Mitophagy in Cancer: A Tale of Adaptation

Vara-Pérez, Mónica; Felipe‐Abrio, Blanca; Agostinis, Patrizia

doi:10.3390/cells8050493

Cited by 180 publications

(160 citation statements)

References 337 publications

(266 reference statements)

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“…Previous studies have shown that activation of AMPK was an important regulator of 204 mitochondrial homeostasis and that this activation initiates synthesis of new mitochondria to 205 replace the damaged ones. In addition, activation of mitophagy pathways acts as key regulator 206 of mitochondrial mass in cancerous cells as well as in homeostasis, bioenergetics, oncogene-207 driven metabolic reprogramming and cell apoptosis (Vara-Perez et al, 2019). Finally, cluster 208 C3 was uniquely enriched in Neurotrophin signaling pathway.…”

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confidence: 99%

Basal-like and Classical cells coexistence in pancreatic cancer revealed by single cell analysis

Juiz

El-Kaoutari

Bigonnet

et al. 2020

Preprint

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26Pancreatic ductal adenocarcinoma (PDAC) is composed of stromal, immune and epithelial 27 cells. Transcriptomic analysis of the epithelial compartment allows a binary classification into 28 mainly two phenotypic subtypes, classical and basal-like. However, little is known about the 29 intra-tumor heterogeneity of the epithelial component. Growing evidences suggest that this 30 two side phenotypic segregation is not so clear and that both could coexist in a single tumor. In 31 order to elucidate this hypothesis, we performed single-cell transcriptomic analyses using 32 combinational barcoding on epithelial cells from 6 different classical PDAC obtained by 33 Endoscopic Ultrasound (EUS) with Fine Needle Aspiration (FNA). In order to purify the 34 epithelial compartment, PDAC were grown as Biopsy Derived Pancreatic Cancer Organoids. 35 Single cell transcriptomic analysis allowed the identification of 4 main cell clusters present in 36 different proportions in all tumors. Remarkably, although these tumors were classified as 37 Classical, one of the clusters corresponded to a basal-like. These results depict the 38 unanticipated high heterogeneity of pancreatic cancers and demonstrated that basal-like cells 39 with a high aggressive phenotype are more widespread than expected. 40 41 42With a survival rate of 5 years in less than 8% of the cases (Siegel et al., 2018) pancreatic 43 ductal adenocarcinoma (PDAC) is still one of the most lethal cancers. A principal problem 44 facing this disease is its heterogeneity that results as a consequence of the combination of 45 genetic, epigenetic, and micro-environmental factors (Lomberk et al., 2019(Lomberk et al., , 2018 Yachida and 46 Iacobuzio-Donahue, 2013). Recently, two main PDAC subtypes have been identified by 47 molecular characterization: 1-classical, that are more frequently resectables, presenting a 48 higher level of differentiation, often associated with fibrosis and inflammation; and 2-basal-49 like, with a poorest clinical outcome and a loss of differentiation (Moffitt et al., 2015; Nicolle 50 et al., 2017). This well-established binary classification could be controverted if cells from a 51 unique tumor contain both phenotypes at the same time. In fact, in addition to the tumor 52 differences between patients that argues in favor of stratification for personalizing PDAC 53 treatments, it is also absolutely necessary to consider the intra-tumor differences since they are 54 playing key roles in the evolution of tumors (i.e.: they can conduce to clonal selection of 55 resistant cells and to the relapse so frequently observed after the first line of chemotherapy). 56Single-cell analysis by transcriptomics is nowadays a powerful strategy to determine the intra-57 tumor heterogeneity, however we need to bypass two main challenging difficulties: The first 58 one is to obtain pure epithelial transformed cells. To do that, we specifically amplified these 59 cells by a few passages in three dimensional (3D) ex vivo culture (Tiriac et al., 2019). Three ...

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confidence: 99%

Basal-like and Classical cells coexistence in pancreatic cancer revealed by single cell analysis

Juiz

El-Kaoutari

Bigonnet

et al. 2020

Preprint

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“…On the other hand, massive mitochondrial oxidative damage can occur upon excessive ROS production and culminate in the activation of mitophagy, the autophagymediated mechanism that, tightly coordinating with the mitochondrial fission/fusion machinery, controls the clearance of dysfunctional mitochondria (78). As such, mitophagy can be exploited by cancer cells to isolate and degrade damaged mitochondria to ensure qualitatively functional organelles.…”

Section: Mitochondria In Melanomamentioning

confidence: 99%

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

2020

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Despite tremendous efforts in the last decade to improve treatments, melanoma still represents a major therapeutic challenge and overall survival of patients remains poor. Therefore, identifying new targets to counteract melanoma is needed. In this scenario, autophagy, the "self-eating" process of the cell, has recently arisen as new potential candidate in melanoma. Alongside its role as a recycling mechanism for dysfunctional and damaged cell components, autophagy also clearly sits at a crossroad with metabolism, thereby orchestrating cell proliferation, bioenergetics and metabolic rewiring, all hallmarks of cancer cells. In this regard, autophagy, both in tumor and host, has been flagged as an essential player in melanomagenesis and progression. To pave the way to a better understanding of such a complex interplay, the use of genetically engineered mouse models (GEMMs), as well as syngeneic mouse models, has been undoubtedly crucial. Herein, we will explore the latest discoveries in the field, with particular focus on the potential of these models in unraveling the contribution of autophagy in melanoma, along with the therapeutic advantages that may arise.

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“…Defective or excessive mitophagy is a pathological factor in chronic diseases like Parkinson's disease (PD), diabetes, MIR injury, AS and cancer [5]. Several mitophagic pathways have been identi ed that counteract therapy-induced mitochondrial damage [5,6]. Guo et al reported that reversing mitophagy inhibition by the PIK3CA/AKT1/MTOR /RPS6KB1 pathway reduced the risk of CRC development [7].…”

Section: Introductionmentioning

confidence: 99%

“…The E3 ubiquitin-ligase ARIH1 and not Parkin mediates PINK1-induced mitophagic responses to cisplatin/etoposide in breast and lung adenocarcinomas [11]. In fact, the predominance of certain mitophagy receptors or mediators in speci c cancer subtypes is a decisive factor in therapy resistance via mitochondrial clearance [6,12], although the underlying mechanisms are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy Promotes Sorafenib Resistance Through a Hypoxia-Inducible ATAD3A Dependent Axis

Wang

Liu

et al. 2020

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BACKGROUND: The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in the resistant hepatoma cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients.METHODS: Hypoxia induced sorafenib resistant cells were established by culturing under 1% O2 with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir. RESULTS: We found a hyperactivated mitophagy regulating by ATAD3A-PINK/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. The classic hypoxia-induced miRNA was upregulated during hypoxia-induced mitophagy and sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice. CONCLUSION: Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC patients.

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Mitophagy in Cancer: A Tale of Adaptation

Cited by 180 publications

References 337 publications

Basal-like and Classical cells coexistence in pancreatic cancer revealed by single cell analysis

Basal-like and Classical cells coexistence in pancreatic cancer revealed by single cell analysis

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

Mitophagy Promotes Sorafenib Resistance Through a Hypoxia-Inducible ATAD3A Dependent Axis

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