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Article ; Online: DNA repair in tumor radioresistance: insights from fruit flies genetics.

Porrazzo, Antonella / Cassandri, Matteo / D'Alessandro, Andrea / Morciano, Patrizia / Rota, Rossella / Marampon, Francesco / Cenci, Giovanni

Cellular oncology (Dordrecht)

2023

Abstract: Background: Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. ... ...

Abstract	Background: Radiation therapy (RT) is a key anti-cancer treatment that involves using ionizing radiation to kill tumor cells. However, this therapy can lead to short- and long-term adverse effects due to radiation exposure of surrounding normal tissue. The type of DNA damage inflicted by radiation therapy determines its effectiveness. High levels of genotoxic damage can lead to cell cycle arrest, senescence, and cell death, but many tumors can cope with this damage by activating protective mechanisms. Intrinsic and acquired radioresistance are major causes of tumor recurrence, and understanding these mechanisms is crucial for cancer therapy. The mechanisms behind radioresistance involve processes like hypoxia response, cell proliferation, DNA repair, apoptosis inhibition, and autophagy. Conclusion: Here we briefly review the role of genetic and epigenetic factors involved in the modulation of DNA repair and DNA damage response that promote radioresistance. In addition, leveraging our recent results on the effects of low dose rate (LDR) of ionizing radiation on Drosophila melanogaster we discuss how this model organism can be instrumental in the identification of conserved factors involved in the tumor resistance to RT.
Language	English
Publishing date	2023-12-14
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2595109-9
ISSN	2211-3436 ; 1875-8606 ; 2211-3428
ISSN (online)	2211-3436
ISSN	1875-8606 ; 2211-3428
DOI	10.1007/s13402-023-00906-6
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Article ; Online: New Insights on the Nuclear Functions and Targeting of FAK in Cancer.

Pomella, Silvia / Cassandri, Matteo / Braghini, Maria Rita / Marampon, Francesco / Alisi, Anna / Rota, Rossella

International journal of molecular sciences

2022 Volume 23, Issue 4

Abstract: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its ... ...

Abstract	Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different ways: a kinase activity in the cytoplasm, mainly dependent on the integrin signaling, and a scaffolding activity into the nucleus by networking with different gene expression regulators. For this reason, FAK has to be considered a target with high therapeutic values. Indeed, evidence suggests that FAK targeting could be effective, either alone or in combination, with other already available treatments. Here, we propose an overview of the novel insights about FAK's structure and nuclear functions, with a special focus on the recent findings concerning the roles of this protein in cancer. Additionally, we provide a recent update on FAK inhibitors that are currently in clinical trials for patients with cancer, and discuss the challenge and future directions of drug-based anti-FAK targeted therapies.
MeSH term(s)	Animals ; Cell Nucleus/metabolism ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Gene Expression Regulation/genetics ; Humans ; Neoplasms/metabolism ; Signal Transduction/physiology
Chemical Substances	Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2)
Language	English
Publishing date	2022-02-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23041998
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Article ; Online: DNA Damage Response Gene Signature as Potential Treatment Markers for Oral Squamous Cell Carcinoma.

Pomella, Silvia / Cassandri, Matteo / Melaiu, Ombretta / Marampon, Francesco / Gargari, Marco / Campanella, Vincenzo / Rota, Rossella / Barillari, Giovanni

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification ... ...

Abstract	Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson's correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely
MeSH term(s)	Humans ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms/drug therapy ; Mouth Neoplasms/genetics ; Mouth Neoplasms/metabolism ; DNA Damage ; Head and Neck Neoplasms
Language	English
Publishing date	2023-01-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24032673
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Article: The ZNF750-RAC1 axis as potential prognostic factor for breast cancer.

Butera, Alessio / Cassandri, Matteo / Rugolo, Francesco / Agostini, Massimiliano / Melino, Gerry

Cell death discovery

2020 Volume 6, Issue 1, Page(s) 135

Abstract: The human zinc finger (C2H2-type) protein ZNF750 is a transcription factor regulated by p63 that plays a critical role in epithelial tissues homoeostasis, as well as being involved in the pathogenesis of cancer. Indeed, missense mutations, truncation and ...

