I González-Ericsson

doi:10.1016/j.cmet.2021.12.001

Abstract

HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.

Highlights

Brain metastases develop following the spread of cells from the primary tumor to the brain through vasculature (Achrol et al, 2019)
Phenotypic selection of synchronous, latent, and metachronous human epidermal growth factor receptor 2 (HER2)+ breast cancer brain metastatic cells To isolate isogeneic S-BM, Lat, and M-BM HER2+ brain metastatic cells, we performed a phenotypic screen in vivo
In the majority of HCC1954 and SKBR3 mice, despite tumor progression, animals were healthy with no overt metastasis after 5 weeks

Summary

Introduction

Brain metastases develop following the spread of cells from the primary tumor to the brain through vasculature (Achrol et al, 2019). The survival dependencies of cancer cells with a similar genomic profile that have differentially adapted to the brain parenchyma are unknown. Understanding these differences is vital to devise effective strategies that identify and treat patients presented with synchronous or delayed metachronous metastases. Metachronous brain metastases are observed in fifty percent of HER2+ breast cancer patients considered disease free after a variable length of time post-primary diagnosis and treatment (Kabraji et al, 2018; Kodack et al, 2015, 2017; Lin, 2015; Lin et al, 2017; Olson and Mullins, 2013; Olson et al, 2013).

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