Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics

Smigiel, Jacob; Parameswaran, Neetha; Jackson, Mark W.

doi:10.3390/cancers10010014

Cited by 26 publications

(32 citation statements)

References 128 publications

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“…Since the undeniable role of these cells in tumorigenesis, therapy resistance and metastasis has been shown, these cells need to be eliminated in order for a therapy to be curative, even more so since even a single CSC is theoretically able to reconstitute the entire tumor. Possible strategies for their elimination have been recently reviewed [103], and include i) a direct targeted elimination of CSCs (known as targeted therapy), ii) promoting an active cell cycle to make quiescent CSCs accessible for therapy or iii) a disruption of the CSC niche and/or TME. Below we highlight some key and important studies.…”

Section: Targeting Csc Plasticity -Therapeutic Optionsmentioning

confidence: 99%

Pancreatic cancer stem cells: A state or an entity?

Hermann

Sáinz

2018

Seminars in Cancer Biology

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Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, has a median overall survival of 6-12 months and a 5-year survival of less than 7%. While PDAC currently represents the 4th most frequent cause of death due to cancer worldwide, it is expected to become the second leading cause of cancer-related death by 2030. These alarming statistics are primarily due to both the inherent chemoresistant and metastatic nature of this tumor, and the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs). Since their discovery in PDAC in 2007, we have come to realize that pancreatic CSCs have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. More importantly, the concept of the CSC as a fixed entity within the tumor has also evolved, and current data suggest that CSCs are states rather than defined entities. Consequently, current treatments for the majority of PDAC patients are not effective, and do not significantly impact overall patient survival, as they do not adequately target the plastic CSC sub-population nor the transient/hybrid cells that can replenish the CSC pool. Thus, it is necessary that we improve our understanding of the characteristics and signals that maintain and drive the pancreatic CSC population in order to develop new therapies to target these cells. Herein, we will provide the latest updates and knowledge on the inherent characteristics of pancreatic CSCs and the CSC niche, specifically the cross-talk that exists between CSCs and niche resident cells. Lastly, we will address the question of whether a CSC is a state or an entity and discuss how the answer to this question can impact treatment approaches.

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Section: Targeting Csc Plasticity -Therapeutic Optionsmentioning

confidence: 99%

Pancreatic cancer stem cells: A state or an entity?

Hermann

Sáinz

2018

Seminars in Cancer Biology

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“…On the other hand, the HS structures show less aggressiveness with more epithelial characteristics. This degree of plasticity provided these cells with cancer stem cell properties that drove them in a series of transformations between the epithelial and mesenchymal cell types [51]. These properties were confirmed via detection of protein levels of respective markers and bioinformatic analyses of the data from the two arrays.…”

Section: Discussionmentioning

confidence: 78%

“…It has been proposed that cancer cells, via activation of the epithelial-to-mesenchymal transition (EMT), gain the ability to migrate and invade distant organs. Contrariwise, mesenchymal-to-epithelial transition (MET) must occur in these cells for successful colonization of the new tissue [51]. Fittingly, the HS/ML in vitro system of the A818-6 PDAC cell line represents a unique system to study these transitions.…”

Section: Hs/ml As a Differentiation Modelmentioning

confidence: 99%

The A818–6 system as an in-vitro model for studying the role of the transportome in pancreatic cancer

