Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers
© 2024. The Author(s)..
BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency.
METHODS: Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature.
RESULTS: Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models.
CONCLUSIONS: Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Breast cancer research : BCR - 26(2024), 1 vom: 19. Feb., Seite 29 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Derouane, Françoise [VerfasserIn] |
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| Links: |
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| Themen: |
Early triple negative breast cancer |
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| Anmerkungen: |
Date Completed 21.02.2024 Date Revised 08.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13058-024-01788-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368641767 |
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| 245 | 1 | 0 | |a Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency | ||
| 520 | |a METHODS: Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature | ||
| 520 | |a RESULTS: Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models | ||
| 520 | |a CONCLUSIONS: Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Early triple negative breast cancer | |
| 650 | 4 | |a Glycolysis | |
| 650 | 4 | |a Metabolism | |
| 650 | 4 | |a Neoadjuvant chemotherapy | |
| 650 | 4 | |a Organoids | |
| 650 | 4 | |a Therapy resistance | |
| 650 | 7 | |a Paclitaxel |2 NLM | |
| 650 | 7 | |a P88XT4IS4D |2 NLM | |
| 700 | 1 | |a Desgres, Manon |e verfasserin |4 aut | |
| 700 | 1 | |a Moroni, Camilla |e verfasserin |4 aut | |
| 700 | 1 | |a Ambroise, Jérôme |e verfasserin |4 aut | |
| 700 | 1 | |a Berlière, Martine |e verfasserin |4 aut | |
| 700 | 1 | |a Van Bockstal, Mieke R |e verfasserin |4 aut | |
| 700 | 1 | |a Galant, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a van Marcke, Cédric |e verfasserin |4 aut | |
| 700 | 1 | |a Vara-Messler, Marianela |e verfasserin |4 aut | |
| 700 | 1 | |a Hutten, Stefan J |e verfasserin |4 aut | |
| 700 | 1 | |a Jonkers, Jos |e verfasserin |4 aut | |
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| 700 | 1 | |a Duhoux, Francois P |e verfasserin |4 aut | |
| 700 | 1 | |a Corbet, Cyril |e verfasserin |4 aut | |
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