scholarly journals Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1790 ◽  
Author(s):  
Timothy P. Cash ◽  
Sonia Alcalá ◽  
María del Rosario Rico-Ferreira ◽  
Elena Hernández-Encinas ◽  
Jennifer García ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Therapeutic Strategy ◽  
Membrane Permeabilization ◽  
Ductal Adenocarcinoma ◽  
Chemical Library ◽  
Specific Chemical ◽  
Pancreatic Cancer Stem Cells

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC.

scholarly journals Transcriptome Profiling of Panc-1 Spheroid Cells with Pancreatic Cancer Stem Cells Properties Cultured by a Novel 3D Semi-Solid System

2018 ◽  
Vol 47 (5) ◽  
pp. 2109-2125 ◽  
Author(s):  
Zhaocong Yang ◽  
Yanfeng Zhang ◽  
Tingting Tang ◽  
Qinhua Zhu ◽  
Wanyue Shi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Culture System ◽  
High Throughput Sequencing ◽  
Semi Solid ◽  
Pancreatic Cancer Stem Cells ◽  
Solid System

Background/Aims: Pancreatic cancer remains one of the deadliest human malignancies, the lethality of which may be attributed to the presence of pancreatic cancer stem cells (PCSCs), a small subpopulation of cells existing within pancreatic tumor with high carcinogenesis. Therefore, it is crucial to establish an efficient enrichment and culture system of PCSCs and identify the key genes involved in the regulation of PCSCs. The three-dimensional (3D) liquid suspension mammosphere culture system has been established for enrichment and culture of PCSCs in vitro as the cell spheres are likely to originate from individual cell clone, but it has been challenged because the cell spheroids could be a result of cell aggregation. Methods: We optimized the existing culture system by adding methylcellulose to create a 3D semi-solid system which prevented the non-specific aggregation. Then we identified the CSC properties of Panc-1 spheroid cells cultured by this system by detecting the genes associated with stemness and by evaluation of the tumorigenicity in vitro and in vivo through invasion, migration and xenograft experiments methods. Subsequently, we performed high-throughput sequencing (HTS) of the Panc-1 spheroid cells. Results: We confirmed the PCSCs properties and high malignancy of the Panc-1 spheroid cells enriched by our novel 3D semi-solid system both in vitro and in vivo. Hundreds of mRNA, microRNA (miRNA) and dozens of long non-coding RNA (LncRNA) were identified to be differentially regulated in PCSCs-like Panc-1 spheroid cells compared with their parental cells by HTS. Conclusions: Our results demonstrate an efficient enrichment and culture system for Panc-1 spheroid cells with the PCSCs properties. The differentially expressed genes and their targets identified by the HTS of the Panc-1 spheroid cells can serve as new potential biomarkers for pancreatic cancer diagnosis and targeted therapy.

scholarly journals Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sandra Valle ◽  
Sonia Alcalá ◽  
Laura Martin-Hijano ◽  
Pablo Cabezas-Sáinz ◽  
Diego Navarro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ductal Adenocarcinoma ◽  
In Vitro System ◽  
Tumorigenic Potential ◽  
Term Enrichment ◽  
Pluripotency Gene ◽  
Pancreatic Cancer Stem Cells

Abstract Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.

scholarly journals The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sabrina Bimonte ◽  
Antonio Barbieri ◽  
Maddalena Leongito ◽  
Giuseppe Palma ◽  
Vitale del Vecchio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Biological Activities ◽  
Biological Properties ◽  
Ductal Adenocarcinoma ◽  
Small Noncoding Rnas ◽  
Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

scholarly journals Dendritic Cells Loaded with Pancreatic Cancer Stem Cells (CSCs) Lysates Induce Antitumor Immune Killing Effect In Vitro

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e114581 ◽  
Author(s):  
Tao Yin ◽  
Pengfei Shi ◽  
Shanmiao Gou ◽  
Qiang Shen ◽  
Chunyou Wang
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Dendritic Cells ◽  
Cancer Stem Cells ◽  
Killing Effect ◽  
Pancreatic Cancer Stem Cells

scholarly journals HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem Cells

2017 ◽  
Author(s):  
Ethan V. Abel ◽  
Masashi Goto ◽  
Brian Magnuson ◽  
Saji Abraham ◽  
Nikita Ramanathan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Target Genes ◽  
Gene Signature ◽  
Biological Properties ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Cancer Stem Cells

