Submit to Cells Review for Cells Propose a Special Issue

Journal Browser

► Journal Browser

Role of KRAS Mutations in Colorectal Cancer

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 34280

Share This Special Issue

Special Issue Editors

Dr. Ana Preto

E-Mail Website
Guest Editor

CBMA (Centre of Molecular and Environmental Biology), Department of Biology, Universidade do Minho, Braga, Portugal
Interests: KRAS signaling pathway; autophagy; colorectal cancer (CRC); yeast model; molecular target
Special Issues, Collections and Topics in MDPI journals

Dr. Sérgia Velho

E-Mail Website
Assistant Guest Editor

i3S/ IPATIMUP, Rua Alfredo Allen, 4200-135 Porto, Portugal
Interests: oncogenic signaling; colorectal cancer; anti-tumor compounds or drugs

Prof. Dr. Maria José Oliveira

E-Mail Website
Assistant Guest Editor

1. i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
2. INEB–Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
3. Departament of Pathology, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
Interests: tumor microenvironment; tumor immunology; colorectal cancer; radiotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is a leading cause of mortality in Europe, and its global therapeutics market is worth billions of Euros. KRAS-activating mutations (KRAS^m): KRAS^G13D, KRAS^G12D and KRAS^G12V are among the most frequent events found in CRC. Metastatic CRC harboring KRAS mutations are generally resistant to chemotherapy, namely to epidermal growth factor receptor (EGFR) inhibitors. This is a relevant clinical problem that urges a resolution. Despite the billions of dollars spent by pharmaceutical companies, so far, inhibition of mutated RAS has not been achieved.

The study of the role of KRAS mutations on colon carcinogenesis, tumor microenvironment, cell survival, autophagy, glycolytic metabolism and invasion/metastization potential is an ever-growing field. A precise understanding of the mechanisms underlying KRAS in colorectal carcinogenesis might help in identifying new molecular targets to overcome the resistance in CRC harboring KRAS mutations.

This Special Issue aims to highlight the most recent advances on the role of KRAS mutations on colorectal carcinogenesis using different cellular models and on their possible therapeutic applications.

We look forward to your contributions.

Dr. Ana Preto
Dr. Sérgia Velho
Dr. Maria José Oliveira
Guest Editors

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. Cells 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 2700 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

KRAS mutations
colorectal cancer
autophagy
tumor microenvironment
invasion/ metastasis
glycolytic metabolism
cell models
therapeutic approaches

Published Papers (9 papers)

Download All Papers

Research

Jump to: Review

18 pages, 2581 KiB

Open AccessArticle

Evaluation of RAS Mutational Status in Liquid Biopsy to Monitor Disease Progression in Metastatic Colorectal Cancer Patients

by Elena Lastraioli, Alessandra Bettiol, Jessica Iorio, Elvira Limatola, Daniele Checcacci, Erica Parisi, Cristina Bianchi, Annarosa Arcangeli, Mauro Iannopollo, Francesco Di Costanzo and Marco Di Lieto

Cells 2023, 12(11), 1458; https://doi.org/10.3390/cells12111458 - 24 May 2023

Viewed by 1354

Abstract

In this study we evaluated both~ K- and N-RAS mutations in plasma samples from patients with metastatic colorectal cancer by means of the BEAMing technology, and we assessed their diagnostic performance compared to RAS analyses performed on tissue. The sensitivity of BEAMing in identifying KRAS mutations was of 89.5%, with a fair specificity. The agreement with tissue analysis was moderate. The sensitivity for NRAS was high with a good specificity, and the agreement between tissue analysis and BEAMing was fair. Interestingly, significantly higher mutant allele fraction (MAF) levels were detected in patients with G2 tumors, liver metastases, and in those who did not receive surgery. NRAS MAF level was significantly higher in patients with mucinous adenocarcinoma and for those with lung metastases. A sharp increase in the MAF values was observed in patients who moved towards disease progression. More strikingly, molecular progression always anticipated the radiological one in these patients. These observations pave the way to the possibility of using liquid biopsy to monitor patients during treatment, and to enable oncologists to anticipate interventions compared to radiological analyses. This will allow time to be saved and ensure a better management of metastatic patients in the near future. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Graphical abstract

16 pages, 3018 KiB

Open AccessArticle

Mutant KRAS-Associated Proteome Is Mainly Controlled by Exogenous Factors

by Patrícia Dias Carvalho, Flávia Martins, Joana Carvalho, Maria José Oliveira and Sérgia Velho