Abstract	The human zinc finger (C2H2-type) protein ZNF750 is a transcription factor regulated by p63 that plays a critical role in epithelial tissues homoeostasis, as well as being involved in the pathogenesis of cancer. Indeed, missense mutations, truncation and genomic deletion have been found in oesophageal squamous cell carcinoma. In keeping, we showed that ZNF750 negatively regulates cell migration and invasion in breast cancer cells; in particular, ZNF750 binds and recruits KDM1A and HDAC1 on the LAMB3 and CTNNAL1 promoters. This interaction, in turn, represses the transcription of LAMB3 and CTNNAL1 genes, which are involved in cell migration and invasion. Given that ZNF750 is emerging as a crucial transcription factor that acts as tumour suppressor gene, here, we show that ZNF750 represses the expression of the small GTPase, Ras-related C3 botulinum toxin substrate 1 (RAC1) in breast cancer cell lines, by directly binding its promoter region. In keeping with ZNF750 controlling RAC1 expression, we found an inverse correlation between ZNF750 and RAC1 in human breast cancer datasets. More importantly, we found a significant upregulation of RAC1 in human breast cancer datasets and we identified a direct correlation between RAC1 expression and the survival rate of breast cancer patient. Overall, our findings provide a novel molecular mechanism by which ZNF750 acts as tumour suppressor gene. Hence, we report a potential clinical relevance of ZNF750/RAC1 axis in breast cancer.
Language	English
Publishing date	2020-11-29
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-020-00371-2
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Article ; Online: New Insights on the Nuclear Functions and Targeting of FAK in Cancer

Silvia Pomella / Matteo Cassandri / Maria Rita Braghini / Francesco Marampon / Anna Alisi / Rossella Rota

International Journal of Molecular Sciences, Vol 23, Iss 1998, p

2022 Volume 1998

Abstract	Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed and activated in both adult and pediatric cancers, where it plays important roles in the regulation of pathogenesis and progression of the malignant phenotype. FAK exerts its functions in cancer by two different ways: a kinase activity in the cytoplasm, mainly dependent on the integrin signaling, and a scaffolding activity into the nucleus by networking with different gene expression regulators. For this reason, FAK has to be considered a target with high therapeutic values. Indeed, evidence suggests that FAK targeting could be effective, either alone or in combination, with other already available treatments. Here, we propose an overview of the novel insights about FAK’s structure and nuclear functions, with a special focus on the recent findings concerning the roles of this protein in cancer. Additionally, we provide a recent update on FAK inhibitors that are currently in clinical trials for patients with cancer, and discuss the challenge and future directions of drug-based anti-FAK targeted therapies.
Keywords	FAK ; adult cancers ; pediatric cancers ; targeted therapy ; combination therapy ; PROTACs ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: DNA Damage Response Gene Signature as Potential Treatment Markers for Oral Squamous Cell Carcinoma

Silvia Pomella / Matteo Cassandri / Ombretta Melaiu / Francesco Marampon / Marco Gargari / Vincenzo Campanella / Rossella Rota / Giovanni Barillari

International Journal of Molecular Sciences, Vol 24, Iss 2673, p

2023 Volume 2673

Abstract	Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson’s correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely CCNB1 , CCNB2 , CDK2 , CDK4 , CHECK1 , E2F1 , FANCD2 , and PRKDC ) that could be predictive for OSCC response to the novel antitumor compounds sorafenib and tipifarnib-P1. Altogether, our data demonstrate that alterations in DDR genes could have an impact on the biology of OSCC. Moreover, here we propose a DDR gene signature whose expression could be predictive of OSCC responsiveness to therapy.
Keywords	oral squamous cell carcinoma ; DNA damage response ; The Cancer Genome Atlas ; DepMap ; bioinformatics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Statin-Sensitive Akt1/Src/Caveolin-1 Signaling Enhances Oxidative Stress Resistance in Rhabdomyosarcoma.

