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Cancers
Special Issues
Targeting Ras/RASSF in Cancer
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Targeting Ras/RASSF in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 18958

Special Issue Editor

Dr. Geoffrey J. Clark

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, University of Louisville, Louisville, United States
Interests: RAS, RASSF, drug discovery, animal models

Special Issue Information

Dear Colleagues,

Ras is the most frequently inactivated tumor suppressor in human cancer. RASSF1A may be the most frequently inactivated tumor suppressor in human cancer. As RAS directly binds RASSF family proteins and uses them as pro-death effectors, the interaction of these proteins is likely to have a major effect on tumor phenotype and drug response. Indeed, in lung cancer patients, the worst prognosis tumors are almost always RAS+/RASSF1A. Moreover, RAS+/RASSF1A–transgenic mouse systems demonstrate enhanced tumorigenesis.

This issue considers novel therapeutic approaches that target RAS activation and/or RASSF protein inactivation. It includes studies describing novel inhibitor approaches, synthetic lethal and collateral lethal effects, rational drug combinations and drug resistance. It may also include more basic studies describing unique metabolic and signaling characteristics of RAS+/RASSF-tumors.  

Dr. Geoffrey J. Clark
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • RAS
  • RASSF
  • synthetic lethal
  • collateral lethal
  • novel inhibitors
  • drug resistance

Published Papers (5 papers)

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Research

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14 pages, 2381 KiB  
Article
The RASSF1A Tumor Suppressor Binds the RasGAP DAB2IP and Modulates RAS Activation in Lung Cancer
by Desmond R. Harrell Stewart, M. Lee Schmidt, Howard Donninger and Geoffrey J. Clark
Cancers 2020, 12(12), 3807; https://doi.org/10.3390/cancers12123807 - 17 Dec 2020
Cited by 3 | Viewed by 1979
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Lung cancer is commonly driven by mutations in the RAS oncogenes, the most frequently activated oncogene family in human disease. RAS-induced tumorigenesis is inhibited by the tumor suppressor RASSF1A, which induces apoptosis in [...] Read more.
Lung cancer is the leading cause of cancer-related death worldwide. Lung cancer is commonly driven by mutations in the RAS oncogenes, the most frequently activated oncogene family in human disease. RAS-induced tumorigenesis is inhibited by the tumor suppressor RASSF1A, which induces apoptosis in response to hyperactivation of RAS. RASSF1A expression is suppressed in cancer at high rates, primarily owing to promoter hypermethylation. Recent reports have shown that loss of RASSF1A expression uncouples RAS from apoptotic signaling in vivo, thereby enhancing tumor aggressiveness. Moreover, a concomitant upregulation of RAS mitogenic signaling upon RASSF1A loss has been observed, suggesting RASSF1A may directly regulate RAS activation. Here, we present the first mechanistic evidence for control of RAS activation by RASSF1A. We present a novel interaction between RASSF1A and the Ras GTPase Activating Protein (RasGAP) DAB2IP, an important negative regulator of RAS. Using shRNA-mediated knockdown and stable overexpression approaches, we demonstrate that RASSF1A upregulates DAB2IP protein levels in NSCLC cells. Suppression of RASSF1A and subsequent downregulation of DAB2IP enhances GTP loading onto RAS, thus increasing RAS mitogenic signaling in both mutant- and wildtype-RAS cells. Moreover, co-suppression of RASSF1A and DAB2IP significantly enhances in vitro and in vivo growth of wildtype-RAS cells. Tumors expressing wildtype RAS, therefore, may still suffer from hyperactive RAS signaling when RASSF1A is downregulated. This may render them susceptible to the targeted RAS inhibitors currently in development. Full article
(This article belongs to the Special Issue Targeting Ras/RASSF in Cancer)
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24 pages, 4146 KiB  
Article
RASSF10 Is a TGFβ-Target That Regulates ASPP2 and E-Cadherin Expression and Acts as Tumor Suppressor That Is Epigenetically Downregulated in Advanced Cancer
by Antje M. Richter, Miriam M. Küster, Michelle L. Woods, Sara K. Walesch, Mira Y. Gökyildirim, Marcus Krueger and Reinhard H. Dammann
Cancers 2019, 11(12), 1976; https://doi.org/10.3390/cancers11121976 - 8 Dec 2019
Cited by 8 | Viewed by 3185
Abstract
The Ras Association Domain Family (RASSF) encodes members of tumor suppressor genes which are frequently inactivated in human cancers. Here, the function and the regulation of RASSF10, that contains a RA (Ras-association) and two coiled domains, was investigated. We utilized mass spectrometry and [...] Read more.
The Ras Association Domain Family (RASSF) encodes members of tumor suppressor genes which are frequently inactivated in human cancers. Here, the function and the regulation of RASSF10, that contains a RA (Ras-association) and two coiled domains, was investigated. We utilized mass spectrometry and immuno-precipitation to identify interaction partners of RASSF10. Additionally, we analyzed the up- and downstream pathways of RASSF10 that are involved in its tumor suppressive function. We report that RASSF10 binds ASPP1 (Apoptosis-stimulating protein of p53) and ASPP2 through its coiled-coils. Induction of RASSF10 leads to increased protein levels of ASPP2 and acts negatively on cell cycle progression. Interestingly, we found that RASSF10 is a target of the EMT (epithelial mesenchymal transition) driver TGFβ (Transforming growth factor beta) and that negatively associated genes of RASSF10 are significantly over-represented in an EMT gene set collection. We observed a positive correlation of RASSF10 expression and E-cadherin that prevents EMT. Depletion of RASSF10 by CRISPR/Cas9 technology induces the ability of lung cancer cells to proliferate and to invade an extracellular matrix after TGFβ treatment. Additionally, knockdown of RASSF10 or ASPP2 induced constitutive phosphorylation of SMAD2 (Smad family member 2). Moreover, we found that epigenetic reduction of RASSF10 levels correlates with tumor progression and poor survival in human cancers. Our study indicates that RASSF10 acts a TGFβ target gene and negatively regulates cell growth and invasion through ASPP2. This data suggests that epigenetic loss of RASSF10 contributes to tumorigenesis by promoting EMT induced by TGFβ. Full article
(This article belongs to the Special Issue Targeting Ras/RASSF in Cancer)
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22 pages, 2943 KiB  
Article
Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial
by Fatéméh Dubois, Maureen Keller, Julien Hoflack, Elodie Maille, Martine Antoine, Virginie Westeel, Emmanuel Bergot, Elisabeth Quoix, Armelle Lavolé, Laurence Bigay-Game, Jean-Louis Pujol, Alexandra Langlais, Franck Morin, Gérard Zalcman and Guénaëlle Levallet
Cancers 2019, 11(12), 1835; https://doi.org/10.3390/cancers11121835 - 21 Nov 2019
Cited by 5 | Viewed by 3106
Abstract
RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 [...] Read more.
RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer. Full article
(This article belongs to the Special Issue Targeting Ras/RASSF in Cancer)
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Review

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22 pages, 1452 KiB  
Review
RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy
by Lucía García-Gutiérrez, Stephanie McKenna, Walter Kolch and David Matallanas
Cancers 2020, 12(1), 229; https://doi.org/10.3390/cancers12010229 - 17 Jan 2020
Cited by 33 | Viewed by 5292
Abstract
The RASSF1A tumour suppressor is a scaffold protein that is involved in cell signalling. Increasing evidence shows that this protein sits at the crossroad of a complex signalling network, which includes key regulators of cellular homeostasis, such as Ras, MST2/Hippo, p53, and death [...] Read more.
The RASSF1A tumour suppressor is a scaffold protein that is involved in cell signalling. Increasing evidence shows that this protein sits at the crossroad of a complex signalling network, which includes key regulators of cellular homeostasis, such as Ras, MST2/Hippo, p53, and death receptor pathways. The loss of expression of RASSF1A is one of the most common events in solid tumours and is usually caused by gene silencing through DNA methylation. Thus, re-expression of RASSF1A or therapeutic targeting of effector modules of its complex signalling network, is a promising avenue for treating several tumour types. Here, we review the main modules of the RASSF1A signalling network and the evidence for the effects of network deregulation in different cancer types. In particular, we summarise the epigenetic mechanism that mediates RASSF1A promoter methylation and the Hippo and RAF1 signalling modules. Finally, we discuss different strategies that are described for re-establishing RASSF1A function and how a multitargeting pathway approach selecting druggable nodes in this network could lead to new cancer treatments. Full article
(This article belongs to the Special Issue Targeting Ras/RASSF in Cancer)
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15 pages, 895 KiB  
Review
Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors
by Patrícia Dias Carvalho, Ana Luísa Machado, Flávia Martins, Raquel Seruca and Sérgia Velho
Cancers 2019, 11(12), 2010; https://doi.org/10.3390/cancers11122010 - 13 Dec 2019
Cited by 32 | Viewed by 4916
Abstract
Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´ aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor [...] Read more.
Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´ aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens. Full article
(This article belongs to the Special Issue Targeting Ras/RASSF in Cancer)
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