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Cancers
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The Signal-Processing in Tumor
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The Signal-Processing in Tumor

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 29627

Special Issue Editors

Dr. Nandini Dey

E-Mail Website
Guest Editor
Senior Scientist & Director, Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD, USA
Interests: personalized precision medicine; pathway targeted drugs; tumor cell signaling
Special Issues, Collections and Topics in MDPI journals
Dr. Pradip De

E-Mail Website
Guest Editor
1. Senior Scientist, Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD, USA
2. Consultant, VieCure, Greenwood Village, CO, USA
Interests: genomics-driven treatment approach in n-of-1 format; tailored immune-therapy; PI3K-mTOR pathway
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumors and their ecosystems co-evolve over time, leading to genomic alterations within tumor cells; thus, anti-tumor treatment must be adapted over the course of the disease. To better understand this process and its mechanisms: How does signal transduction in tumors cells shape the tumor ecosystem? Tumor cells send and receive bidirectional signals to and from adjacent tumor cells as well as the tumor microenvironment, endothelium, immune cells, and fibroblasts. Via this exchange of signals, tumor cells control their stromal milieu to sustain their growth, evolve, respond to drugs, and advance. Thus, signal transduction pathways play key roles in initiation, progression, and metastasis processes. These pathways, which control normal cell growth, are frequently disrupted and altered in cancer cells. Cells that have abnormal signaling molecules may become cancer cells. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. This leads to genetic changes, epigenetic alterations, mutations, chromosomal rearrangement, and protein overexpression/phosphorylation (post-translational modification with selectivity for cells with a high proliferative capacity, survival, invasion, and metastasis). It is now known that there is a variety of signal transduction methods and pathways in cells, which engage in multiple levels of cross-talk, constituting a very complicated network. The choreographic language of these signals is the fundamental basis of treatment approaches in cancer management.

Dr. Nandini Dey
Dr. Pradip De
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. 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.

Published Papers (6 papers)

