Mathematical Modeling of Pancreatic Cancer Treatment with Cancer Stem Cells

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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The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-09979-x ◽

2021 ◽

Author(s):

Kalyani Patil ◽

Farheen B. Khan ◽

Sabah Akhtar ◽

Aamir Ahmad ◽

Shahab Uddin

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Disease Recurrence ◽

Resistance Mechanisms ◽

Cytotoxic Agents ◽

Plastic State ◽

Metastatic Progression ◽

Acquired Drug Resistance ◽

Natural Agents

AbstractThe ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

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PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β3-KRAS-dependent pancreatic cancer stem cells

Scientific Reports ◽

10.1038/s41598-020-65804-5 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Jiongjia Cheng ◽

John R. Cashman

Keyword(s):

Cell Cycle ◽

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cell Cycle Arrest ◽

Specific Inhibitor ◽

Feedback Mechanism ◽

Major Health Problem ◽

Cycle Arrest ◽

Drug Inhibition

Abstract Today, pancreatic cancer (PC) remains a major health problem in the US. The fact that cancer stem cells (CSCs) become enriched in humans following anti-cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. A highly validated CSC model (FGβ3 cells) was used to test a novel compound (PAWI-2) to eradicate CSCs. Compared to parental bulk FG cells, PAWI-2 showed greater potency to inhibit cell viability and self-renewal capacity of FGβ3 cells. For FGβ3 cells, dysregulated integrin β3-KRAS signaling drives tumor progression. PAWI-2 inhibited β3-KRAS signaling independent of KRAS. This is clinically relevant. PAWI-2 targeted the downstream TBK1 phosphorylation cascade that was negatively regulated by optineurin phosphorylation via a feedback mechanism. This was confirmed by TBK1 genetic knockdown or co-treatment with TBK1-specific inhibitor (MRT67307). PAWI-2 also overcame erlotinib (an EGFR inhibitor) resistance in FGβ3 cells more potently than bortezomib. In the proposed working model, optineurin acts as a key regulator to link inhibition of KRAS signaling and cell cycle arrest (G2/M). The findings show PAWI-2 is a new approach to reverse tumor stemness that resensitizes CSC tumors to drug inhibition.

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206 Identification and Whole Transcriptome Characterization of Pancreatic Cancer Stem Cells

Gastroenterology ◽

10.1016/s0016-5085(12)60195-4 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-50-S-51

Author(s):

Christina Vorvis ◽

George A. Poultsides ◽

Jeffrey A. Norton ◽

Maria Hatziapostolou ◽

Dimitrios Iliopoulos

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Whole Transcriptome ◽

Pancreatic Cancer Stem Cells

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Targeting pancreatic cancer stem cells for cancer therapy

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2012.06.002 ◽

2012 ◽

Vol 1826 (2) ◽

pp. 385-399 ◽

Cited By ~ 6

Author(s):

Jun Xia ◽

Changjie Chen ◽

Zhiwen Chen ◽

Lucio Miele ◽

Fazlul H. Sarkar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Therapy ◽

Cancer Stem Cells ◽

Pancreatic Cancer Stem Cells

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Graphene oxide selectively targets cancer stem cells, across multiple tumor types: Implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”

Oncotarget ◽

10.18632/oncotarget.3348 ◽

2015 ◽

Vol 6 (6) ◽

pp. 3553-3562 ◽

Cited By ~ 102

Author(s):

Marco Fiorillo ◽

Andrea F. Verre ◽

Maria Iliut ◽

Maria Peiris-Pagés ◽

Bela Ozsvari ◽

...

Keyword(s):

Stem Cells ◽

Graphene Oxide ◽

Cancer Stem Cells ◽

Cancer Treatment ◽

Multiple Tumor ◽

Tumor Types

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MicroRNA Targeted Therapy for Overcoming Drug Resistance, Reversal of EMT and Elimination of Cancer Stem Cells in Prostate and Pancreatic Cancer

MicroRNA Targeted Cancer Therapy ◽

10.1007/978-3-319-05134-5_12 ◽

2014 ◽

pp. 199-217 ◽

Cited By ~ 3

Author(s):

Yiwei Li ◽

Dejuan Kong ◽

Aamir Ahmad ◽

Bin Bao ◽

Fazlul H. Sarkar

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Targeted Therapy ◽

Cancer Stem Cells ◽

Resistance Reversal

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Long noncoding RNA LINC00261 upregulates ITIH5 to impair tumorigenic ability of pancreatic cancer stem cells

Cell Death Discovery ◽

10.1038/s41420-021-00575-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Lijuan Zou ◽

Hengpeng He ◽

Zhiguo Li ◽

Ou Chen ◽

Xiukun Jia ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cell Proliferation ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Noncoding Rna ◽

Cell Subset ◽

Luciferase Reporter ◽

Stem Cell Markers ◽

Self Renewal

AbstractLong noncoding RNAs (lncRNAs) are implicated tumor development in a range of different cancers, including pancreatic cancer (PC). Cancer stem cells (CSCs), a drug-resistant cancer cell subset, drive tumor progression in PC. In this work, we aimed to investigate the mechanism by which lncRNA LINC00261 affects the biological functions of CSCs during the progression of PC. Microarray analysis of differentially expressed genes and lncRNAs suggested that LINC00261 is downregulated in PC. Both LINC00261 and ITIH5 were confirmed to be downregulated in PC cells and PC stem cells. Gain-of-function and loss-of-function investigations were performed to analyze their effects on cell proliferation, drug resistance, cell cycle distribution, self-renewal, invasion, and ultimately overall tumorigenicity. These experiments revealed that the expression of stem cell markers was reduced, and cell proliferation, self-renewal ability, cell invasion, drug resistance, and tumorigenicity were all suppressed by upregulation of LINC00261 or ITIH5. The results of dual-luciferase reporter gene, ChIP, and RIP assays indicated that LINC00261 binds directly to GATA6, increasing its activity at the ITIH5 promoter. The presence of LINC00261 and GATA6 inhibited the self-renewal and tumorigenesis of PC stem cells, while silence of ITIH5 rescued those functions. Collectively, this study identifies the tumor suppressive activity of LINC00261 in PC, showing that this lncRNA limits the functions of PC stem through an ITIH5/GATA6 regulatory pathway.

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