Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence

Science Advances, Год журнала: 2024, Номер 10(14)

Опубликована: Апрель 5, 2024

Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal reprogramming residual disease recurrence xenografts with varying sensitivities the chemotherapeutic drug paclitaxel. Optical imaging coupled metabolomics reported an increase non–glucose–driven mitochondrial metabolism intratumoral heterogeneity during regression resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake minimal changes or observed over tumors’ therapeutic life cycles. Further, day-matched revealed a higher reliance elevated compared Together, flexibility, increased metabolism, are defining characteristics persistent disease, features that will inform appropriate type timing therapies.

Язык: Английский

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Fast autofluorescence imaging to evaluate dynamic changes in cell metabolism

Journal of Biomedical Optics, Год журнала: 2024, Номер 29(12)

Опубликована: Дек. 19, 2024

SignificanceCellular metabolic dynamics can occur within milliseconds, yet there are no optimal tools to spatially and temporally capture these events. Autofluorescence imaging provide information on the cellular level due intrinsic fluorescence of reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] flavin (FAD).AimOur goal is build evaluate a widefield microscope optimized for rapid autofluorescence changes in cells.ApproachA widefield, was assembled from an inverted base, light-emitting diode (LED) excitation, image splitter simultaneous but separate two bandwidths emission (451/106 560/94 nm) single scientific complementary metal–oxide–semiconductor (sCMOS) camera. MCF-7 cells primary murine hippocampal neurons were metabolically perturbed using cyanide imaged optimize illumination camera exposure. To change metabolism, starved 1 h while reintroduced glucose.ResultsSignificant differences optical redox ratio (ORR) intensity NAD(P)H divided by summed intensities FAD quantified cyanide-treated at powers above 0.30 mW exposures as low 5 ms; however, hindered ability identify subcellular features. Minimal photobleaching 30 s continuous illuminations 4.14 below. Using power exposure 10 ms, demonstrated rapid, heterogeneous, increase ORR upon glucose.ConclusionsUltimately, this system allowed dynamic quantification metabolism 99.6 Hz.

Язык: Английский

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Mitochondrial adaptation decreases drug sensitivity of persistent triple negative breast cancer cells surviving combinatory and sequential chemotherapy

Neoplasia, Год журнала: 2023, Номер 46, С. 100949 - 100949

Опубликована: Ноя. 11, 2023

Triple negative breast cancer (TNBC) is an aggressive malignancy for which chemotherapy remains the standard treatment. However, between 3 and 5 years after chemotherapy, about half patients will relapse it essential to identify vulnerabilities of cells surviving neoadujuvant therapy. In this study, we established persistent TNBC cell models treating MDA-MB-231 SUM159-PT lines with epirubicin cyclophosphamide, then paclitaxel, a total 18 weeks. The resulting chemo-persistent were more proliferative, both in vitro xenografted mice. Interestingly, became less sensitive chemotherapeutic drugs, whereas kept similar sensitivity compared control cells. reduced was found be associated increased oxidative phosphorylation (OXPHOS) modified levels tricarboxylic acid cycle (TCA) intermediates. Integration data from proteomics metabolomics demonstrated TCA among most upregulated pathways absence glucose pyruvate impeded OXPHOS cells, while glutamine did not. contrast, not independently substrates, indicating that evolved towards dependent profile. Finally, inhibition entry into mitochondria UK-5099 re-sensitized therapeutic agents. Together, these findings suggest targeting mitochondrial metabolism may help overcome adaptation TNBC.

Язык: Английский

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Differential Mitochondrial Redox Responses to the Inhibition of NAD+ Salvage Pathway of Triple Negative Breast Cancer Cells

Cancers, Год журнала: 2024, Номер 17(1), С. 7 - 7

Опубликована: Дек. 24, 2024

Background/Objectives: Cancer cells rely on metabolic reprogramming that is supported by altered mitochondrial redox status and an increased demand for NAD+. Over expression of Nampt, the rate-limiting enzyme NAD+ biosynthesis salvage pathway, common in breast cancer cells, more so triple negative (TNBC) cells. Targeting pathway has been pursued therapy. However, TNBC have heterogeneous responses to Nampt inhibition, which contributes diverse outcomes. There a lack imaging biomarkers differentiate among under stress identify are responsive. We aimed characterize panel cell lines NAD-deficient subtypes dependent NAD pathway. Methods: Optical (ORI), label-free live microscopy technique was utilized acquire intrinsic fluorescence intensities NADH FAD-containing flavoproteins (Fp) thus ratio Fp/(NADH + Fp) lines. Various probes were then added cultures image ROS, membrane potential, mass, number. Results: sensitive inhibition dose- time-dependent manner, they differential responses; furthermore, indices linearly correlated with ROS induced various doses inhibitor. Moreover, changes growth inhibition. Additionally, state found fully recovered after removing Conclusions: This study supports utility ORI rapid phenotyping responsive treatment response, facilitating combination therapy strategies.

Язык: Английский

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Challenges in Metabolite Biomarkers as Avenues of Diagnosis and Prognosis of Cancer

Journal of Cancer Prevention, Год журнала: 2024, Номер 29(4), С. 105 - 112

Опубликована: Дек. 30, 2024

Given the evolutionary nature of tumor complexities and heterogeneity, early diagnosis cancer encounters various challenges.Complexities at level metabolite reprogramming are compelling in background invasiveness, metastasis, drug-and radiation-induced metabolic alterations, immunotherapy-influenced changes, pro-tumor niche including microbiome.Therefore, it is crucial to examine both current future obstacles associated with detection specifically context biomarkers preclinical clinical levels.In conclusion, significance must be aligned a comprehensive approach achbieve prognosis patients by securing solutions formidable challenges.

Язык: Английский

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