Codenotti, Silvia / Sandrini, Leonardo / Mandracchia, Delia / Lorenzi, Luisa / Corsetti, Giovanni / Poli, Maura / Asperti, Michela / Salvi, Valentina / Bosisio, Daniela / Monti, Eugenio / Mitola, Stefania / Triggiani, Luca / Guescini, Michele / Pozzo, Enrico / Sampaolesi, Maurilio / Gastaldello, Stefano / Cassandri, Matteo / Marampon, Francesco / Fanzani, Alessandro

Cancers

2024 Volume 16, Issue 5

Abstract: Identifying the molecular mechanisms underlying radioresistance is a priority for the treatment of RMS, a myogenic tumor accounting for approximately 50% of all pediatric soft tissue sarcomas. We found that irradiation (IR) transiently increased ... ...

Abstract	Identifying the molecular mechanisms underlying radioresistance is a priority for the treatment of RMS, a myogenic tumor accounting for approximately 50% of all pediatric soft tissue sarcomas. We found that irradiation (IR) transiently increased phosphorylation of Akt1, Src, and Cav1 in human RD and RH30 lines. Synthetic inhibition of Akt1 and Src phosphorylation increased ROS levels in all RMS lines, promoting cellular radiosensitization. Accordingly, the elevated activation of the Akt1/Src/Cav1 pathway, as detected in two RD lines characterized by overexpression of a myristoylated Akt1 form (myrAkt1) or Cav1 (RDCav1), was correlated with reduced levels of ROS, higher expression of catalase, and increased radioresistance. We found that treatment with cholesterol-lowering drugs such as lovastatin and simvastatin promoted cell apoptosis in all RMS lines by reducing Akt1 and Cav1 levels and increasing intracellular ROS levels. Combining statins with IR significantly increased DNA damage and cell apoptosis as assessed by γ histone 2AX (γH2AX) staining and FACS analysis. Furthermore, in combination with the chemotherapeutic agent actinomycin D, statins were effective in reducing cell survival through increased apoptosis. Taken together, our findings suggest that the molecularly linked signature formed by Akt1, Src, Cav1, and catalase may represent a prognostic determinant for identifying subgroups of RMS patients with higher probability of recurrence after radiotherapy. Furthermore, statin-induced oxidative stress could represent a treatment option to improve the success of radiotherapy.
Language	English
Publishing date	2024-02-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16050853
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Article ; Online: ZFP750 affects the cutaneous barrier through regulating lipid metabolism.

Butera, Alessio / Agostini, Massimiliano / Cassandri, Matteo / De Nicola, Francesca / Fanciulli, Maurizio / D'Ambrosio, Lorenzo / Falasca, Laura / Nardacci, Roberta / Wang, Lu / Piacentini, Mauro / Knight, Richard A / Jia, Wei / Sun, Qiang / Shi, Yufang / Wang, Ying / Candi, Eleonora / Melino, Gerry

Science advances

2023 Volume 9, Issue 17, Page(s) eadg5423

Abstract: An essential function of the epidermis is to provide a physical barrier that prevents the loss of water. Essential mediators of this barrier function include ceramides, cholesterol, and very long chain fatty acids, and their alteration causes human ... ...

Abstract	An essential function of the epidermis is to provide a physical barrier that prevents the loss of water. Essential mediators of this barrier function include ceramides, cholesterol, and very long chain fatty acids, and their alteration causes human pathologies, including psoriasis and atopic dermatitis. A frameshift mutation in the human
MeSH term(s)	Animals ; Humans ; Mice ; Ceramides/metabolism ; Cholesterol/metabolism ; Epidermis/metabolism ; Lipid Metabolism ; Skin/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; Repressor Proteins/metabolism
Chemical Substances	Ceramides ; Cholesterol (97C5T2UQ7J) ; Transcription Factors ; Tumor Suppressor Proteins ; ZNF750 protein, human ; Repressor Proteins
Language	English
Publishing date	2023-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adg5423
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Article: Radioresistance in rhabdomyosarcomas: Much more than a question of dose.

