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1.
Commun Biol ; 5(1): 1159, 2022 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-36316440

RESUMEN

Despite the fact that 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), the response rates in patients is limited to 50%. The mechanisms underlying 5-FU toxicity are debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic heterogeneity, relate to the 5-FU response remains obscure. This largely relies on the limited number of studies performed in pre-clinical models able to recapitulate the key features of CRC. Here, we analyzed the 5-FU response in patient-derived organoids that reproduce the different stages of CRC. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death in the actively proliferating cancer cells deficient in p53. Importantly, p53-deficiency leads to cell death due to impaired cell cycle arrest. Moreover, we find that targeting the Warburg effect in KRASG12D glycolytic tumor organoids enhances 5-FU toxicity by further altering the nucleotide pool and, importantly, without affecting non-transformed WT cells. Thus, p53 emerges as an important factor in determining the 5-FU response, and targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.


Asunto(s)
Neoplasias Colorrectales , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Glucosa
2.
STAR Protoc ; 2(1): 100386, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33778780

RESUMEN

Addressing bioenergetics is key to evaluate the impact of metabolism on the regulation of biological processes and its alteration in disease. Organoids are in vitro grown self-organizing structures derived from healthy and diseased tissue that recapitulate with high fidelity the tissue of origin. Bioenergetics is commonly analyzed by Seahorse XF analysis. However, its application to organoid studies is technically challenging. Here, we share our in-house optimized protocols to examine organoid bioenergetics in response to drugs, gene knockdown, or to characterize the metabolism of specific cell types. For complete details on the use and execution of this protocol, please refer to Ludikhuize et al. (2020).


Asunto(s)
Metabolismo Energético/fisiología , Análisis de Flujos Metabólicos/métodos , Organoides/metabolismo , Animales , Técnicas de Cultivo de Célula/métodos , Humanos , Organoides/fisiología , Oxígeno/metabolismo , Consumo de Oxígeno/efectos de los fármacos
3.
Cell Metab ; 32(5): 889-900.e7, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33147486

RESUMEN

Differential WNT and Notch signaling regulates differentiation of Lgr5+ crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showed that mitochondrial activity supports CBCs, while adjacent Paneth cells (PCs) show reduced mitochondrial activity. This implies that CBC differentiation into PCs involves a metabolic transition toward downregulation of mitochondrial dependency. Here we show that Forkhead box O (FoxO) transcription factors and Notch signaling interact in determining CBC fate. In agreement with the organoid data, Foxo1/3/4 deletion in mouse intestine induces secretory cell differentiation. Importantly, we show that FOXO and Notch signaling converge on regulation of mitochondrial fission, which in turn provokes stem cell differentiation into goblet cells and PCs. Finally, scRNA-seq-based reconstruction of CBC differentiation trajectories supports the role of FOXO, Notch, and mitochondria in secretory differentiation. Together, this points at a new signaling-metabolic axis in CBC differentiation and highlights the importance of mitochondria in determining stem cell fate.


Asunto(s)
Células Caliciformes , Intestinos/citología , Mitocondrias/metabolismo , Células de Paneth , Células Madre , Animales , Diferenciación Celular , Línea Celular , Factores de Transcripción Forkhead/metabolismo , Células Caliciformes/citología , Células Caliciformes/metabolismo , Ratones , Dinámicas Mitocondriales , Células de Paneth/citología , Células de Paneth/metabolismo , Receptores Notch/metabolismo , Células Madre/citología , Células Madre/metabolismo
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