@article{771a2c45b1c04853bf8665b534c5186d,
title = "Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness",
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.",
keywords = "HER2, breast cancer brain metastasis, immune surveillance, late recurrences, metabolism, metastasis, metastatic dormancy, metastatic latency, redox homeostasis, relapse",
author = "Parida, {Pravat Kumar} and Mauricio Marquez-Palencia and Vidhya Nair and Kaushik, {Akash K.} and Kangsan Kim and Jessica Sudderth and Eduardo Quesada-Diaz and Ambar Cajigas and Vamsidhara Vemireddy and Gonzalez-Ericsson, {Paula I.} and Sanders, {Melinda E.} and Mobley, {Bret C.} and Kenneth Huffman and Sunati Sahoo and Prasanna Alluri and Cheryl Lewis and Yan Peng and Bachoo, {Robert M.} and Arteaga, {Carlos L.} and Hanker, {Ariella B.} and DeBerardinis, {Ralph J.} and Srinivas Malladi",
note = "Funding Information: A.B.H. has received research grant support from Takeda and travel support from Puma Biotechnology. C.L.A. receives or has received research grant support from Pfizer, Lilly, and Takeda; holds stock options in Provista and Y-TRAP; and serves or has served in an advisory role to Novartis, Lilly, TAIHO Oncology, Daiichi Sankyo, Merck, AstraZeneca, OrigiMed, Immunomedics, and Susan G. Komen Foundation. R.J.D. is a founder of Atavistik Biosciences and an advisor for Agios Pharmaceuticals, Nirogy Therapeutics, and Vida Ventures. Funding Information: This work was supported by CPRIT training grant RP210041 to P.K.P.; NSF grant 2019281049 to M.M.P.; NCI grant R35CA22044901 to R.J.D.; and CPRIT ( RR170003 ), ACS ( RSG-20-47-01-CSM ), and METAvivor ( GAA202106-0027 ) grants to S.M. We gratefully acknowledge the assistance of preclinical radiation core facility supported by CPRIT RP180770 for bioluminescence imaging and Cancer Center Support grant ( P30 CA142543 ) for tissue management shared resource and small animal imaging. Illustrations created with https://biorender.com/ . Funding Information: This work was supported by CPRIT training grant RP210041 to P.K.P.; NSF grant 2019281049 to M.M.P.; NCI grant R35CA22044901 to R.J.D.; and CPRIT (RR170003), ACS (RSG-20-47-01-CSM), and METAvivor (GAA202106-0027) grants to S.M. We gratefully acknowledge the assistance of preclinical radiation core facility supported by CPRIT RP180770 for bioluminescence imaging and Cancer Center Support grant (P30 CA142543) for tissue management shared resource and small animal imaging. Illustrations created with https://biorender.com/. Conceptualization, P.K.P. and S.M.; methodology, P.K.P. M.M.-P. V.N. A.K.K. and S.M.; investigation, P.K.P. M.M.-P. V.N. A.K.K. K.K. J.S. E.Q.-D. A.C. V.V. C.L. and S.M.; writing ? original draft, S.M.; writing ? review & editing, P.K.P. C.L.A. A.B.H. R.J.D. and S.M.; funding acquisition, S.M.; resources, P.I.G.-E. M.E.S. B.C.M. C.L. Y.P. and A.B.H.; supervision, S.M. A.B.H. has received research grant support from Takeda and travel support from Puma Biotechnology. C.L.A. receives or has received research grant support from Pfizer, Lilly, and Takeda; holds stock options in Provista and Y-TRAP; and serves or has served in an advisory role to Novartis, Lilly, TAIHO Oncology, Daiichi Sankyo, Merck, AstraZeneca, OrigiMed, Immunomedics, and Susan G. Komen Foundation. R.J.D. is a founder of Atavistik Biosciences and an advisor for Agios Pharmaceuticals, Nirogy Therapeutics, and Vida Ventures. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2022",
month = jan,
day = "4",
doi = "10.1016/j.cmet.2021.12.001",
language = "English (US)",
volume = "34",
pages = "90--105.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}