Mitochondrial biology in cancer stem cells

Loureiro, Rute; Mesquita, Katia A.; Magalhães-Novais, Sílvia; Oliveira, Paulo J.; Vega‐Naredo, Ignacio

doi:10.1016/j.semcancer.2017.06.012

Cited by 46 publications

(41 citation statements)

References 216 publications

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“…Mitochondrial respiration has been recently implicated in maintaining cancer cell stemness (Sancho et al , ; Loureiro et al , ). Since the homeostasis of mtDNA in slow‐cycling cells (such as CSC) depends on the mitochondrial deoxynucleoside salvage pathway, we hypothesized that DGUOK depletion might inhibit lung cancer tumor growth and metastasis through suppressing cancer cell stemness.…”

Section: Resultsmentioning

confidence: 99%

“…The role of mitochondrial OXPHOS in CSC self-renewal is cancer type-dependent (Loureiro et al, 2017). In CSCs from breast cancer and hepatocellular carcinoma, mitochondrial OXPHOS is suppressed (Dong et al, 2013;Chen et al, 2016), while in lung cancer and pancreatic cancer, mitochondrial OXPHOS is essential for CSC selfrenewal (Ye et al, 2011;Sancho et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

et al. 2019

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The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate‐limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self‐renewal of lung cancer stem‐like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self‐renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self‐renewal through AMPK‐YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK‐mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline‐inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC‐mediated therapy resistance and metastatic recurrence.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

et al. 2019

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“…Cellular metabolism is beginning to be recognized as a central controller of the occurrence and function of CSCs [4][5][6][7][8][9], and we are rapidly amassing knowledge of the metabolic features that are important for the functional traits that define CSCs. Metabolic traits such as bioener-getic/biosynthetic retuning, redox balance, and switching (activation/deactivation) of energy-sensing integrators can no longer be viewed as secondary consequences of the acquisition of cancer stemness, as they appear to elicit the CSC phenotype.…”

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confidence: 99%

“…Most research on the apparent dependence of CSCs on mitochondrial function has focused on the relationship between mitochondrial bioenergetics and the distinguishing metabolic profiles of CSCs. While it remains a matter of debate why and how CSCs present a highly glycolytic or a mitochondrial-dependent primary phenotype in a cancer type-and/or environment-dependent manner [4][5][6][7][8], it is clear that mitochondrial function per se takes central stage in CSC functionality irrespective of the metabolic features of the primary tumor. This mitochondrial dependence of stemness and cell fate specification compels us to reconsider mito-CONTACT Javier A. Menendez jmenendez@iconcologia.net; jmenendez@idibgi.org chondria as (the) key signaling organelles that can be therapeutically exploited to eliminate the dynamic pool of CSCs within heterogeneous cancer populations.…”

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confidence: 99%

Mitostemness

et al. 2018

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Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer. Mitochondria are increasingly recognized key drivers in the origin and development of CSC functional traits. We here propose the new term "mitostemness" to designate the mitochondria-dependent signaling functions that, evolutionary rooted in the bacterial origin of mitochondria, regulate the maintenance of CSC self-renewal and resistance to differentiation. Mitostemness traits, namely mitonuclear communication, mitoproteome components, and mitochondrial fission/fusion dynamics, can be therapeutically exploited to target the CSC state. We briefly review the pre-clinical evidence of action of investigational compounds on mitostemness traits and discuss ongoing strategies to accelerate the clinical translation of new mitostemness drugs. The recognition that the bacterial origin of present-day mitochondria can drive decision-making signaling phenomena may open up a new therapeutic dimension against life-threatening CSCs. New therapeutics aimed to target mitochondria not only as biochemical but also as biophysical and morpho-physiological hallmarks of CSC might certainly guide improvements to cancer treatment.

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“…In further support of this notion, please see the following articles for further reading on the subject [39–45]. …”

Section: Discussionmentioning

confidence: 99%

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

et al. 2018

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Here, we wish to propose a new systematic approach to cancer therapy, based on the targeting of mitochondrial metabolism, especially in cancer stem cells (CSCs). In the future, we envision that anti-mitochondrial therapy would ultimately be practiced as an add-on to more conventional therapy, largely for the prevention of tumor recurrence and cancer metastasis. This mitochondrial based oncology platform would require a panel of FDA-approved therapeutics (e.g. Doxycycline) that can safely be used to inhibit mitochondrial OXPHOS and/or biogenesis in CSCs. In addition, new therapeutics that target mitochondria could also be developed, to optimize their ability to eradicate CSCs. Finally, in this context, mitochondrial-based biomarkers (i.e. “Mito-signatures”) could be utilized as companion diagnostics, to identify high-risk cancer patients at diagnosis, facilitating the early detection of tumor recurrence and the prevention of treatment failure. In summary, we suggest that new clinical trials are warranted to test and possibly implement this emerging treatment strategy, in a variety of human cancer types. This general approach, using FDA-approved antibiotics to target mitochondria, was effective in killing CSCs originating from many different cancer types, including DCIS, breast (ER(+) and ER(-)), prostate, ovarian, lung and pancreatic cancers, as well as melanoma and glioblastoma, among others. Thus, we propose the term MITO-ONC-RX, to describe this anti-mitochondrial platform for targeting CSCs. The use of re-purposed FDA-approved drugs will undoubtedly help to accelerate the clinical evaluation of this approach, as these drugs can move directly into Phase II clinical trials, saving considerable amounts of time (10–15 y) and billions in financial resources.

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Mitochondrial biology in cancer stem cells

Cited by 46 publications

References 216 publications

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma

Mitostemness

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

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