Cells 2022, 11(13), 1988; https://doi.org/10.3390/cells11131988 - 21 Jun 2022

Cited by 1 | Viewed by 2033

Abstract

Understanding how mutant KRAS signaling is modulated by exogenous stimuli is of utmost importance to elucidate resistance mechanisms underlying pathway inhibition failure, and to uncover novel therapeutic targets for mutant KRAS patients. Hence, aiming at perceiving KRAS-autonomous versus -non autonomous mechanisms, we studied the response of two mutant KRAS colorectal cancer cell lines (HCT116 and LS174T) upon KRAS silencing and treatment with rhTGFβ1-activated fibroblasts secretome. A proteomic analysis revealed that rhTGFβ1-activated fibroblast-secreted factors triggered cell line-specific proteome alterations and that mutant KRAS governs 43% and 38% of these alterations in HCT116 and LS174T cells, respectively. These KRAS-dependent proteins were localized and displayed molecular functions that were common to both cell lines (e.g., extracellular exosome, RNA binding functions). Moreover, 67% and 78% of the KRAS-associated proteome of HCT116 and LS174T cells, respectively, was controlled in a KRAS-non-autonomous manner, being dependent on fibroblast-secreted factors. In HCT116 cells, KRAS-non-autonomously controlled proteins were mainly involved in proteoglycans in cancer, p53, and Rap1 signaling pathways; whereas in LS174T cells, they were associated with substrate adhesion-dependent cell-spreading and involved in metabolic processes. This work highlights the context-dependency of KRAS-associated signaling and reinforces the importance of integrating the tumor microenvironment in the study of KRAS-associated effects. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Figure 1

13 pages, 1278 KiB

Open AccessArticle

Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS

by Emil Lou, Joanne Xiu, Yasmine Baca, Andrew C. Nelson, Benjamin A. Weinberg, Muhammad Shaalan Beg, Mohamed E. Salem, Heinz-Josef Lenz, Philip Philip, Wafik S. El-Deiry and W. Michael Korn

Cells 2021, 10(6), 1275; https://doi.org/10.3390/cells10061275 - 21 May 2021

Cited by 4 | Viewed by 3179

Abstract

The molecular heterogeneity of KRAS is well established, with a pool of variants comprising >75% of all known mutations; this pool includes mutations in classic codons 12, 13, and 61, as well as 146 and 117. In addition, there are rare variants that are more frequently encountered clinically due to the advances in next-generation sequencing and more widespread implementation of All-RAS sequencing over the past five years. We have previously identified a missense variant of KRAS, A59T, in a patient with CRC that was associated with a response to an epidermal growth factor inhibitor when added to chemotherapy, supporting the hypothesis that distinct biochemical impacts of different KRAS mutations may produce varied responses to targeted therapy. In this study, we explored a large genomic database comprising 17,909 cases of CRC to determine the prevalence of the A59T mutation and characterized the concurrent genomic alterations associated with this variant in more detail, particularly in relation to the expanding set of potential predictive immuno-oncologic biomarkers. We identified 14 cases of A59 mutations in this dataset (0.08% prevalence). We evaluated the prevalence of high tumor mutation burden (TMB), positive PD-L1 expression, and microsatellite instability-high/mismatch repair-deficiency (MSI-H/dMMR) using both next generation sequencing (NGS) and immunohistochemistry (IHC). The genomic features of pertinent signaling pathways were also described, including RAS pathway, chromatin remodeling, DDR, hedgehog signaling, PI3K, receptor tyrosine kinases, signal transduction, TGF-beta, TP53, and WNT. We uncovered a high level of association of predictive markers of responsiveness to checkpoint inhibition and potentially other forms of immunotherapy, with nearly half of all cases harboring microsatellite instability as assessed using NGS. A59T was also detected in 11 additional cancer types, most prominently in cases of gynecologic or other gastrointestinal sites of origin. This study provides supportive evidence that A59T, and possibly other similarly rare KRAS variants, co-occur with predictive biomarkers of response to immunotherapy. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Figure 1

18 pages, 6191 KiB

Open AccessArticle

NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer

by Tung-Yung Huang, Tung-Cheng Chang, Yu-Tang Chin, Yi-Shin Pan, Wong-Jin Chang, Feng-Cheng Liu, Ema Dwi Hastuti, Shih-Jiuan Chiu, Shwu-Huey Wang, Chun A. Changou, Zi-Lin Li, Yi-Ru Chen, Hung-Ru Chu, Ya-Jung Shih, R. Holland Cheng, Alexander Wu, Hung-Yun Lin, Kuan Wang, Jacqueline Whang-Peng, Shaker A Mousa and Paul J. Davis Show full author list Hide full author list

Cells 2020, 9(8), 1830; https://doi.org/10.3390/cells9081830 - 3 Aug 2020

Cited by 20 | Viewed by 4000

Abstract

The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn’t inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Figure 1

15 pages, 888 KiB

Open AccessArticle

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

by Nuria Garcia-Carbonero, Javier Martinez-Useros, Weiyao Li, Alberto Orta, Nuria Perez, Cristina Carames, Tatiana Hernandez, Irene Moreno, Gloria Serrano and Jesus Garcia-Foncillas

