Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma

Raggi, Chiara; Taddei, Maria Letizia; Sacco, Elena; Navari, N.; Correnti, Margherita; Piombanti, Benedetta; Pastore, Mirella; Campani, Claudia; Pranzini, Erica; Iorio, Jessica; Lori, Giulia; Lottini, Tiziano; Peano, Clelia; Cibella, Javier; Lewińska, Monika; Andersen, Jesper B.; Tommaso, Luca Di; Viganò, Luca; Maira, Giovanni Di; Madiai, Stefania; Ramazzotti, Matteo; Orlandi, Ivan; Arcangeli, Annarosa; Chiarugi, Paola; Marra, Fabio

doi:10.1016/j.jhep.2020.12.031

Cited by 88 publications

(61 citation statements)

References 49 publications

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“…For instance, the Mito stress test includes modulators of the electron transport chain to investigate their role in sustaining cell metabolism. This technology has been exploited, for instance, to perform metabolic phenotyping of cancer cells in standard conditions and under perturbed conditions [ 15 ], to discover the metabolic switches responsible for the acquisition of malignant features (e.g., metastasis) [ 16 ], to observe metabolic heterogeneity in cancer through the identification of cell subpopulations harboring different metabolic profiles (e.g., cancer stem cells) [ 17 , 18 ], and many other studies of cancer metabolism [ 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

An Optimized Workflow for the Analysis of Metabolic Fluxes in Cancer Spheroids Using Seahorse Technology

Campioni

Pasquale

Busti

et al. 2022

Cells

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Three-dimensional cancer models, such as spheroids, are increasingly being used to study cancer metabolism because they can better recapitulate the molecular and physiological aspects of the tumor architecture than conventional monolayer cultures. Although Agilent Seahorse XFe96 (Agilent Technologies, Santa Clara, CA, United States) is a valuable technology for studying metabolic alterations occurring in cancer cells, its application to three-dimensional cultures is still poorly optimized. We present a reliable and reproducible workflow for the Seahorse metabolic analysis of three-dimensional cultures. An optimized protocol enables the formation of spheroids highly regular in shape and homogenous in size, reducing variability in metabolic parameters among the experimental replicates, both under basal and drug treatment conditions. High-resolution imaging allows the calculation of the number of viable cells in each spheroid, the normalization of metabolic parameters on a per-cell basis, and grouping of the spheroids as a function of their size. Multivariate statistical tests on metabolic parameters determined by the Mito Stress test on two breast cancer cell lines show that metabolic differences among the studied spheroids are mostly related to the cell line rather than to the size of the spheroid. The optimized workflow allows high-resolution metabolic characterization of three-dimensional cultures, their comparison with monolayer cultures, and may aid in the design and interpretation of (multi)drug protocols.

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Section: Introductionmentioning

confidence: 99%

An Optimized Workflow for the Analysis of Metabolic Fluxes in Cancer Spheroids Using Seahorse Technology

Campioni

Pasquale

Busti

et al. 2022

Cells

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“…Cells were then incubated in a non-CO 2 incubator for 1 h at 37 °C to pre-equilibrate the cells before analysis. An XF Mito Stress Test was performed to assay the cells’ ability to exploit mitochondrial oxidative metabolism, according to the manufacturer’s instructions [ 31 ]. This analysis was performed via the real-time measurement of extracellular acidification (ECAR) and oxygen consumption rate (OCR) after the injection of a sequence of compounds that interfere with the electron transport chain: oligomycin (1 µM), carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone (FCCP) (1 µM), and Rotenone/Antimycin A (0.5 µM).…”

Section: Methodsmentioning

confidence: 99%

The miR-27a/FOXJ3 Axis Dysregulates Mitochondrial Homeostasis in Colorectal Cancer Cells

Barisciano

Leo

Muccillo

et al. 2021

Cancers

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miR-27a plays a driver role in rewiring tumor cell metabolism. We searched for new miR-27a targets that could affect mitochondria and identified FOXJ3, an apical factor of mitochondrial biogenesis. We analyzed FOXJ3 levels in an in vitro cell model system that was genetically modified for miR-27a expression and validated it as an miR-27a target. We showed that the miR-27a/FOXJ3 axis down-modulates mitochondrial biogenesis and other key members of the pathway, implying multiple levels of control. As assessed by specific markers, the miR-27a/FOXJ3 axis also dysregulates mitochondrial dynamics, resulting in fewer, short, and punctate organelles. Consistently, in high miR-27a-/low FOXJ3-expressing cells, mitochondria are functionally characterized by lower superoxide production, respiration capacity, and membrane potential, as evaluated by OCR assays and confocal microscopy. The analysis of a mouse xenograft model confirmed FOXJ3 as a target and suggested that the miR-27a/FOXJ3 axis affects mitochondrial abundance in vivo. A survey of the TCGA-COADREAD dataset supported the inverse relationship of FOXJ3 with miR-27a and reinforced cellular component organization or biogenesis as the most affected pathway. The miR-27a/FOXJ3 axis acts as a central hub in regulating mitochondrial homeostasis. Its discovery paves the way for new therapeutic strategies aimed at restraining tumor growth by targeting mitochondrial activities.

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“…However, there is also growing evidence that mitochondrial oxidative metabolism is the preferred form of energy production in CSCs, including CD133+ colon cancer cells[ 32 ], CD44+ and CD117+ ovarian cancer cells[ 33 ], cholangiocarcinoma cells[ 34 ], brain tumor cells[ 35 ], and leukemia cells[ 36 ]. In addition, it is found that pancreatic CSCs (PaCSCs) are enriched in the oxidative phosphorylation (OXPHOS) promotion system using galactose instead of glucose as carbon source in vitro .…”

Section: Metabolic Reprogramming In Cscsmentioning

confidence: 99%

Abnormal lipid synthesis as a therapeutic target for cancer stem cells

Wang¹,

Hu²,

Wu³

et al. 2022

WJSC

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Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.

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Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma

Cited by 88 publications

References 49 publications

An Optimized Workflow for the Analysis of Metabolic Fluxes in Cancer Spheroids Using Seahorse Technology

An Optimized Workflow for the Analysis of Metabolic Fluxes in Cancer Spheroids Using Seahorse Technology

The miR-27a/FOXJ3 Axis Dysregulates Mitochondrial Homeostasis in Colorectal Cancer Cells

Abnormal lipid synthesis as a therapeutic target for cancer stem cells

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