RAS in pancreatic cancer

Abstract The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the endocrine portion of the pancreas. On the contrary, pancreatic exocrine neoplasms include pancreatic ductal adenocarcinoma (PDAC) and acinar cell carcinoma. PDAC is the most common type of pancreatic cancer and one of the leading causes of cancer-related death. It has been shown that less than 3% of PDAC patients have an overall survival of up to 5 years in the U.K. This mainly arises since the majority of patients diagnosed with PDAC present with advanced unresectable disease, which is highly resistant to all forms of chemotherapy and radiotherapy. Activating mutations of an isoform of the RAS protein, KRAS, are found in almost all PDAC cases and occur during early stages of malignant transformation. KRAS mutations play a critical role as they are involved in both initiating and maintaining PDAC development. The interaction of RAS with GDP/GTP along with its recruitment to the membrane affects transduction of its activating signals to downstream effectors. In this review, we aim to summarise different mutations of RAS and their prevalence in pancreatic cancer along with other RAS-induced tumours. In addition, we briefly discuss the genetically engineered mouse models that have been developed to study KRAS-mutated adenocarcinomas in the pancreas. These provide an opportunity to also address the importance of targeting RAS for better treatment response in PDAC patients along with the challenges incurred herein.

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Concerted cell and in vivo screen for pancreatic ductal adenocarcinoma (PDA) chemotherapeutics

Scientific Reports ◽

10.1038/s41598-020-77373-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Somayeh Layeghi-Ghalehsoukhteh ◽

Shreoshi Pal Choudhuri ◽

Ozhan Ocal ◽

Yalda Zolghadri ◽

Victor Pashkov ◽

...

Keyword(s):

Cell Culture ◽

Suppressor Gene ◽

Genetically Engineered ◽

Ductal Adenocarcinoma ◽

Rgs Proteins ◽

Contributing Factors ◽

Gfp Expression ◽

Kras Mutations ◽

In Vivo Screen

AbstractPDA is a major cause of US cancer-related deaths. Oncogenic Kras presents in 90% of human PDAs. Kras mutations occur early in pre-neoplastic lesions but are insufficient to cause PDA. Other contributing factors early in disease progression include chronic pancreatitis, alterations in epigenetic regulators, and tumor suppressor gene mutation. GPCRs activate heterotrimeric G-proteins that stimulate intracellular calcium and oncogenic Kras signaling, thereby promoting pancreatitis and progression to PDA. By contrast, Rgs proteins inhibit Gi/q-coupled GPCRs to negatively regulate PDA progression. Rgs16::GFP is expressed in response to caerulein-induced acinar cell dedifferentiation, early neoplasia, and throughout PDA progression. In genetically engineered mouse models of PDA, Rgs16::GFP is useful for pre-clinical rapid in vivo validation of novel chemotherapeutics targeting early lesions in patients following successful resection or at high risk for progressing to PDA. Cultured primary PDA cells express Rgs16::GFP in response to cytotoxic drugs. A histone deacetylase inhibitor, TSA, stimulated Rgs16::GFP expression in PDA primary cells, potentiated gemcitabine and JQ1 cytotoxicity in cell culture, and Gem + TSA + JQ1 inhibited tumor initiation and progression in vivo. Here we establish the use of Rgs16::GFP expression for testing drug combinations in cell culture and validation of best candidates in our rapid in vivo screen.

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Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms221910219 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10219

Author(s):

Shirin Hafezi ◽

Maha Saber-Ayad ◽

Wael M. Abdel-Rahman

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Human Cancer ◽

Ductal Adenocarcinoma ◽

Ras Gene ◽

Kras Mutations ◽

Oncogenic Mutations ◽

History Of ◽

Novel Therapeutic Strategies ◽

The Impact

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

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Pre-clinical Models of Metastasis in Pancreatic Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.748631 ◽

2021 ◽

Vol 9 ◽

Author(s):

Maria Miquel ◽

Shuman Zhang ◽

Christian Pilarsky

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Genetically Engineered ◽

Ductal Adenocarcinoma ◽

Preclinical Models ◽

Genetically Engineered Mouse Models ◽

Solid Malignancy ◽

Clinical Models ◽

System Tumor ◽

Molecular Aspects

Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.

