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Cells
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Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies
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Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies

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

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 41561

Special Issue Editor

Dr. Luis Costa

E-Mail Website
Guest Editor
Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
Interests: oncobiology; tumor microenvironment; bone metastases

Special Issue Information

Dear Colleagues,

We are delighted to invite you to contribute to a Special Issue in the journal Cells, entitled “Translational Oncology: From Molecular Mechanisms to Targeted Therapies.” In this Special Issue, we plan to demonstrate how science is close to patients in some of the most representative fields of oncology. Indeed, since the definition of the hallmarks of cancer by Douglas Hanahan and Robert Weinberg (Cell. 2011 Mar 4;144(5):646-74), a setting of discoveries confirmed how relevant they can be in the development of cancer treatments from bench to bedside. In this Special Issue, we intend to assemble contributions on translational medicine applied to cancer patients. Additionally, we will address the future contribution of computational biology and nanomedicine to oncology.

We are looking forward to your contributions to this Special Issue.

Dr. Luis Costa
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. 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

  • carcinogenesis
  • signal transduction
  • microenvironment
  • immuno-oncology
  • metabolomics
  • stem cells
  • liquid biopsy
  • nanomedicine
  • artificial intelligence

Published Papers (10 papers)

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Research

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24 pages, 11575 KiB  
Article
Kidney Cancer Biomarker Selection Using Regularized Survival Models
by Carolina Peixoto, Marta Martins, Luís Costa and Susana Vinga
Cells 2022, 11(15), 2311; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152311 - 27 Jul 2022
Cited by 1 | Viewed by 2440
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC showing a significant percentage of mortality. One of the priorities of kidney cancer research is to identify RCC-specific biomarkers for early detection and screening of the disease. With the development [...] Read more.
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC showing a significant percentage of mortality. One of the priorities of kidney cancer research is to identify RCC-specific biomarkers for early detection and screening of the disease. With the development of high-throughput technology, it is now possible to measure the expression levels of thousands of genes in parallel and assess the molecular profile of individual tumors. Studying the relationship between gene expression and survival outcome has been widely used to find genes associated with cancer survival, providing new information for clinical decision-making. One of the challenges of using transcriptomics data is their high dimensionality which can lead to instability in the selection of gene signatures. Here we identify potential prognostic biomarkers correlated to the survival outcome of ccRCC patients using two network-based regularizers (EN and TCox) applied to Cox models. Some genes always selected by each method were found (COPS7B, DONSON, GTF2E2, HAUS8, PRH2, and ZNF18) with known roles in cancer formation and progression. Afterward, different lists of genes ranked based on distinct metrics (logFC of DEGs or β coefficients of regression) were analyzed using GSEA to try to find over- or under-represented mechanisms and pathways. Some ontologies were found in common between the gene sets tested, such as nuclear division, microtubule and tubulin binding, and plasma membrane and chromosome regions. Additionally, genes that were more involved in these ontologies and genes selected by the regularizers were used to create a new gene set where we applied the Cox regression model. With this smaller gene set, we were able to significantly split patients into high/low risk groups showing the importance of studying these genes as potential prognostic factors to help clinicians better identify and monitor patients with ccRCC. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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13 pages, 2027 KiB  
Article
Src-Family Protein Kinase Inhibitors Suppress MYB Activity in a p300-Dependent Manner
by Abhiruchi Biyanee, Maria V. Yusenko and Karl-Heinz Klempnauer
Cells 2022, 11(7), 1162; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11071162 - 30 Mar 2022
Cited by 3 | Viewed by 2034
Abstract
Recent studies have disclosed transcription factor MYB as a potential drug target for malignancies that are dependent on deregulated MYB function, including acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often regarded as undruggable, successful targeting of MYB [...] Read more.
Recent studies have disclosed transcription factor MYB as a potential drug target for malignancies that are dependent on deregulated MYB function, including acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Although transcription factors are often regarded as undruggable, successful targeting of MYB by low-molecular-weight compounds has recently been demonstrated. In an attempt to repurpose known drugs as novel MYB-inhibitory agents, we have screened libraries of approved drugs and drug-like compounds for molecules with MYB-inhibitory potential. Here, we present initial evidence for the MYB-inhibitory activity of the protein kinase inhibitors bosutinib, PD180970 and PD161570, that we identified in a recent screen. We show that these compounds interfere with the activity of the MYB transactivation domain, apparently by disturbing the ability of MYB to cooperate with the coactivator p300. We show that treatment of the AML cell line HL60 with these compounds triggers the up-regulation of the myeloid differentiation marker CD11b and induces cell death. Importantly, we show that these effects are significantly dampened by forced expression of an activated version of MYB, confirming that the ability to suppress MYB function is a relevant activity of these compounds. Overall, our work identifies several protein kinase inhibitors as novel MYB-inhibitory agents and suggests that the inhibition of MYB function may play a role in their pharmacological impact on leukemic cells. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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17 pages, 7432 KiB  