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Research

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16 pages, 1582 KiB  
Article
Jun Dimerization Protein 2 (JDP2) Increases p53 Transactivation by Decreasing MDM2
by Kasey Price, William H. Yang, Leticia Cardoso, Chiung-Min Wang, Richard H. Yang and Wei-Hsiung Yang
Cancers 2024, 16(5), 1000; https://doi.org/10.3390/cancers16051000 - 29 Feb 2024
Viewed by 593
Abstract
The AP-1 protein complex primarily consists of several proteins from the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. JDP2 has been shown to interact with the cAMP response element (CRE) site present in many cis-elements of downstream target [...] Read more.
The AP-1 protein complex primarily consists of several proteins from the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. JDP2 has been shown to interact with the cAMP response element (CRE) site present in many cis-elements of downstream target genes. JDP2 has also demonstrates important roles in cell-cycle regulation, cancer development and progression, inhibition of adipocyte differentiation, and the regulation of antibacterial immunity and bone homeostasis. JDP2 and ATF3 exhibit significant similarity in their C-terminal domains, sharing 60–65% identities. Previous studies have demonstrated that ATF3 is able to influence both the transcriptional activity and p53 stability via a p53-ATF3 interaction. While some studies have shown that JDP2 suppresses p53 transcriptional activity and in turn, p53 represses JDP2 promoter activity, the direct interaction between JDP2 and p53 and the regulatory role of JDP2 in p53 transactivation have not been explored. In the current study, we provide evidence, for the first time, that JDP2 interacts with p53 and regulates p53 transactivation. First, we demonstrated that JDP2 binds to p53 and the C-terminal domain of JDP2 is crucial for the interaction. Second, in p53-null H1299 cells, JDP2 shows a robust increase of p53 transactivation in the presence of p53 using p53 (14X)RE-Luc. Furthermore, JDP2 and ATF3 together additively enhance p53 transactivation in the presence of p53. While JDP2 can increase p53 transactivation in the presence of WT p53, JDP2 fails to enhance transactivation of hotspot mutant p53. Moreover, in CHX chase experiments, we showed that JDP2 slightly enhances p53 stability. Finally, our findings indicate that JDP2 has the ability to reverse MDM2-induced p53 repression, likely due to decreased levels of MDM2 by JDP2. In summary, our results provide evidence that JDP2 directly interacts with p53 and decreases MDM2 levels to enhance p53 transactivation, suggesting that JDP2 is a novel regulator of p53 and MDM2. Full article
(This article belongs to the Special Issue The Signal-Processing in Tumor)
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20 pages, 8783 KiB  
Article
CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged Sarcomas
by Arnaud Bakaric, Luisa Cironi, Viviane Praz, Rajendran Sanalkumar, Liliane C. Broye, Kerria Favre-Bulle, Igor Letovanec, Antonia Digklia, Raffaele Renella, Ivan Stamenkovic, Christopher J. Ott, Takuro Nakamura, Cristina R. Antonescu, Miguel N. Rivera and Nicolò Riggi
Cancers 2024, 16(2), 457; https://doi.org/10.3390/cancers16020457 - 21 Jan 2024
Viewed by 1229
Abstract
CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding [...] Read more.
CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here, we generated a genome-wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild-type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation; additionally, we find its pharmacological inhibition to significantly impact tumor growth in vitro and in vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation. Full article
(This article belongs to the Special Issue The Signal-Processing in Tumor)
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13 pages, 2390 KiB  
Article
HuR (ELAVL1) Stabilizes SOX9 mRNA and Promotes Migration and Invasion in Breast Cancer Cells
by Jesús Morillo-Bernal, Patricia Pizarro-García, Gema Moreno-Bueno, Amparo Cano, María J. Mazón, Pilar Eraso and Francisco Portillo
Cancers 2024, 16(2), 384; https://doi.org/10.3390/cancers16020384 - 16 Jan 2024
Viewed by 937
Abstract
RNA-binding proteins play diverse roles in cancer, influencing various facets of the disease, including proliferation, apoptosis, angiogenesis, senescence, invasion, epithelial–mesenchymal transition (EMT), and metastasis. HuR, a known RBP, is recognized for stabilizing mRNAs containing AU-rich elements (AREs), although its complete repertoire of mRNA [...] Read more.
RNA-binding proteins play diverse roles in cancer, influencing various facets of the disease, including proliferation, apoptosis, angiogenesis, senescence, invasion, epithelial–mesenchymal transition (EMT), and metastasis. HuR, a known RBP, is recognized for stabilizing mRNAs containing AU-rich elements (AREs), although its complete repertoire of mRNA targets remains undefined. Through a bioinformatics analysis of the gene expression profile of the Hs578T basal-like triple-negative breast cancer cell line with silenced HuR, we have identified SOX9 as a potential HuR-regulated target. SOX9 is a transcription factor involved in promoting EMT, metastasis, survival, and the maintenance of cancer stem cells (CSCs) in triple-negative breast cancer. Ribonucleoprotein immunoprecipitation assays confirm a direct interaction between HuR and SOX9 mRNA. The half-life of SOX9 mRNA and the levels of SOX9 protein decreased in cells lacking HuR. Cells silenced for HuR exhibit reduced migration and invasion compared to control cells, a phenotype similar to that described for SOX9-silenced cells. Full article
(This article belongs to the Special Issue The Signal-Processing in Tumor)
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12 pages, 19571 KiB  
Article
Potential Tumor Suppressor Role of Polo-like Kinase 5 in Cancer
by Shengqin Su, Mary Ann Ndiaye, Glorimar Guzmán-Pérez, Rebecca Michael Baus, Wei Huang, Manish Suresh Patankar and Nihal Ahmad
Cancers 2023, 15(22), 5457; https://doi.org/10.3390/cancers15225457 - 17 Nov 2023
Viewed by 913
Abstract
The polo-like kinase (PLK) family of serine/threonine kinases contains five members (PLK1–5). Most PLKs are involved in cell cycle regulation and DNA damage response. However, PLK5 is different as it lacks a functional kinase domain and is not involved in cell cycle control. [...] Read more.
The polo-like kinase (PLK) family of serine/threonine kinases contains five members (PLK1–5). Most PLKs are involved in cell cycle regulation and DNA damage response. However, PLK5 is different as it lacks a functional kinase domain and is not involved in cell cycle control. PLK5 remains the least-studied family member, and its role in oncogenesis remains enigmatic. Here, we identified tissues with high PLK5 expression by leveraging the Protein Atlas and GTEx databases with relevant literature and selected ovarian, lung, testis, endometrium, cervix, and fallopian tube tissues as candidates for further investigation. Subsequently, we performed immunohistochemical staining for PLK5 on multiple tissue microarrays followed by Vectra scanning and quantitative inForm analysis. This revealed consistently downregulated PLK5 expression in these cancers compared to normal tissues. To validate and extend our findings, we performed pan-cancer analysis of PLK5 expression using public RNAseq databases (TCGA and GTEx). We found PLK5 is downregulated in 18 cancer types, including our selected candidates. Interestingly, we also observed PLK5 expression remains consistently low in later stages of cancer, suggesting PLK5 may have a greater role in tumor initiation than cancer progression. Overall, our study demonstrates PLK5 downregulation in multiple cancers, highlighting its role as a tumor suppressor. Full article
(This article belongs to the Special Issue The Signal-Processing in Tumor)
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17 pages, 37764 KiB  
Article
Ceramide Synthase 1 Inhibits Brain Metastasis of Non-Small Cell Lung Cancer by Interacting with USP14 and Downregulating the PI3K/AKT/mTOR Signaling Pathway
by Yiquan Xu, Junfan Pan, Ying Lin, Yun Wu, Yusheng Chen and Hongru Li
Cancers 2023, 15(7), 1994; https://doi.org/10.3390/cancers15071994 - 27 Mar 2023
Cited by 4 | Viewed by 1723
Abstract
Brain metastasis (BM) is common in patients with non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Ceramide synthase 1 (CERS1) participates in malignancy development, but its potential role in NSCLC BM remains unclear. This study aimed to explore the [...] Read more.
Brain metastasis (BM) is common in patients with non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Ceramide synthase 1 (CERS1) participates in malignancy development, but its potential role in NSCLC BM remains unclear. This study aimed to explore the physiological effects and molecular mechanism of CERS1 in NSCLC BM. CERS1 expression was evaluated in NSCLC tissues and cell lines, and its physiological roles were subsequently explored in vivo and in vitro. Mass spectrometry and co-immunoprecipitation were performed to explore CERS1-interacting proteins. The associated signaling pathways of CERS1 in NSCLC BM were further investigated using bioinformatics analysis and molecular biotechnology. We demonstrated that CERS1 was significantly downregulated in NSCLC cell lines and BM tissues, and its upregulation was associated with better prognoses. In vitro, CERS1 overexpression inhibited cell migration, invasion, and the ability to penetrate the blood-brain barrier. Moreover, CERS1 interacted with ubiquitin-specific protease 14 (USP14) and inhibited BM progression by downregulating the PI3K/AKT/mTOR signaling pathway. Further, CERS1 expression substantially suppressed BM tumor formation in vivo. This study demonstrated that CERS1 plays a suppressor role in NSCLC BM by interacting with USP14 and downregulating the PI3K/AKT/mTOR signaling pathway, thereby serving as a novel therapeutic target for NSCLC BM. Full article
(This article belongs to the Special Issue The Signal-Processing in Tumor)
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Review