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Mitophagy in Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.616079 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yangchun Xie ◽

Jiao Liu ◽

Rui Kang ◽

Daolin Tang

Keyword(s):

Poor Response ◽

Genetically Engineered ◽

Dual Role ◽

Cytotoxic Agents ◽

Ductal Adenocarcinoma ◽

Membrane Structures ◽

Kras Mutations ◽

Genetically Engineered Mouse Models ◽

Current Therapies ◽

Quality Control Mechanism

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive solid malignancies, is characterized by the presence of oncogenic KRAS mutations, poor response to current therapies, prone to metastasis, and a low 5-year overall survival rate. Macroautophagy (herein referred to as autophagy) is a lysosome-dependent degradation system that forms a series of dynamic membrane structures to engulf, degrade, and recycle various cargoes, such as unused proteins, damaged organelles, and invading pathogens. Autophagy is usually upregulated in established cancers, but it plays a dual role in the regulation of the initiation and progression of PDAC. As a type of selective autophagy, mitophagy is a mitochondrial quality control mechanism that uses ubiquitin-dependent (e.g., the PINK1-PRKN pathway) and -independent (e.g., BNIP3L/NIX, FUNDC1, and BNIP3) pathways to regulate mitochondrial turnover and participate in the modulation of metabolism and cell death. Genetically engineered mouse models indicate that the loss of PINK1 or PRKN promotes, whereas the depletion of BNIP3L inhibits oncogenic KRAS-driven pancreatic tumorigenesis. Mitophagy also play a dual role in the regulation of the anticancer activity of certain cytotoxic agents (e.g., rocaglamide A, dichloroacetate, fisetin, and P. suffruticosa extracts) in PDAC cells or xenograft models. In this min-review, we summarize the latest advances in understanding the complex role of mitophagy in the occurrence and treatment of PDAC.

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Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models

Cancers ◽

10.3390/cancers14010071 ◽

2021 ◽

Vol 14 (1) ◽

pp. 71

Author(s):

Yuriko Saiki ◽

Can Jiang ◽

Masaki Ohmuraya ◽

Toru Furukawa

Keyword(s):

Pancreatic Cancer ◽

Mouse Models ◽

Tumor Biology ◽

Genetically Engineered ◽

Lineage Tracing ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Precursor Lesions ◽

Genetically Engineered Mouse Models ◽

Molecular Alterations

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.

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Epigenomics of Pancreatic Cancer: A Critical Role for Epigenome-Wide Studies

Epigenomes ◽

10.3390/epigenomes3010005 ◽

2019 ◽

Vol 3 (1) ◽

pp. 5

Author(s):

Rahul Singh ◽

Katie Reindl ◽

Rick Jansen

Keyword(s):

Pancreatic Cancer ◽

High Frequency ◽

Poor Prognosis ◽

Association Studies ◽

Critical Role ◽

Common Type ◽

Ductal Adenocarcinoma ◽

Effective Prevention ◽

Survival Estimate ◽

Relapse Rates

Several challenges present themselves when discussing current approaches to the prevention or treatment of pancreatic cancer. Up to 45% of the risk of pancreatic cancer is attributed to unknown causes, making effective prevention programs difficult to design. The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is generally diagnosed at a late stage, leading to a poor prognosis and 5-year survival estimate. PDAC tumors are heterogeneous, leading to many identified cell subtypes within one patient’s primary tumor. This explains why there is a high frequency of tumors that are resistant to standard treatments, leading to high relapse rates. This review will discuss how epigenetic technologies and epigenome-wide association studies have been used to address some of these challenges and the future promises these approaches hold.

