On Friday, January 31, Natalia Sanz and Nuria García predoctoral IDIVAL-UC present their doctoral thesis at the Faculty of Medicine at 11:00 and 12:00 hours respectively.
Doctoral thesis: “Differentiation induced by DNA damage, a common physiological response in stratified epithelia and prognostic marker in HNSCC”
Speaker: Natalia Sanz, pre-doctoral scholarship IDIVAL-UC (PREVAL 04/16) in 2015 in the Research Group Cell Cycle, Stem Cells and Cancer of IDIVAL.
Thesis Director: Alberto Gandarillas Solinis
Date and place: Degrees Room of the Faculty of Medicine, Faculty of Medicine, 11:00 hours.
Epidermoid cancer is the leading cause of cancer death. Epidermoid or squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer worldwide. HNSCC originates from stratified squamous epithelia that are in continuous renewal and exposed to mutagenic agents. Therefore, keratinocytes must have potent protective mechanisms to eliminate precancerous cells. In this doctoral work we have found a differentiation response induced by DNA damage (DDDR) in head and neck keratinocytes common with the epidermis. The results show that this mechanism protects cells against genetic damage induced by ultraviolet radiation or replication stress through the G2 / mitosis control points, and with mitotic slippage, endorreplication and terminal differentiation. We have also shown that mitosis kinases control squamous differentiation in vivo. In addition, we found a relationship between DDDR and the aggressiveness of HNSCC carcinomas. The results suggest that cellular DDDR could maintain squamous homeostasis automatically and that its alteration contributes to the aggressiveness of epidermoid cancer.
PUBLICACIONES SURGIDAS DE LA TESIS DOCTORAL
1. Gandarillas, A., Molinuevo, R., and Sanz-Gomez, N. (2018). Mammalian endoreplication emerges to reveal a potential developmental timer. Cell Death and Differentiation, 25(3), 471–476.
2. Sanz-Gomez, N., Freije, A., Ceballos, L., Obeso, S., Sanz, J. R., Garcia-Reija, F., Morales-Angulo, C. and Gandarillas, A. (2018). Response of head and neck epithelial cells to a DNA damage-differentiation checkpoint involving polyploidization. Head and Neck, 40(11), 2487–2497.
3. de Pedro, I., Alonso-Lecue, P., Sanz-Gomez, N., Freije, A., and Gandarillas, A. (2018). Sublethal UV irradiation induces squamous differentiation via a p53-independent, DNA damage-mitosis checkpoint. Cell Death and Disease, 9(11), 1094.
4. Gandarillas, A., Sanz-Gomez, N., and Freije, A. (2019). Polyploidy and the mitosis path to epidermal cell fate. Cell Cycle (Georgetown, Tex.), 18(3), 359–362.
5. Sanz-Gomez, N., Freije, A., and Gandarillas, A. (2019). Keratinocyte Differentiation by Flow Cytometry. Methods in Molecular Biology (Clifton, N.J.).
6. Freije, A., Sanz-Gomez, N., and Gandarillas, A. (2019). Genetic Modification of Human Primary Keratinocytes by Lentiviral Vectors. Methods in Molecular Biology (Clifton, N.J.).
7. Sanz-Gómez, N., de Pedro, I., Ortigosa, B., Santamaría, D., Malumbres, M., de Carcer, G. and Gandarillas, A. (En prensa). Squamous differentiation requires G2/mitosis slippage to avoid apoptosis. Cell Death and Differentiation.
Doctoral thesis: “Novel mechanisms of tumorigenesis and progression of cutaneous T cell lymphoma: role of PLCG1-PRKCQ-STAT3 signalling network”
Speaker: Nuria García, IDIVAL-UC predoctoral fellowship (PREVAL 16/01) in 2015 in the IDIVAL Clinical and Translational Research Group on Digestive Diseases.
Thesis directors: José Pedro Vaque Díez and Miguel Ángel Piris Pinilla.
Date and place: Audiovisual Classroom of the Faculty of Medicine at 12: 00 hours.
The work carried out in this doctoral thesis has been to study the role of the PLCG1-PRKCQ-STAT3 malignant signaling network controlling the biological processes of cutaneous T-cell lymphoma (LCCT). To this end, different biomarkers have been studied by immunohistochemistry in 78 LCCT patients and it has been seen that the activation of STAT3 is a marker of disease progression, which could be an important characteristic with relevant clinical implications. In addition, we have studied the possible mechanisms that could lead to the activation of this protein as activating mutations of JAK and PLCG1 and / or amplifications of PRKCQ, all of them described in LCCT patients. These mechanisms have been analyzed both in cellular models of the disease and in a novel animal model for the field of cutaneous lymphomas: the chicken embryo model, which has allowed PRKCQ to be described as an important mediator of tumorigenesis and progression control. of the illness. It also proposes novel approaches to the development of targeted therapies, including calcineurin inhibitors, PRKCQ or JAK used both individually and in combination.
PUBLICATIONS OF THE DOCTORAL THESIS
1. Pérez C, González-Rincón J, Onaindia A, Almaráz C, García-Díaz N, Pisonero H, Curiel-Olmo S, Gómez S, Cereceda L, Madureira R, Hospital M, Suárez-Massa D, Rodriguez-Peralto JL, Postigo C, Leon-Castillo A, González-Vela C, Martinez N, Ortiz-Romero P, Sánchez-Beato M, Piris MÁ, Vaqué JP. Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma. Haematologica. 2015 Nov;100(11):e450-3. doi: 10.3324/haematol.2015.132837
2. Pérez C, Mondéjar R, García-Díaz N, Cereceda L, León A, Montes S, Durán Vian C, Pérez Paredes MG, González-Morán A, Alegre de Miguel V, Sanz Anquela JM, Frías J, Limeres MA, González LM, Martín Dávila F, Beltrán M, Mollejo M, Méndez JR, González MA, González García J, López R, Gómez A, Izquierdo F, Ramos R, Camacho C, Rodriguez-Pinilla SM, Martínez N, Vaqué JP, Ortiz-Romero PL, Piris MA. Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways. The British journal of dermatology. 2019 May 3. doi: 10.1111/bjd.18098
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