Alba López‐Rodríguez

Universidad de Granada

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Germaine Escames

Universidad de Granada

Laura Martinez‐Ruiz

Instituto de Investigación Biosanitaria de Granada

Javier Florido

Hospital de Galdakao

Holger Sudhoff

Klinikum Bielefeld

Felix Oppel

Klinikum Bielefeld

Darío Acuña‐Castroviejo

Universidad de Granada

César Rodríguez-Santana

Universidad de Granada

Tobias Busche

Bielefeld University

Harkiren Pabla

Klinikum Bielefeld

Sarah Gendreizig

Klinikum Bielefeld

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Universidad de Granada

Bielefeld University

Instituto de Investigación Biosanitaria de Granada

Klinikum Bielefeld

Parque Tecnológico de la Salud

Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable

Instituto de Salud Carlos III

Spanish Ovarian Cancer Research Group

Complexo Hospitalario Universitario A Coruña

Hospital Son Llatzer

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Abstract 5818: Differentiation of human papillomavirus-positive head and neck squamous cell carcinoma cells

Cancer Research (2024)

Sarah Gendreizig Laura Martinez‐Ruiz Javier Florido Alba López‐Rodríguez Harkiren Pabla

Abstract Head and neck squamous cell carcinoma (HNSCC) represents a highly malignant disease and death rates remain at approximately 50% for decades. Thus, new tumor-targeting treatment strategies are desperately needed. In a previous study, we dissected human papillomavirus (HPV)-negative HNSCC cell differentiation via cornification and detected an epigenetically determined loss of cell malignancy. Analyzing the mechanisms underlying the differentiation of HNSCC cells may identify targets for anti-tumor therapy. Using patient-derived tumor cells, we created an HNSCC differentiation model in HPV+ tumor cells. Similar to HPV- cells, we observed a loss of malignant characteristics in HPV+ cell cultures in differentiating cell culture conditions including irregular enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. Even though cornification was detected in HPV+ tumor cell cultures and HPV+ FFPE tumor tissue sections, cornification was not induced during HPV+ cell differentiation. Instead, RNA-seq and subsequent Gene Ontology analysis showed myocyte-like differentiation with upregulation of markers of myofibril assembly including TPM1, TAGLN, and ACTA1. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers, reminiscent of myoblast-lineage cells. Moreover, multi-marker immunofluorescence analysis of HPV+ tumor tissue sections revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like differentiation observed in vitro also occurred in human tissue. Normal tissue displayed a co-expression of TPM1, TAGLN, and ACTA1 in differentiating keratinocytes between the basal cell layer and the fully differentiated corneocytes. This shows that the expression of myocyte-lineage markers is reflected in differentiating non-malignant mucosal tissue. Our study suggests that the targeted differentiation of tumor cells might be therapeutically valuable in HPV+ HNSCCs as well. Citation Format: Sarah Gendreizig, Laura Martinez-Ruiz, Javier Florido, Alba López-Rodríguez, Harkiren Pabla, Frank Brasch, Germaine Escames, Tobias Busche, Holger Sudhoff, Lars U. Scholtz, Ingo Todt, Felix Oppel. Differentiation of human papillomavirus-positive head and neck squamous cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5818.

10.1158/1538-7445.am2024-5818

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Patient-derived tumor models in cancer research: Evaluation of the oncostatic effects of melatonin

Biomedicine & Pharmacotherapy (2023)

Laura Martinez‐Ruiz Alba López‐Rodríguez Javier Florido César Rodríguez-Santana José M. Rodríguez Ferrer

The development of new anticancer therapies tends to be very slow. Although their impact on potential candidates is confirmed in preclinical studies, ∼95 % of these new therapies are not approved when tested in clinical trials. One of the main reasons for this is the lack of accurate preclinical models. In this context, there are different patient-derived models, which have emerged as a powerful oncological tool: patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and patient-derived cells (PDCs). Although all these models are widely applied, PDXs, which are created by engraftment of patient tumor tissues into mice, is considered more reliable. In fundamental research, the PDX model is used to evaluate drug-sensitive markers and, in clinical practice, to select a personalized therapeutic strategy. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. However, the literature regarding the oncostatic effect of melatonin in patient-derived tumor models is scant. This review aims to describe the important role of patient-derived models in the development of anticancer treatments, focusing, in particular, on PDX models, as well as their use in cancer research. This review also summarizes the existing literature on the anti-tumoral effect of melatonin in patient-derived models in order to propose future anti-neoplastic clinical applications.

