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

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

doi:10.1016/j.cmet.2021.12.001

Cited by 46 publications

(47 citation statements)

References 62 publications

(69 reference statements)

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“…During metastatic progression, tumor cells undergo metabolic adaptations to survive in circulation and distal organs ( Faubert et al., 2020 ; Hanahan and Weinberg, 2011 ; Parida et al., 2022 ; Pavlova and Thompson, 2016 ). Understanding metabolic adaptations of metastatic cells in distal organs may provide insights that inform clinical management of disease and help in developing new diagnostic and therapeutic strategies.…”

Section: Before You Beginmentioning

confidence: 99%

“…Through a phenotypic screen in mice, we isolated isogenic HER2+ synchronous (S-BM) and metachronous (M-BM) brain metastatic cells. By investigating these phenotypically distinct brain-tropic S-BM and M-BM cells, we uncovered the metabolic differences within these metastatic population using isotope tracing and steady state metabolite analysis ( Parida et al., 2022 ). Isotope tracing revealed key differences in glucose and glutamine catabolism between S-BM and M-BM brain metastases.…”

Section: Expected Outcomesmentioning

confidence: 99%

“… (C) M+5/M+4 citrate ratios highlighting reductive carboxylation of glutamine in S-BM and oxidative carboxylation in M-BM. Reprinted with permission from Parida et al., 2022 . …”

Section: Expected Outcomesmentioning

confidence: 99%

“…Finally, we outline steps for sample collection, processing for metabolite extraction, and analyzing mass spectrometry data. For complete details on the use and execution of this protocol, please refer to Parida et al. (2022) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Parida et al. (2022) .…”

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confidence: 99%

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

et al. 2022

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Section: Before You Beginmentioning

confidence: 99%

Section: Expected Outcomesmentioning

confidence: 99%

“… (C) M+5/M+4 citrate ratios highlighting reductive carboxylation of glutamine in S-BM and oxidative carboxylation in M-BM. Reprinted with permission from Parida et al., 2022 . …”

Section: Expected Outcomesmentioning

confidence: 99%

mentioning

confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Parida et al. (2022) .…”

mentioning

confidence: 99%

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

et al. 2022

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Lactate Efflux Inhibition by Syrosingopine/LOD Co‐Loaded Nanozyme for Synergetic Self‐Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling

et al. 2023

Advanced Science

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An effective systemic mechanism regulates tumor development and progression; thus, a rational design in a one‐stone‐two‐birds strategy is meant for cancer treatment. Herein, a hollow Fe3O4 catalytic nanozyme carrier co‐loading lactate oxidase (LOD) and a clinically‐used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self‐replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti‐tumor immune microenvironment. The synergetic bio‐effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co‐delivered LOD and intracellular acidification enabled the augmented self‐replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti‐tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1‐polarize tumor‐associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof‐of‐concept study represents a promising candidate nanoplatform for synergetic cancer treatment.

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Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism

Filipe,

Velayuthar,

Philp

et al. 2024

Advanced Science

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In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.

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

Cited by 46 publications

References 62 publications

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

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

Lactate Efflux Inhibition by Syrosingopine/LOD Co‐Loaded Nanozyme for Synergetic Self‐Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling

Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism

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