et al. 2020

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Background: The human pancreatic cancer cell line A818-6 can be grown in vitro either as a highly malignant, undifferentiated monolayer (ML) or as three-dimensional (3D) single layer hollow spheres (HS) simulating a benign, highly differentiated, duct-like pancreatic epithelial structure. This characteristic allowing A818-6 cells to switch from one phenotype to another makes these cells a unique system to characterize the cellular and molecular modifications during differentiation on one hand and malignant transformation on the other hand. Ion channels and transport proteins (transportome) have been implicated in malignant transformation. Therefore, the current study aimed to analyse the transportome gene expression profile in the A818-6 cells growing as a monolayer or as hollow spheres. Methods & Results: The study identified the differentially expressed transportome genes in both cellular states of A818-6 using Agilent and Nanostring arrays and some targets were validated via immunoblotting. Additionally, these results were compared to a tissue Affymetrix microarray analysis of pancreatic adenocarcinoma patients' tissues. The overall transcriptional profile of the ML and HS cells confirmed the formerly described mesenchymal features of ML and epithelial nature of HS which was further verified via high expression of E-cadherin and low expression of vimentin found in HS in comparison to ML. Among the predicted features between HS and ML was the involvement of miRNA-9 in this switch. Importantly, the bioinformatics analysis also revealed substantial number (n = 126) of altered transportome genes. Interestingly, three genes upregulated in PDAC tissue samples (GJB2, GJB5 and SLC38A6) were found to be also upregulated in ML and 3 down-regulated transportome genes (KCNQ1, TRPV6 and SLC4A) were also reduced in ML. Conclusion: This reversible HS/ML in vitro system might help in understanding the pathophysiological impact of the transportome in the dedifferentiation process in pancreatic carcinogenesis. Furthermore, the HS/ML model represents a novel system for studying the role of the transportome during the switch from a more benign, differentiated (HS) to a highly malignant, undifferentiated (ML) phenotype.

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“…Pancreatic cancer (PC) is a highly malignant digestive tract tumour that has a poor prognosis . PC cells are often overexpressed epidermal growth factor receptor (EGFR) and its endogenous ligand, therefore, important progress has been made in the EGFR targeting strategies of advanced PC .…”

Section: Introductionmentioning

confidence: 99%

“…Pancreatic cancer (PC) is a highly malignant digestive tract tumour that has a poor prognosis. [1] PC cells are often overexpressed epidermal growth factor receptor (EGFR) and its endogenous ligand, therefore, important progress has been made in the EGFR targeting strategies of advanced PC. [2] Erlotinib, a small molecule EGFR-tyrosine kinase inhibitor (EGFR-TKI), can effectively improve the clinical efficacy of gemcitabine-based chemotherapies in the treatment of advanced PC, as shown by improving overall survival and clinical benefit response.…”

Section: Introductionmentioning

confidence: 99%

Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Chemotheraputic drug resistance is a critical factor associated with the poor survival in advanced/metastatic pancreatic cancer (PC) patients. Methods Human pancreatic cell lines Capan‐1 and BXPC‐3 were cultured with different concentrations of erlotinib (0, 10, 50, and 100 μm) for 48 h. The relative cell viability and apoptosis was detected using MTT assays and flow cytometry apoptosis analysis, respectively. Transfection of pcDNA‐EphA2, si‐EphA2 and miR‐124 mimic/inhibitor was used to modulate the intracellular level of EphA2 and miR‐124. The interaction between miR‐124 and the 3′UTR of EphA2 was explored using dual luciferase reporter assay. Key findings Compared with BXPC‐3 cells, Capan‐1 cells showed resistance to differential concentration treatment of erlotinib. The expression of EphA‐2 was significantly increased and the expression of miR‐124 was significantly decreased in Capan‐1 cells. Overexpressing EphA2 induced resistance of BXPC‐3 cells to erlotinib treatment. And EphA2 was identified as a novel target gene for miR‐124. MiR‐124 overexpression was able to sensitize the response of Capan‐1 cells to erlotinib through inhibiting EphA2. Furthermore, both miR‐124 overexpression and EphA2 inhibition sensitized Capan‐1 cells to erlotinib in xenograft model. Conclusions Our study demonstrated that EphA2 rescued by miR‐124 downregulation conferred the erlotinib resistance of PC cell Capan‐1 with K‐RAS mutation.

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Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics

Cited by 26 publications

References 128 publications

Pancreatic cancer stem cells: A state or an entity?

Pancreatic cancer stem cells: A state or an entity?

The A818–6 system as an in-vitro model for studying the role of the transportome in pancreatic cancer

Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer

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