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3 pages, 171 KiB

Open AccessEditorial

New Insights into Metabolic Alterations and Mitochondria Re-Arrangements in Pancreatic Adenocarcinoma

by Ilaria Dando and Elisa Dalla Pozza

Cancers 2023, 15(15), 3906; https://doi.org/10.3390/cancers15153906 - 1 Aug 2023

Viewed by 876

Abstract

Among the most aggressive cancer types, pancreatic ductal adenocarcinoma (PDAC) represents one with the highest lethality due to its resistance to therapies and to the frequent metastatic spread [...] Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

Research

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22 pages, 3496 KiB

Open AccessArticle

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

by Cristian Andres Carmona-Carmona, Elisa Dalla Pozza, Giulia Ambrosini, Barbara Cisterna, Marta Palmieri, Ilaria Decimo, José M. Cuezva, Emanuela Bottani and Ilaria Dando

Cancers 2022, 14(14), 3432; https://doi.org/10.3390/cancers14143432 - 14 Jul 2022

Cited by 11 | Viewed by 2869

Abstract

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, [...] Read more.

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. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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19 pages, 4156 KiB

Open AccessArticle

3-Bromo-Isoxazoline Derivatives Inhibit GAPDH Enzyme in PDAC Cells Triggering Autophagy and Apoptotic Cell Death

by Raffaella Pacchiana, Nidula Mullappilly, Andrea Pinto, Stefania Bova, Stefania Forciniti, Gregorio Cullia, Elisa Dalla Pozza, Emanuela Bottani, Ilaria Decimo, Ilaria Dando, Stefano Bruno, Paola Conti and Massimo Donadelli

Cancers 2022, 14(13), 3153; https://doi.org/10.3390/cancers14133153 - 27 Jun 2022

Cited by 14 | Viewed by 2492

Abstract

A growing interest in the study of aerobic glycolysis as a key pathway for cancer-cell energetic metabolism, favouring tumour progression and invasion, has led to consider GAPDH as an effective drug target to specifically hit cancer cells. In this study, we have investigated [...] Read more.

A growing interest in the study of aerobic glycolysis as a key pathway for cancer-cell energetic metabolism, favouring tumour progression and invasion, has led to consider GAPDH as an effective drug target to specifically hit cancer cells. In this study, we have investigated a panel of 3-bromo-isoxazoline derivatives based on previously identified inhibitors of Plasmodium falciparum GAPDH (PfGAPDH). The compounds are active, to a different extent, as inhibitors of human-recombinant GAPDH. They showed an antiproliferative effect on pancreatic ductal-adenocarcinoma cells (PDAC) and pancreatic-cancer stem cells (CSCs), and among them two promising compounds were selected to be tested in vivo. Interestingly, these compounds were not effective in fibroblasts. The AXP-3019 derivative was able to block PDAC-cell growth in mice xenograft without apparent toxicity. The overall results support the assumption that selective inhibition of the glycolytic pathway, by targeting GAPDH, is an effective therapy for pancreatic cancer and that 3-bromo-isoxazoline derivatives represent a new class of anti-cancer compounds targeting glycolysis. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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14 pages, 3226 KiB

Open AccessArticle

TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase

by Ji Hye Kim, Jinyoung Lee, Young-Ra Cho, So-Yeon Lee, Gi-Jun Sung, Dong-Myung Shin, Kyung-Chul Choi and Jaekyoung Son

Cancers 2021, 13(3), 483; https://doi.org/10.3390/cancers13030483 - 27 Jan 2021

Cited by 25 | Viewed by 3620

Abstract

Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, [...] Read more.

Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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Review

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16 pages, 518 KiB

Open AccessReview

The Role of Genetic, Metabolic, Inflammatory, and Immunologic Mediators in the Progression of Intraductal Papillary Mucinous Neoplasms to Pancreatic Adenocarcinoma

by Kylie E. Shockley, Briana To, Wei Chen, Gerard Lozanski, Zobeida Cruz-Monserrate and Somashekar G. Krishna

Cancers 2023, 15(6), 1722; https://doi.org/10.3390/cancers15061722 - 11 Mar 2023

Cited by 4 | Viewed by 2682

Abstract

Intraductal papillary mucinous neoplasms (IPMN) have the potential to progress to pancreatic ductal adenocarcinoma (PDAC). As with any progression to malignancy, there are a variety of genetic and metabolic changes, as well as other disruptions to the cellular microenvironment including immune alterations and [...] Read more.