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Meta-Analysis of Circulating Cell-Free DNA’s Role in the Prognosis of Pancreatic Cancer

Cancers ◽

10.3390/cancers13143378 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3378

Author(s):

Jelena Milin-Lazovic ◽

Petar Madzarevic ◽

Nina Rajovic ◽

Vladimir Djordjevic ◽

Nikola Milic ◽

...

Keyword(s):

Pancreatic Cancer ◽

Meta Analysis ◽

Locally Advanced ◽

Progression Free Survival ◽

Ductal Adenocarcinoma ◽

Cochrane Library ◽

Molecular Characteristics ◽

Kras Mutations ◽

Additional Tool ◽

Number Of Patients

Introduction: The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. Material and Methods: We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients’ survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I2 statistic. Results: In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95–2.99 and HR = 2.46, 95% CI: 2.01–3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90–3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I2 = 87% and I2 = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I2 = 24% and I2 = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02–27.63). Conclusion: The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.

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Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers

Pharmaceutics ◽

10.3390/pharmaceutics13121987 ◽

2021 ◽

Vol 13 (12) ◽

pp. 1987

Author(s):

Nagabhishek Sirpu Natesh ◽

Brianna M. White ◽

Maia M. C. Bennett ◽

Metin Uz ◽

Rakhee Rathnam Kalari Kandy ◽

...

Keyword(s):

Pancreatic Cancer ◽

Critical Role ◽

Tumor Development ◽

Treatment Strategies ◽

Underlying Mechanism ◽

Therapeutic Interventions ◽

Ductal Adenocarcinoma ◽

Desmoplastic Reaction ◽

Cancer Pathogenesis ◽

Effective Delivery

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.

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An Essential Role forArgonaute 2in EGFR-KRAS Signaling in Pancreatic Cancer Development

10.1101/227264 ◽

2017 ◽

Cited By ~ 1

Author(s):

Sunita Shankar ◽

Jean Ching-Yi Tien ◽

Ronald F. Siebenaler ◽

Seema Chugh ◽

Vijaya L. Dommeti ◽

...

Keyword(s):

Pancreatic Cancer ◽

Specific Inhibitor ◽

Genetically Engineered ◽

Cancer Development ◽

Ductal Adenocarcinoma ◽

Ras Signaling ◽

Biphasic Model ◽

Genetic Ablation ◽

Pancreatic Cancer Cells ◽

Genetically Engineered Mouse Model

KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss ofAGO2inKRASG12D-driven pancreatic cancer. Genetic ablation ofAGO2does not interfere with development of the normal pancreas orKRASG12D-driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however,AGO2is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis.AGO2ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss ofTrp53(p53) in this model obviates the requirement ofAGO2for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2Y393by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRASG12C-AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: anAGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and anAGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.

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The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

Journal of Clinical Medicine ◽

10.3390/jcm8091369 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1369 ◽

Cited By ~ 2

Author(s):

Weng ◽

Lin ◽

Cheng

Keyword(s):

Pancreatic Cancer ◽

Mouse Models ◽

Cancer Biology ◽

Gene Knockout ◽

Genetically Engineered ◽

Ductal Adenocarcinoma ◽

Neoplastic Progression ◽

Driver Genes ◽

Genetically Engineered Mouse Models ◽

Oncology Research

Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival. Reflecting on the history of failed clinical trials, genetically engineered mouse models (GEMMs) in oncology research provides the inspiration to discover new treatments for pancreatic cancer that come from better knowledge of pathogenesis mechanisms, not only of the derangements in and consequently acquired capabilities of the cancer cells, but also in the aberrant microenvironment that becomes established to support, sustain, and enhance neoplastic progression. On the other hand, the existing mutational profile of pancreatic cancer guides our understanding of the disease, but leaves many important questions of pancreatic cancer biology unanswered. Over the past decade, a series of transgenic and gene knockout mouse modes have been produced that develop pancreatic cancers with features reflective of metastatic pancreatic ductal adenocarcinoma (PDAC) in humans. Animal models of PDAC are likely to be essential to understanding the genetics and biology of the disease and may provide the foundation for advances in early diagnosis and treatment.

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