Camero, Simona / Cassandri, Matteo / Pomella, Silvia / Milazzo, Luisa / Vulcano, Francesca / Porrazzo, Antonella / Barillari, Giovanni / Marchese, Cinzia / Codenotti, Silvia / Tomaciello, Miriam / Rota, Rossella / Fanzani, Alessandro / Megiorni, Francesca / Marampon, Francesco

Frontiers in oncology

2022 Volume 12, Page(s) 1016894

Abstract: Management of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, frequently accounting the genitourinary tract is complex and requires a multimodal therapy. In particular, as a consequence of the advancement in dose conformity ... ...

Abstract	Management of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, frequently accounting the genitourinary tract is complex and requires a multimodal therapy. In particular, as a consequence of the advancement in dose conformity technology, radiation therapy (RT) has now become the standard therapeutic option for patients with RMS. In the clinical practice, dose and timing of RT are adjusted on the basis of patients' risk stratification to reduce late toxicity and side effects on normal tissues. However, despite the substantial improvement in cure rates, local failure and recurrence frequently occur. In this review, we summarize the general principles of the treatment of RMS, focusing on RT, and the main molecular pathways and specific proteins involved into radioresistance in RMS tumors. Specifically, we focused on DNA damage/repair, reactive oxygen species, cancer stem cells, and epigenetic modifications that have been reported in the context of RMS neoplasia in both
Language	English
Publishing date	2022-09-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.1016894
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Article: Spermine oxidase induces DNA damage and sensitizes fusion negative rhabdomyosarcoma cells to irradiation.

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1061570

Abstract: Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma that includes fusion-positive (FP) and fusion-negative (FN) molecular subtypes. FP-RMS expresses PAX3-FOXO1 fusion protein and often shows dismal prognosis. FN-RMS shows cytogenetic ... ...

Abstract	Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma that includes fusion-positive (FP) and fusion-negative (FN) molecular subtypes. FP-RMS expresses PAX3-FOXO1 fusion protein and often shows dismal prognosis. FN-RMS shows cytogenetic abnormalities and frequently harbors RAS pathway mutations. Despite the multimodal heavy chemo and radiation therapeutic regimens, high risk metastatic/recurrent FN-RMS shows a 5-year survival less than 30% due to poor sensitivity to chemo-radiotherapy. Therefore, the identification of novel targets is needed. Polyamines (PAs) such as putrescine (PUT), spermidine (SPD) and spermine (SPM) are low-molecular-mass highly charged molecules whose intracellular levels are strictly modulated by specific enzymes. Among the latter, spermine oxidase (SMOX) regulates polyamine catabolism oxidizing SPM to SPD, which impacts cellular processes such as apoptosis and DNA damage response. Here we report that low SMOX levels are associated with a worse outcome in FN-RMS, but not in FP-RMS, patients. Consistently, SMOX expression is downregulated in FN-RMS cell lines as compared to normal myoblasts. Moreover, SMOX transcript levels are reduced FN-RMS cells differentiation, being indirectly downregulated by the muscle transcription factor MYOD. Noteworthy, forced expression of SMOX in two cell lines derived from high-risk FN-RMS: 1) reduces SPM and upregulates SPD levels; 2) induces G0/G1 cell cycle arrest followed by apoptosis; 3) impairs anchorage-independent and tumor spheroids growth; 4) inhibits cell migration; 5) increases γH2AX levels and foci formation indicative of DNA damage. In addition, forced expression of SMOX and irradiation synergize at activating ATM and DNA-PKCs, and at inducing γH2AX expression and foci formation, which suggests an enhancement in DNA damage response. Irradiated SMOX-overexpressing FN-RMS cells also show significant decrease in both colony formation capacity and spheroids growth with respect to single approaches. Thus, our results unveil a role for SMOX as inhibitor of tumorigenicity of FN-RMS cells
Language	English
Publishing date	2023-01-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1061570
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