Drug Development

10.1016/j.biopha.2023.115581

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Human papillomavirus-associated head and neck squamous cell carcinoma cells lose viability during triggered myocyte lineage differentiation

Cell Death and Disease (2024)

Sarah Gendreizig Laura Martinez‐Ruiz Alba López‐Rodríguez Harkiren Pabla Leonie Hose

Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, and death rates have remained at approximately 50% for decades. New tumor-targeting strategies are desperately needed, and a previous report indicated the triggered differentiation of HPV-negative HNSCC cells to confer therapeutic benefits. Using patient-derived tumor cells, we created a similar HNSCC differentiation model of HPV+ tumor cells from two patients. We observed a loss of malignant characteristics in differentiating cell culture conditions, including irregularly enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. RNA-Seq showed myocyte-like differentiation with upregulation of markers of myofibril assembly. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers reminiscent of myoblast-lineage cells. Moreover, immunofluorescence of HPV+ tumor tissue revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like in vitro differentiation occurs in human tissue. We are the first to report that carcinoma cells can undergo a triggered myocyte-like differentiation, and our study suggests that the targeted differentiation of HPV+ HNSCCs might be therapeutically valuable.

10.1038/s41419-024-06867-4

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Differentiation of cells from head and neck squamous cell carcinoma that are positive for human papillomavirus

Laryngo-Rhino-Otologie (2024)

Sarah Gendreizig Laura Martinez‐Ruiz Javier Florido Alba López‐Rodríguez Harkiren Pabla

Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, death rates have remained at around 50%. Therefore, new treatment strategies are urgently needed. In a previous study, we investigated the differentiation of human papillomavirus (HPV)-negative HNSCC cells through cornification and discovered that cell malignancy was lost due to epigenetic factors. Understanding the mechanisms underlying HNSCC cell differentiation can help identify targets for anti-tumor therapy. We created an HNSCC differentiation model in HPV-positive tumor cells. Observed a loss of malignant characteristics in HPV-positive cell cultures similar to HPV-negative cells. This included irregular enlarged cell morphology, cell cycle arrest with Ki67 downregulation, and reduced cell viability. Although cornification was detected in HPV-positive tumor cell cultures and HPV-positive FFPE tumor tissue sections, it was not induced during HPV-positive cell differentiation. Instead, RNA-seq and subsequent gene ontology analysis showed myocyte-like differentiation with upregulation of markers of myofibril assembly, including TPM1, TAGLN, and ACTA1. Immunofluorescence staining of primary HPV-positive HNSCC cells confirmed the upregulation of these markers and the formation of parallel actin fibers, reminiscent of myoblast-lineage cells. Moreover, multi-marker immunofluorescence analysis of HPV-positive tumor tissue sections revealed areas of cells co-expressing markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17. This indicates that the observed myocyte-like differentiation also occurred in human tissue.

Koilocyte

10.1055/s-0044-1784739

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Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress

Biomedicine & Pharmacotherapy (2023)

Laura Martinez‐Ruiz Javier Florido César Rodríguez-Santana Alba López‐Rodríguez Ana Guerra‐Librero

Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment.

Tumor progression

10.1016/j.biopha.2023.115518

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Bevacizumab alone or with chemotherapy in highly pretreated, relapsed, epithelial ovarian cancer patients.

Journal of Clinical Oncology (2011)

B. Ojeda Antonio Casado Ariadna Tibau Andrés Redondo Miguel Beltrán

e15590

10.1200/jco.2011.29.15_suppl.e15590

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Role of Melatonin in Cancer: Effect on Clock Genes

International Journal of Molecular Sciences (2023)

César Rodríguez-Santana Javier Florido Laura Martinez‐Ruiz Alba López‐Rodríguez Darío Acuña‐Castroviejo

The circadian clock is a regulatory system, with a periodicity of approximately 24 h, that generates rhythmic changes in many physiological processes. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, resulting in multiple diseases, including cancer. In this context, tumor cells have an altered circadian machinery compared to normal cells, which deregulates the cell cycle, repair mechanisms, energy metabolism and other processes. Melatonin is the main hormone produced by the pineal gland, whose production and secretion oscillates in accordance with the light:dark cycle. In addition, melatonin regulates the expression of clock genes, including those in cancer cells, which could play a key role in the numerous oncostatic effects of this hormone. This review aims to describe and clarify the role of clock genes in cancer, as well as the possible mechanisms of the action of melatonin through which it regulates the expression of the tumor's circadian machinery, in order to propose future anti-neoplastic clinical treatments.

