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Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence
Enakshi D Sunassee1, Riley J Deutsch1, Victoria W D'Agostino1
1Department of Biomedical Engineering, Duke University, Durham, NC, USA.
Abstract:
Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.
Insights
Triple-negative breast cancer cells evade chemotherapy by altering their metabolism. Resistant tumors show increased mitochondrial activity and metabolic diversity, unlike sensitive tumors, offering new therapeutic targets.
Area of Science:
- Oncology
- Metabolic Research
- Cancer Biology
Background:
- Triple-negative breast cancer (TNBC) has limited treatment options, with most patients not achieving long-term chemotherapy response.
- Resistant tumor cells survive chemotherapy by utilizing alternative metabolic pathways, leading to recurrence.
Purpose of the Study:
- To investigate longitudinal metabolic reprogramming in residual and recurrent TNBC xenografts with differential paclitaxel sensitivity.
- To identify metabolic characteristics associated with therapy resistance and residual disease in TNBC.
Main Methods:
- In vivo longitudinal optical imaging and metabolomics were employed.
- TNBC xenograft models with varying sensitivities to paclitaxel (MDA-MB-231 and HCC-1806) were utilized.
- Metabolic reprogramming, mitochondrial metabolism, and intratumoral metabolic heterogeneity were analyzed.
Main Results:
- Resistant MDA-MB-231 tumors exhibited increased non-glucose-driven mitochondrial metabolism and metabolic heterogeneity during regression and residual disease.
- Sensitive HCC-1806 tumors primarily relied on glucose uptake with minimal metabolic changes.
- Resistant HCC-1806 tumors showed greater reliance on mitochondrial metabolism and higher heterogeneity compared to sensitive counterparts.
Conclusions:
- Metabolic flexibility, increased mitochondrial metabolism, and heightened metabolic heterogeneity characterize persistent residual disease in TNBC.
- These metabolic features provide insights for selecting appropriate therapies and treatment timing for TNBC patients.
- Understanding metabolic reprogramming is crucial for overcoming chemotherapy resistance in triple-negative breast cancer.
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