ABSTRACTThe biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, PCSC depletion, and downregulation of OCT4 expression. Conversely, HNF1A overexpression increased PCSC numbers and tumorsphere formation in pancreatic cancer cells and drove PDA cell growth. Importantly, depletion of HNF1A in primary tumor xenografts impaired tumor growth and depleted PCSCs in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of the PCSC state and novel oncogene in pancreatic ductal adenocarcinoma.

scholarly journals Carbon-Ion Beam Irradiation and the miR-200c Mimic Effectively Eradicate Pancreatic Cancer Stem Cells Under in vitro and in vivo Conditions

2021 ◽  
Vol Volume 14 ◽  
pp. 4749-4760
Author(s):  
Sei Sai ◽  
Eun Ho Kim ◽  
Woong Sub Koom ◽  
Guillaume Vares ◽  
Masao Suzuki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ion Beam ◽  
Beam Irradiation ◽  
Ion Beam Irradiation ◽  
Carbon Ion Beam ◽  
Pancreatic Cancer Stem Cells

scholarly journals Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

2020 ◽  
Vol 21 (20) ◽  
pp. 7437
Author(s):  
Sonia Alcalá ◽  
Víctor Mayoral-Varo ◽  
Laura Ruiz-Cañas ◽  
Juan Carlos López-Gil ◽  
Christopher Heeschen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tyrosine Kinases ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Src Kinases ◽  
Tyrosine Protein Kinase ◽  
Pancreatic Cancer Stem Cells ◽  
Future Treatment Option

The proto-oncogene nonreceptor tyrosine-protein kinase SRC is a member of the SRC family of tyrosine kinases (SFKs), and its activation and overexpression have been shown to play a protumorigenic role in multiple solid cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is currently the seventh-leading cause of cancer-related death worldwide, and, by 2030, it is predicted to become the second-leading cause of cancer-related death in the United States. PDAC is characterized by its high lethality (5-year survival of rate of <10%), invasiveness, and chemoresistance, all of which have been shown to be due to the presence of pancreatic cancer stem cells (PaCSCs) within the tumor. Due to the demonstrated overexpression of SRC in PDAC, we set out to determine if SRC kinases are important for PaCSC biology using pharmacological inhibitors of SRC kinases (dasatinib or PP2). Treatment of primary PDAC cultures established from patient-derived xenografts with dasatinib or PP2 reduced the clonogenic, self-renewal, and tumor-initiating capacity of PaCSCs, which we attribute to the downregulation of key signaling factors such as p-FAK, p-ERK1-2, and p-AKT. Therefore, this study not only validates that SRC kinases are relevant and biologically important for PaCSCs but also suggests that inhibitors of SRC kinases may represent a possible future treatment option for PDAC patients, although further studies are still needed.

scholarly journals Integrated lipidomics and proteomics reveal cardiolipin alterations, upregulation of HADHA and long chain fatty acids in pancreatic cancer stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claudia Di Carlo ◽  
Bebiana C. Sousa ◽  
Marcello Manfredi ◽  
Jessica Brandi ◽  
Elisa Dalla Pozza ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Fatty Acid ◽  
Cancer Stem Cells ◽  
Acyl Chain ◽  
Fatty Acid Elongase ◽  
Acyl Chains ◽  
A Chain ◽  
Pancreatic Cancer Stem Cells ◽  
Long Chain

AbstractPancreatic cancer stem cells (PCSCs) play a key role in the aggressiveness of pancreatic ductal adenocarcinomas (PDAC); however, little is known about their signaling and metabolic pathways. Here we show that PCSCs have specific and common proteome and lipidome modulations. PCSCs displayed downregulation of lactate dehydrogenase A chain, and upregulation of trifunctional enzyme subunit alpha. The upregulated proteins of PCSCs are mainly involved in fatty acid (FA) elongation and biosynthesis of unsaturated FAs. Accordingly, lipidomics reveals an increase in long and very long-chain unsaturated FAs, which are products of fatty acid elongase-5 predicted as a key gene. Moreover, lipidomics showed the induction in PCSCs of molecular species of cardiolipin with mixed incorporation of 16:0, 18:1, and 18:2 acyl chains. Our data indicate a crucial role of FA elongation and alteration in cardiolipin acyl chain composition in PCSCs, representing attractive therapeutic targets in PDAC.

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