10.3390/ijms24031919

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Citations (19)

Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells

Antioxidants (2022)

Javier Florido César Rodríguez-Santana Laura Martinez‐Ruiz Alba López‐Rodríguez Darío Acuña‐Castroviejo

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications.

Mechanism of Action

Cell Signaling

10.3390/antiox11081621

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Citations (33)

HPV-positive head and neck squamous cell carcinoma cells lose viability during triggered myocyte lineage differentiation

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Sarah Gendreizig Laura Martinez‐Ruiz Alba López‐Rodríguez Harkiren Pabla Leonie Hose

Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, and death rates have remained at approximately 50% for decades. New tumor-targeting treatment strategies are desperately needed. Using patient-derived tumor cells, we created an HNSCC differentiation model of HPV+ tumor cells from two patients. We observed a loss of malignant characteristics in differentiating cell culture conditions, including irregularly enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. RNA-seq showed myocyte-like differentiation with upregulation of markers of myofibril assembly, including TPM1, TAGLN, and ACTA1. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers reminiscent of myoblast-lineage cells. Moreover, immunofluorescence of HPV+ tumor tissue revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like in vitro differentiation occurs in human tissue. A recent sarcoma study was able to turn rhabdomyosarcoma into muscle-like cells. We are the first to report that carcinoma cells can undergo a triggered myocyte differentiation. Our study suggests that the targeted myo-differentiation of tumor cells might be therapeutically valuable in HPV+ HNSCCs.

Lineage (genetic)

Cell lineage

10.1101/2024.03.28.587125

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Differenzierung humaner Papillomavirus-positiver Plattenepithelkarzinom-Zellen des Kopfes und Halses

Laryngo-Rhino-Otologie (2024)

Sarah Gendreizig Laura Martinez‐Ruiz Javier Florido Alba López‐Rodríguez Harkiren Pabla

Das Plattenepithelkarzinom (HNSCC) ist eine hochgradig bösartige Erkrankung, bei der die Sterblichkeitsrate bei etwa 50% liegt. Daher sind neue, auf den Tumor ausgerichtete Behandlungsstrategien dringend erforderlich. In einer früheren Studie untersuchten wir die Differenzierung von humanen Papillomavirus (HPV)-negativen HNSCC-Zellen durch Verhornung und entdeckten, dass die Malignität der Zellen durch epigenetische Faktoren verloren geht. Das Verständnis der Mechanismen, die der Differenzierung von HNSCC-Zellen zugrunde liegen, kann dazu beitragen, Angriffspunkte für eine Anti-Tumor-Therapie zu identifizieren. Unter Verwendung von Tumorzellen, die von Patienten stammen, haben wir ein HNSCC-Differenzierungsmodell in HPV-positiven Tumorzellen etabliert. Wir beobachteten bei HPV-positiven Zellkulturen einen Verlust maligner Eigenschaften, ähnlich wie bei HPV-negativen Zellen. Dazu gehörten eine unregelmäßig vergrößerte Zellmorphologie, ein Zellzyklusarrest mit heruntereguliertem Ki67 und eine verringerte Lebensfähigkeit der Zellen. Obwohl die Verhornung in HPV-positiven Tumorzellkulturen und HPV-positiven FFPE-Tumorgewebeschnitten nachgewiesen wurde, konnte diese während der HPV-positiven Zelldifferenzierung nicht induziert werden. Stattdessen zeigten RNA-seq und anschließende Gen-Ontologie-Analysen eine myozytenähnliche Differenzierung mit einer Hochregulierung von Markern für den Aufbau von Myofibrillen, darunter TPM1, TAGLN und ACTA1. Die Immunfluoreszenzfärbung von primären HPV-positiven HNSCC-Zellen bestätigte die Hochregulierung dieser Marker und die Bildung paralleler Aktinfasern, die an Zellen der Myoblasten-Linie erinnern.

10.1055/s-0044-1784139

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