Article
Discriminating Epithelial to Mesenchymal Transition Phenotypes in Circulating Tumor Cells Isolated from Advanced Gastrointestinal Cancer Patients
by Adriana Carneiro, Paulina Piairo, Alexandra Teixeira, Dylan Ferreira, Sofia Cotton, Carolina Rodrigues, Alexandre Chícharo, Sara Abalde-Cela, Lúcio Lara Santos, Luís Lima and Lorena Diéguez
Cells 2022, 11(3), 376; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030376 - 22 Jan 2022
Cited by 12 | Viewed by 3833
Abstract
Gastrointestinal (GI) cancers constitute a group of highest morbidity worldwide, with colorectal cancer (CRC) and gastric cancer being among the most frequently diagnosed. The majority of gastrointestinal cancer patients already present metastasis by the time of diagnosis, which is widely associated with cancer-related [...] Read more.
Gastrointestinal (GI) cancers constitute a group of highest morbidity worldwide, with colorectal cancer (CRC) and gastric cancer being among the most frequently diagnosed. The majority of gastrointestinal cancer patients already present metastasis by the time of diagnosis, which is widely associated with cancer-related death. Accumulating evidence suggests that epithelial-to-mesenchymal transition (EMT) in cancer promotes circulating tumor cell (CTCs) formation, which ultimately drives metastasis development. These cells have emerged as a fundamental tool for cancer diagnosis and monitoring, as they reflect tumor heterogeneity and the clonal evolution of cancer in real-time. In particular, EMT phenotypes are commonly associated with therapy resistance. Thus, capturing these CTCs is expected to reveal important clinical information. However, currently available CTC isolation approaches are suboptimal and are often targeted to capture epithelial CTCs, leading to the loss of EMT or mesenchymal CTCs. Here, we describe size-based CTCs isolation using the RUBYchip™, a label-free microfluidic device, aiming to detect EMT biomarkers in CTCs from whole blood samples of GI cancer patients. We found that, for most cases, the mesenchymal phenotype was predominant, and in fact a considerable fraction of isolated CTCs did not express epithelial markers. The RUBYchip™ can overcome the limitations of label-dependent technologies and improve the identification of CTC subpopulations that may be related to different clinical outcomes. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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12 pages, 4645 KiB  
Communication
Prognostic Significance of Dysregulated Epigenomic and Chromatin Modifiers in Cervical Cancer
by Aswathy Mary Paul, Madhavan Radhakrishna Pillai and Rakesh Kumar
Cells 2021, 10(10), 2665; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102665 - 05 Oct 2021
Cited by 4 | Viewed by 1791
Abstract
To broaden the understanding of the epigenomic and chromatin regulation of cervical cancer, we examined the status and significance of a set of epigenomic and chromatin modifiers in cervical cancer using computational biology. We observed that 61 of 917 epigenomic and/or chromatin regulators [...] Read more.
To broaden the understanding of the epigenomic and chromatin regulation of cervical cancer, we examined the status and significance of a set of epigenomic and chromatin modifiers in cervical cancer using computational biology. We observed that 61 of 917 epigenomic and/or chromatin regulators are differentially upregulated in human cancer, including 25 upregulated in invasive squamous cell carcinomas and 29 in cervical intraepithelial neoplasia 3 (CIN3), of which 14 are upregulated in cervical intraepithelial neoplasia 2 (CIN2). Interestingly, 57 of such regulators are uniquely upregulated in cervical cancer, but not ovarian and endometrial cancers. The observed overexpression of 57 regulators was found to have a prognostic significance in cervical cancer. The collective overexpression of these regulators, as well as its subsets belonging to specific histone modifications and corresponding top ten positively co-overexpressed genes, correlated with reduced survival of patients with high expressions of the tested overexpressed regulators compared to cases with low expressions. Using cell-dependency datasets from human cervical cancer cells, we found that 20 out of 57 epigenomic and chromatin regulators studied here appeared to be essential genes, as the depletion of these genes was accompanied by the loss in cellular viability. In brief, the results presented here provide further insights into the role of epigenomic and chromatin regulators in the oncobiology of cervical cancer and broaden the list of new potential molecules of therapeutic importance. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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19 pages, 8355 KiB  
Article
Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics
by Bijesh George, P. Mukundan Pillai, Aswathy Mary Paul, Revikumar Amjesh, Kim Leitzel, Suhail M. Ali, Oleta Sandiford, Allan Lipton, Pranela Rameshwar, Gabriel N. Hortobagyi, Madhavan Radhakrishna Pillai and Rakesh Kumar
Cells 2021, 10(2), 433; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020433 - 18 Feb 2021
Cited by 5 | Viewed by 3658
Abstract
To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out [...] Read more.
To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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Review

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18 pages, 2144 KiB  
Review
Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications
by Inês Conde, Ana Sofia Ribeiro and Joana Paredes
Cells 2022, 11(6), 934; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11060934 - 09 Mar 2022
Cited by 10 | Viewed by 4292
Abstract
Breast cancer is the most common malignancy affecting women worldwide. Importantly, there have been significant improvements in prevention, early diagnosis, and treatment options, which resulted in a significant decrease in breast cancer mortality rates. Nevertheless, the high rates of incidence combined with therapy [...] Read more.
Breast cancer is the most common malignancy affecting women worldwide. Importantly, there have been significant improvements in prevention, early diagnosis, and treatment options, which resulted in a significant decrease in breast cancer mortality rates. Nevertheless, the high rates of incidence combined with therapy resistance result in cancer relapse and metastasis, which still contributes to unacceptably high mortality of breast cancer patients. In this context, a small subpopulation of highly tumourigenic cancer cells within the tumour bulk, commonly designated as breast cancer stem cells (BCSCs), have been suggested as key elements in therapy resistance, which are responsible for breast cancer relapses and distant metastasis. Thus, improvements in BCSC-targeting therapies are crucial to tackling the metastatic progression and might allow therapy resistance to be overcome. However, the design of effective and specific BCSC-targeting therapies has been challenging since there is a lack of specific biomarkers for BCSCs, and the most common clinical approaches are designed for commonly altered BCSCs signalling pathways. Therefore, the search for a new class of BCSC biomarkers, such as the expression of membrane proteins with cancer stem cell potential, is an area of clinical relevance, once membrane proteins are accessible on the cell surface and easily recognized by specific antibodies. Here, we discuss the significance of BCSC membrane biomarkers as potential prognostic and therapeutic targets, reviewing the CSC-targeting therapies under clinical trials for breast cancer. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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35 pages, 2612 KiB  
Review
Bringing Macrophages to the Frontline against Cancer: Current Immunotherapies Targeting Macrophages
by Mariana Reis-Sobreiro, Afonso Teixeira da Mota, Carolina Jardim and Karine Serre
Cells 2021, 10(9), 2364; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092364 - 09 Sep 2021
Cited by 13 | Viewed by 8041
Abstract
Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly [...] Read more.
Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly detail the multi-functional, protumoral, and antitumoral roles of macrophages in the tumor microenvironment. Our objective is to focus on the ever-growing therapeutic opportunities, with promising preclinical and clinical results developed in recent years, to modulate the contribution of macrophages in oncologic diseases. While the majority of cancer immunotherapies target T cells, we believe that macrophages have a promising therapeutic potential as tumoricidal effectors and in mobilizing their surroundings towards antitumor immunity to efficiently limit cancer progression. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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26 pages, 1210 KiB  
Review
The Roadmap of RANKL/RANK Pathway in Cancer
by Sandra Casimiro, Guilherme Vilhais, Inês Gomes and Luis Costa
Cells 2021, 10(8), 1978; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081978 - 04 Aug 2021
Cited by 28 | Viewed by 6739
Abstract
The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including [...] Read more.
The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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23 pages, 1881 KiB  
Review
Sarcoma Metabolomics: Current Horizons and Future Perspectives
by Miguel Esperança-Martins, Isabel Fernandes, Joaquim Soares do Brito, Daniela Macedo, Hugo Vasques, Teresa Serafim, Luís Costa and Sérgio Dias
Cells 2021, 10(6), 1432; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061432 - 08 Jun 2021
Cited by 5 | Viewed by 3729
Abstract
The vast array of metabolic adaptations that cancer cells are capable of assuming, not only support their biosynthetic activity, but also fulfill their bioenergetic demands and keep their intracellular reduction–oxidation (redox) balance. Spotlight has recently been placed on the energy metabolism reprogramming strategies [...] Read more.
The vast array of metabolic adaptations that cancer cells are capable of assuming, not only support their biosynthetic activity, but also fulfill their bioenergetic demands and keep their intracellular reduction–oxidation (redox) balance. Spotlight has recently been placed on the energy metabolism reprogramming strategies employed by cancer cells to proliferate. Knowledge regarding soft tissue and bone sarcomas metabolome is relatively sparse. Further characterization of sarcoma metabolic landscape may pave the way for diagnostic refinement and new therapeutic target identification, with benefit to sarcoma patients. This review covers the state-of-the-art knowledge on cancer metabolomics and explores in detail the most recent evidence on soft tissue and bone sarcoma metabolomics. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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Other

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13 pages, 3135 KiB  
Brief Report
Establishment of Pancreatobiliary Cancer Zebrafish Avatars for Chemotherapy Screening
by Mariana Tavares Barroso, Bruna Costa, Cátia Rebelo de Almeida, Mireia Castillo Martin, Nuno Couto, Tânia Carvalho and Rita Fior
Cells 2021, 10(8), 2077; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082077 - 13 Aug 2021
Cited by 8 | Viewed by 3881
Abstract
Background: Cancers of the pancreas and biliary tree remain one of the most aggressive oncological malignancies, with most patients relying on systemic chemotherapy. However, effective biomarkers to predict the best therapy option for each patient are still lacking. In this context, an assay [...] Read more.
Background: Cancers of the pancreas and biliary tree remain one of the most aggressive oncological malignancies, with most patients relying on systemic chemotherapy. However, effective biomarkers to predict the best therapy option for each patient are still lacking. In this context, an assay able to evaluate individual responses prior to treatment would be of great value for clinical decisions. Here we aimed to develop such a model using zebrafish xenografts to directly challenge pancreatic cancer cells to the available chemotherapies. Methods: Zebrafish xenografts were generated from a Panc-1 cell line to optimize the pancreatic setting. Pancreatic surgical resected samples, without in vitro expansion, were used to establish zebrafish patient-derived xenografts (zAvatars). Upon chemotherapy exposure, zAvatars were analyzed by single-cell confocal microscopy. Results: We show that Panc-1 zebrafish xenografts are able to reveal tumor responses to both FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel in just 4 days. Moreover, we established pancreatic and ampullary zAvatars with patient-derived tumors representative of different histological types. Conclusion: Altogether, we provide a short report showing the feasibility of generating and analyzing with single-cell resolution zAvatars from pancreatic and ampullary cancers, with potential use for future preclinical studies and personalized treatment. Full article
(This article belongs to the Special Issue Translational Oncobiology: From Molecular Mechanisms to Targeted Therapies)
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