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Cancers
Special Issues
Cellular Plasticity: Tumorigenesis and Therapy
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Cellular Plasticity: Tumorigenesis and Therapy

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

Deadline for manuscript submissions: 1 July 2024 | Viewed by 5558

Special Issue Editors

Dr. Claudia Peitzsch

E-Mail Website
Guest Editor
Center for Regenerative Therapies Dresden (CRTD), 01307 Dresden, Germany
Interests: cancer stem cells; circulating tumor cells; radioresistance; immune profiling
Dr. Ina Kurth

E-Mail Website
Guest Editor
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Interests: radioresistance mechanisms; cancer stem cells; spatial omics; tumor microenvironment

Special Issue Information

Dear Colleagues,

Complex tumors contain cancer cells with phenotypical and functional heterogeneity. Although genomic alterations usually initiate the process of malignant transformation within the cell of origin, specific cellular properties are rather determined on the transcriptional, proteomic, metabolic, and epigenomic level. This enables cells to change their phenotypes rapidly and permits functional adaptations to therapeutical pressure and environmental cues. In particular, metabolic and epigenetic plasticity are additionally key hallmarks of cancer that determine specific cellular states. Simultaneously, the process of stable clonal selection occurs and transforms heterogeneous tumors into a therapy-resistant, fast-progressing, and metastatic stage. Our current knowledge regarding molecular principles and cellular traits during these processes is rather limited.

Hence, this Special Issue collects papers on the therapeutic balance of anticancer therapies such as surgery, radiotherapy, and targeted therapies between tumor cell killing and induction of drug-resistant, persisting tumor cells.

Dr. Claudia Peitzsch
Dr. Ina Kurth
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.

Keywords

  • cell-of-origin
  • cellular plasticity
  • clonal evolution
  • cellular states
  • metastatic cascade
  • therapy resistance

Published Papers (3 papers)

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Research

21 pages, 3981 KiB  
Article
Epigenetic Targeting to Overcome Radioresistance in Head and Neck Cancer
by Iñaki Schniewind, Maria José Besso, Sebastian Klicker, Franziska Maria Schwarz, Wahyu Wijaya Hadiwikarta, Susan Richter, Steffen Löck, Annett Linge, Mechthild Krause, Anna Dubrovska, Michael Baumann, Ina Kurth and Claudia Peitzsch
Cancers 2024, 16(4), 730; https://doi.org/10.3390/cancers16040730 - 09 Feb 2024
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Abstract
(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may [...] Read more.
(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy. Full article
(This article belongs to the Special Issue Cellular Plasticity: Tumorigenesis and Therapy)
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25 pages, 14556 KiB  
Article
The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence
by Silvia Barbosa, Natalia Koerich Laureano, Wahyu Wijaya Hadiwikarta, Fernanda Visioli, Mahnaz Bonrouhi, Kinga Pajdzik, Cristina Conde-Lopez, Christel Herold-Mende, Gustavo Eidt, Renan Langie, Marcelo Lazzaron Lamers, Fabian Stögbauer, Jochen Hess, Ina Kurth and Adriana Jou
Cancers 2024, 16(2), 439; https://doi.org/10.3390/cancers16020439 - 19 Jan 2024
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Abstract
Head and neck squamous cell carcinoma (HNSCC) exhibits considerable variability in patient outcome. It has been reported that SOX2 plays a role in proliferation, tumor growth, drug resistance, and metastasis in a variety of cancer types. Additionally, SOX9 has been implicated in immune [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) exhibits considerable variability in patient outcome. It has been reported that SOX2 plays a role in proliferation, tumor growth, drug resistance, and metastasis in a variety of cancer types. Additionally, SOX9 has been implicated in immune tolerance and treatment failures. SOX2 and SOX9 induce treatment failure by a molecular mechanism that has not yet been elucidated. This study explores the inverse association of SOX2/SOX9 and their distinct expression in tumors, influencing the tumor microenvironment and radiotherapy responses. Through public RNA sequencing data, human biopsy samples, and knockdown cellular models, we explored the effects of inverted SOX2 and SOX9 expression. We found that patients expressing SOX2LowSOX9High showed decreased survival compared to SOX2HighSOX9Low. A survival analysis of patients stratified by radiotherapy and human papillomavirus brings additional clinical relevance. We identified a gene set signature comprising newly discovered candidate genes resulting from inverted SOX2/SOX9 expression. Moreover, the TGF-β pathway emerges as a significant predicted contributor to the overexpression of these candidate genes. In vitro findings reveal that silencing SOX2 enhances tumor radioresistance, while SOX9 silencing enhances radiosensitivity. These discoveries lay the groundwork for further studies on the therapeutic potential of transcription factors in optimizing HNSCC treatment. Full article
(This article belongs to the Special Issue Cellular Plasticity: Tumorigenesis and Therapy)
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16 pages, 3131 KiB  
Article
Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms
by Kristin Pape, Anna J. Lößner, Doreen William, Tabea Czempiel, Elke Beyreuther, Anna Klimova, Claudia Lehmann, Tim Schmäche, Sebastian R. Merker, Max Naumann, Anne-Marlen Ada, Franziska Baenke, Therese Seidlitz, Rebecca Bütof, Antje Dietrich, Mechthild Krause, Jürgen Weitz, Barbara Klink, Cläre von Neubeck and Daniel E. Stange
Cancers 2022, 14(20), 4984; https://doi.org/10.3390/cancers14204984 - 11 Oct 2022
Viewed by 2301
Abstract
Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, [...] Read more.
Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient’s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients. Full article
(This article belongs to the Special Issue Cellular Plasticity: Tumorigenesis and Therapy)
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