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23 pages, 811 KiB  
Review
Evolution of the Targeted Therapy Landscape for Cholangiocarcinoma: Is Cholangiocarcinoma the ‘NSCLC’ of GI Oncology?
by Amol Gupta, Razelle Kurzrock and Jacob J. Adashek
Cancers 2023, 15(5), 1578; https://doi.org/10.3390/cancers15051578 - 03 Mar 2023
Cited by 8 | Viewed by 23670
Abstract
In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their [...] Read more.
In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their genomic aberrations are now recognized; remarkably, taken together, almost 70% of NSCLCs now have a druggable anomaly. Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis. Novel molecular alterations have been recently identified in patients with CCA, and the potential for targeted therapy is being realized. In 2019, a fibroblast growth factor receptor 2 (FGFR2) inhibitor, pemigatinib, was the first approved targeted therapy for patients with locally advanced or metastatic intrahepatic CCA who had FGFR2 gene fusions or rearrangement. More regulatory approvals for matched targeted therapies as second-line or subsequent treatments in advanced CCA followed, including additional drugs that target FGFR2 gene fusion/rearrangement. Recent tumor-agnostic approvals include (but are not limited to) drugs that target mutations/rearrangements in the following genes and are hence applicable to CCA: isocitrate dehydrogenase 1 (IDH1); neurotrophic tropomyosin-receptor kinase (NTRK); the V600E mutation of the BRAF gene (BRAFV600E); and high tumor mutational burden, high microsatellite instability, and gene mismatch repair-deficient (TMB-H/MSI-H/dMMR) tumors. Ongoing trials investigate HER2, RET, and non-BRAFV600E mutations in CCA and improvements in the efficacy and safety of new targeted treatments. This review aims to present the current status of molecularly matched targeted therapy for advanced CCA. Full article
(This article belongs to the Special Issue The Signal-Processing in Tumor)
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