Cells 2020, 9(1), 219; https://doi.org/10.3390/cells9010219 - 15 Jan 2020

Cited by 43 | Viewed by 4988

Abstract

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Figure 1

14 pages, 2168 KiB

Open AccessArticle

Microarray Approach Combined with ddPCR: An Useful Pipeline for the Detection and Quantification of Circulating Tumour DNA Mutations

by Silvia Galbiati, Francesco Damin, Lucia Ferraro, Nadia Soriani, Valentina Burgio, Monica Ronzoni, Luca Gianni, Maurizio Ferrari and Marcella Chiari

Cells 2019, 8(8), 769; https://doi.org/10.3390/cells8080769 - 24 Jul 2019

Cited by 10 | Viewed by 4140

Abstract

It has now been established that in biological fluids such as blood, it is possible to detect cancer causing genomic alterations by analysing circulating tumour DNA (ctDNA). Information derived from ctDNA offers a unique opportunity to enrich our understanding of cancer biology, tumour evolution and therapeutic efficacy and resistance. Here, we propose a workflow to identify targeted mutations by a customized microarray-based assay for the simultaneous detection of single point mutations in different oncogenes (KRAS, NRAS and BRAF) followed by droplet digital PCR (ddPCR) to determine the fractional abundance of the mutated allele. Genetic variants were determined in the plasma of 20 metastatic colorectal cancer (mCRC) patients previously genotyped on tissue biopsy at the diagnosis for medication planning (T0) and following the tumour genetic evolution during treatment phase (T1 and T2) with the objective of allowing therapy response prediction and monitoring. Our preliminary results show that this combined approach is suitable for routine clinical practice. The microarray platform enables for a rapid, specific and sensitive detection of the most common mutations suitable for high-throughput analysis without costly instrumentation while, the ddPCR, consents an absolute quantification of the mutated allele in a longitudinal observational study on patients undergoing targeted therapy. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Figure 1

Review

Jump to: Research

23 pages, 4069 KiB

Open AccessReview

Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications

by Anabela Ferreira, Flávia Pereira, Celso Reis, Maria José Oliveira, Maria João Sousa and Ana Preto

Cells 2022, 11(14), 2183; https://doi.org/10.3390/cells11142183 - 13 Jul 2022

Cited by 17 | Viewed by 3885

Abstract

KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Graphical abstract

15 pages, 4148 KiB

Open AccessFeature PaperReview

KRAS as a Modulator of the Inflammatory Tumor Microenvironment: Therapeutic Implications

by Flávia Pereira, Anabela Ferreira, Celso Albuquerque Reis, Maria João Sousa, Maria José Oliveira and Ana Preto

Cells 2022, 11(3), 398; https://doi.org/10.3390/cells11030398 - 24 Jan 2022

Cited by 22 | Viewed by 4918

Abstract

KRAS mutations are one of the most frequent oncogenic mutations of all human cancers, being more prevalent in pancreatic, colorectal, and lung cancers. Intensive efforts have been encouraged in order to understand the effect of KRAS mutations, not only on tumor cells but also on the dynamic network composed by the tumor microenvironment (TME). The relevance of the TME in cancer biology has been increasing due to its impact on the modulation of cancer cell activities, which can dictate the success of tumor progression. Here, we aimed to clarify the pro- and anti-inflammatory role of KRAS mutations over the TME, detailing the context and the signaling pathways involved. In this review, we expect to open new avenues for investigating the potential of KRAS mutations on inflammatory TME modulation, opening a different vision of therapeutic combined approaches to overcome KRAS-associated therapy inefficacy and resistance in cancer. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Graphical abstract

20 pages, 2447 KiB

Open AccessReview

Recent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology

by Loretta László, Anita Kurilla, Tamás Takács, Gyöngyi Kudlik, Kitti Koprivanacz, László Buday and Virag Vas

Cells 2021, 10(3), 667; https://doi.org/10.3390/cells10030667 - 17 Mar 2021

Cited by 24 | Viewed by 4404

Abstract

The most commonly mutated isoform of RAS among all cancer subtypes is KRAS. In this review, we focus on the special role of KRAS mutations in colorectal cancer (CRC), aiming to collect recent data on KRAS-driven enhanced cell signalling, in vitro and in vivo research models, and CRC development-related processes such as metastasis and cancer stem cell formation. We attempt to cover the diverse nature of the effects of KRAS mutations on age-related CRC development. As the incidence of CRC is rising in young adults, we have reviewed the driving forces of ageing-dependent CRC. Full article

(This article belongs to the Special Issue Role of KRAS Mutations in Colorectal Cancer)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Role of KRAS Mutations in Colorectal Cancer

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI