Study of epigenetic modifications related to cancer stem cells accumulation in head and neck cancer: implications in chemoresistance

• Grant number: 17/11780-8
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2018
• End date: January 31, 2024
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Luciana Oliveira de Almeida
• Grantee: Luciana Oliveira de Almeida
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Andréia Machado Leopoldino ; Rogerio Moraes Castilho
• Associated scholarship(s): 21/13268-8 - Profile of epigenetic modifications of histones and their regulators in tumor stem cells (TCCs) and exosomes in oral Carcinoma cell lines, BP.IC; 20/02740-5 - Epigenetic control of WNT/b-catenin signaling in chemoresistant cancer stem cells accumulation in oral carcinoma, BP.MS; 19/19045-0 - Epigenetic regulation of head and neck tumors resistant to cisplatin: differences between intrinsic and adquired resistance, BP.IC; + associated scholarships 19/19301-7 - The role of HDAC6 in the regulation of oxidative stress and chemoresistance of cancer stem cells in oral carcinoma, BP.MS; 19/05782-3 - Involvement of NFkB signaling in CSC accumulation of head and neck carcinoma cell lines resistant to chemotherapy, BP.MS; 18/17478-4 - Characterization of the mechanism of cancer stem cells accumulation in head and neck squamous carcinoma after chemotherapy, BP.IC; 18/13764-2 - Establishment and characterization of head and neck squamous cell carcinoma cell lines resistant to cisplatin, BP.IC; 18/02959-7 - Study of epigenetic modifications related to cancer stem cells accumulation in head and neck cancer: implications in chemoresistance, BP.JP - associated scholarships

Abstract

Chemoresistance is a major cause of the failure in the therapy used for the cancer treatment, increasing rates of recurrence and metastasis. It has been suggested that chemoresistance is driven by a small group of cells identified as cancer stem cells. In head and neck cancer, cancer stem cells population is accumulated after chemotherapy e epigenetic modifications may be controlling this process. NFkB pathway has been associated with chemoresistance and its involvement in the epigenetic regulation suggests that NFkB may be modulating cancer stem cells. Thereby, understanding the epigenetic modifications that promote chemoresistance, exploring the behavior of cancer stem cells and the signaling that regulates renewing and differentiation may enable us to modulate epigenetically the cancer stem cells signaling as a therapeutic strategy. Our project aims: (i) identify epigenetic modifications that may be contributing to the chemoresistance of cancer stem cells; (ii) explore the involvement of NFkB protein in the cellular signaling associated with cancer stem cells; (iii) select and characterize the role of genes epigenetically modulated upon cancer stem cells in chemoresistant tumors; (iv) find therapeutic strategies more efficient to ensure the complete abrogation of the cancer stem cells population. We will apply strategies of: stablishment of head and neck cancer cell lines cisplatin-resistant; isolation of cancer stem cell population using flow cytometry assay; identification of gene epigenetically regulated using ATAC-seq, ChIP and MSP; drug screening and in vivo studies using xenograft models. The results will contribute to improve the knowledge about the epigenetic signaling driving the accumulation of chemoresistant cancer stem cells as well as to identify more effective drugs to abbrogate cancer stem cells. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BIGHETTI-TREVISAN, RAYANA L.; SOUSA, LUCAS O.; CASTILHO, ROGERIO M.; ALMEIDA, LUCIANA O.. Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics. STEM CELLS INTERNATIONAL, v. 2019, NOV 12 2019. (17/11780-8, 18/02959-7)

MILAN, THAIS MORE; ESKENAZI, ANA PATRICIA ESPALADORI; DE OLIVEIRA, LUCAS DIAS; DA SILVA, GABRIEL; BIGHETTI-TREVISAN, RAYANA LONGO; FREITAS, GILEADE PEREIRA; ALMEIDA, LUCIANA OLIVEIRA. Interplay between EZH2/β-catenin in stemness of cisplatin-resistant HNSCC and their role as therapeutic targets. CELLULAR SIGNALLING, v. 109, p. 13-pg., 2023-09-01. (20/02740-5, 17/11780-8)

MILAN, THAIS MORE; ESPALADORI ESKENAZI, ANA PATRICIA; BIGHETTI-TREVISAN, RAYANA LONGO; DE ALMEIDA, LUCIANA OLIVEIRA. Epigenetic modifications control loss of adhesion and aggressiveness of cancer stem cells derived from head and neck squamous cell carcinoma with intrinsic resistance to cisplatin. ARCHIVES OF ORAL BIOLOGY, v. 141, p. 11-pg., 2022-06-06. (18/02959-7, 17/11780-8, 19/19045-0)

TAVARES, MARCELA OLIVEIRA; MILAN, THAIS MORE; BIGHETTI-TREVISAN, RAYANA LONGO; LEOPOLDINO, ANDREIA MACHADO; DE ALMEIDA, LUCIANA OLIVEIRA. Pharmacological inhibition of HDAC6 overcomes cisplatin chemoresistance by targeting cancer stem cells in oral squamous cell carcinoma. JOURNAL OF ORAL PATHOLOGY & MEDICINE, v. N/A, p. 9-pg., 2022-06-28. (19/19301-7, 17/11780-8)