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Grant support

This work was supported by the Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Rome, Italy. C.A.C.-C. participated in the INVITE project of the University of Verona. INVITE project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 754345.

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Article

Mitochondrial Elongation and OPA1 Play Crucial Roles during the Stemness Acquisition Process in Pancreatic Ductal Adenocarcinoma

Publicated to:Cancers. 14 (14): 3432- - 2022-07-01 14(14), DOI: 10.3390/cancers14143432

Authors: Carmona-Carmona, Cristian Andres; Dalla Pozza, Elisa; Ambrosini, Giulia; Cisterna, Barbara; Palmieri, Marta; Decimo, Ilaria; Cuezva, Jose M.; Bottani, Emanuela; Dando, Ilaria;

Affiliations

Univ Autonoma Madrid CSIC UAM, CSIC, ISCIII,Ctr Biol Mol Severo Ochoa,Dept Biol Mol, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28049, Spain - Author
Univ Autonoma Madrid, Inst Invest Hosp Octubre 12, Madrid 28049, Spain - Author
Univ Verona, Dept Diagnost & Publ Hlth, Sect Pharmacol, I-37134 Verona, Italy - Author
Univ Verona, Dept Neurosci Biomed & Movement Sci, I-37134 Verona, Italy - Author

Abstract

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal neoplasia and the currently used treatments are not effective in a wide range of patients. Presently, the evidence points out that cancer stem cells (CSCs) are key players during tumor development, metastasis, chemoresistance, and tumor relapse. The study of the metabolism of CSCs, specifically the mitochondrial alterations, could pave the way to the discovery of new therapeutical targets. In this study, we show that during progressive de-differentiation, pancreatic CSCs undergo changes in mitochondrial mass, dynamics, and function. Interestingly, the silencing of OPA1, a protein involved in mitochondrial fusion, significantly inhibits the formation of CSCs. These results reveal new insight into mitochondria and stemness acquisition that could be useful for the design of novel potential therapies in PDAC. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate of less than 9%. The high aggressiveness of PDAC is linked to the presence of a subpopulation of cancer cells with a greater tumorigenic capacity, generically called cancer stem cells (CSCs). CSCs present a heterogeneous metabolic profile that might be supported by an adaptation of mitochondrial function; however, the role of this organelle in the development and maintenance of CSCs remains controversial. To determine the role of mitochondria in CSCs over longer periods, which may reflect more accurately their quiescent state, we studied the mitochondrial physiology in CSCs at short-, medium-, and long-term culture periods. We found that CSCs show a significant increase in mitochondrial mass, more mitochondrial fusion, and higher mRNA expression of genes involved in mitochondrial biogenesis than parental cells. These changes are accompanied by a regulation of the activities of OXPHOS complexes II and IV. Furthermore, the protein OPA1, which is involved in mitochondrial dynamics, is overexpressed in CSCs and modulates the tumorsphere formation. Our findings indicate that CSCs undergo mitochondrial remodeling during the stemness acquisition process, which could be exploited as a promising therapeutic target against pancreatic CSCs.

Keywords

cancer stem cellsmitochondrial dynamicsmitochondrial fusionopa1BiogenesisCancer stem cellsCancer-cellsDeterminesIf1Mitochondrial dynamicsMitochondrial fusionOpa1Oxidative-phosphorylationPancreatic ductal adenocarcinomaShiftSupercomplex

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cancers due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.58. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.9 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 4.79 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-01, the following number of citations:

  • WoS: 7
  • Scopus: 11
  • Europe PMC: 10

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-01:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 9 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

    • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
    • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/706824

    Leadership analysis of institutional authors

    This work has been carried out with international collaboration, specifically with researchers from: Italy.