Intraductal papillary mucinous neoplasms (IPMN) have the potential to progress to pancreatic ductal adenocarcinoma (PDAC). As with any progression to malignancy, there are a variety of genetic and metabolic changes, as well as other disruptions to the cellular microenvironment including immune alterations and inflammation, that can contribute to tumorigenesis. Previous studies further characterized these alterations, revealing changes in lipid and glucose metabolism, and signaling pathways that mediate the progression of IPMN to PDAC. With the increased diagnosis of IPMNs and pancreatic cysts on imaging, the opportunity to attenuate risk with the removal of high-risk lesions is possible with the understanding of what factors accelerate malignant progression and how they can be clinically utilized to determine the level of dysplasia and stratify the risk of progression. Here, we reviewed the genetic, metabolic, inflammatory, and immunologic pathways regulating the progression of IPMN to PDAC. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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31 pages, 1969 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy

by Hafiza Padinharayil, Vikrant Rai and Alex George

Cancers 2023, 15(4), 1070; https://doi.org/10.3390/cancers15041070 - 8 Feb 2023

Cited by 6 | Viewed by 3359

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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19 pages, 1941 KiB

Open AccessReview

Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review

by Graziantonio Lauria, Rosita Curcio, Paola Lunetti, Stefano Tiziani, Vincenzo Coppola, Vincenza Dolce, Giuseppe Fiermonte and Amer Ahmed

Cancers 2023, 15(2), 411; https://doi.org/10.3390/cancers15020411 - 8 Jan 2023

Cited by 6 | Viewed by 3717

Abstract

Pancreatic cancer is among the deadliest cancers worldwide and commonly presents as pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming is a hallmark of PDAC. Glucose and glutamine metabolism are extensively rewired in order to fulfil both energetic and synthetic demands of this aggressive tumour [...] Read more.

Pancreatic cancer is among the deadliest cancers worldwide and commonly presents as pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming is a hallmark of PDAC. Glucose and glutamine metabolism are extensively rewired in order to fulfil both energetic and synthetic demands of this aggressive tumour and maintain favorable redox homeostasis. The mitochondrial pyruvate carrier (MPC), the glutamine carrier (SLC1A5_Var), the glutamate carrier (GC), the aspartate/glutamate carrier (AGC), and the uncoupling protein 2 (UCP2) have all been shown to influence PDAC cell growth and progression. The expression of MPC is downregulated in PDAC and its overexpression reduces cell growth rate, whereas the other four transporters are usually overexpressed and the loss of one or more of them renders PDAC cells unable to grow and proliferate by altering the levels of crucial metabolites such as aspartate. The aim of this review is to comprehensively evaluate the current experimental evidence about the function of these carriers in PDAC metabolic rewiring. Dissecting the precise role of these transporters in the context of the tumour microenvironment is necessary for targeted drug development. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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18 pages, 708 KiB

Open AccessReview

Divergent Roles of Mitochondria Dynamics in Pancreatic Ductal Adenocarcinoma

by Cristian Andres Carmona-Carmona, Elisa Dalla Pozza, Giulia Ambrosini, Andrea Errico and Ilaria Dando

Cancers 2022, 14(9), 2155; https://doi.org/10.3390/cancers14092155 - 26 Apr 2022

Cited by 9 | Viewed by 3126

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors; it is often diagnosed at an advanced stage and is hardly treatable. These issues are strictly linked to the absence of early diagnostic markers and the low efficacy of treatment approaches. Recently, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors; it is often diagnosed at an advanced stage and is hardly treatable. These issues are strictly linked to the absence of early diagnostic markers and the low efficacy of treatment approaches. Recently, the study of the metabolic alterations in cancer cells has opened the way to important findings that can be exploited to generate new potential therapies. Within this scenario, mitochondria represent important organelles within which many essential functions are necessary for cell survival, including some key reactions involved in energy metabolism. These organelles remodel their shape by dividing or fusing themselves in response to cellular needs or stimuli. Interestingly, many authors have shown that mitochondrial dynamic equilibrium is altered in many different tumor types. However, up to now, it is not clear whether PDAC cells preferentially take advantage of fusion or fission processes since some studies reported a wide range of different results. This review described the role of both mitochondria arrangement processes, i.e., fusion and fission events, in PDAC, showing that a preference for mitochondria fragmentation could sustain tumor needs. In addition, we also highlight the importance of considering the metabolic arrangement and mitochondria assessment of cancer stem cells, which represent the most aggressive tumor cell type that has been shown to have distinctive metabolic features to that of differentiated tumor cells. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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13 pages, 783 KiB

Open AccessReview

Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer

by Yoshiaki Sunami, Artur Rebelo and Jörg Kleeff

Cancers 2021, 13(17), 4391; https://doi.org/10.3390/cancers13174391 - 31 Aug 2021

Cited by 13 | Viewed by 4126

Abstract

Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, especially lipid metabolism, plays an important role in progression and metastasis of many types of [...] Read more.

Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, especially lipid metabolism, plays an important role in progression and metastasis of many types of cancer, including pancreatic and liver cancer. Lipid droplets are intracellular organelles that store neutral lipids, but also act as molecular messengers, and signaling factors. It is becoming increasingly evident that alterations in the regulation of lipid droplets and their associated factors influence the risk of developing not only metabolic disease but also fibrosis and cancer. In the current review article, we summarized recent findings concerning the roles of lipid droplet-associated factors, patatin-like phospholipase domain-containing 3, Transmembrane 6 superfamily member 2, and 17β-hydroxysteroid dehydrogenase 11 and 13 as well as genetic variants in pancreatic and hepatic diseases. A better understanding of cancer type- and cell type-specific roles of lipid droplet-associated factors is important for establishing new therapeutic options in the future. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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