Dr. Víctor Javier Sánchez-Arévalo Lobo  victor.sanchezarevalo@ufv.es

Raúl Muñoz Velasco (UFV, biotechnology)
Ana García García (UFV, biotechnology)

Alberto Mora Perdiguero (Bioinformatician)

Esther Polanco (URJC, Biomedical Engineering)
Paula Pena González (UFV, Biomedical Engineering)

María Ferrer Aporta (Master in Therapies UFV, Biomedicine)
Germán Vallejo Palma (Master in Biocomputing UAM, Biology)
Antonio Giráldez (Master in Biocomputing UAM, Biotechnology)
Alejandra Gavia (Master in Biocomputing UAM, Health Biology)
Ramón González (Master in Bioinformatics in Personalized Medicine ENT, ISCIII Hospital Quirón, Medical Oncologist)

Elena di Simone (UFV, Biotechnology, Pharmacy)
Lucia Gozalo (UAH, Health Biology)

Dr. Bruno Amati (European Institute of Oncology, Milan, Italy)
Dr. Francisco X. Real (Centro Nacional de Investigaciones Oncológicas, Madrid)
Dra. Sandra Rodríguez (Centro Nacional de Investigaciones Oncológicas, Madrid)
Dr. Javier Hernández Losa (Hospital Vall d´Hebron, Barcelona)
Dr. Santiago Ramón y Cajal (Hospital Vall d´Hebron, Barcelona)
Dr. José Luis Rodríguez Peralto (Hospital 12 de Octubre, Madrid)
Dra. Yolanda Rodríguez Gil (Hospital 12 de Octubre, Madrid)
Dr. Ricardo Sánchez-Prieto (Regional Centre for Biomedical Research, Faculty of Medicine, Universidad de Albacete)
Dr. Bruno Sainz (Instituto de Investigaciones Biomédicas, IIB, CSIC)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a survival rate of less than 5%. This difficult prognosis is due to its late diagnosis – when the tumor has already metastasized – and its chemo-resistance. The only effective therapy at present is surgery, but this is only possible in 15-20% of cases. Therefore, finding new therapeutic strategies is a clinical urgency.

The linear model to explain the origin and progression of APD is similar to that described for colon, where a series of molecular alterations correlate with histological abnormalities – called pancreatic intraepithelial lesions (PanINs). The precursor lesion, PanIN-1A and 1B are characterized by elongation of ductal cells, abundant mucus and presence of mutations in KRAS; PanIN-1Bs are characterized by papillary morphology and molecularly by inactivation of CDKN2A. As PanINs lesions progress to PanIN-2, inactivation of the INK4A gene occurs, which correlates with mitotic abnormalities and cell spreading into the lumen. Molecularly they are characterized by inactivation or loss of the SMAD4 gene. Finally, PanIN-3 is considered carcinoma in situ, and is characterized by loss of the TP53 tumor suppressor, overexpression of the c-MYC oncogene – in 42% of APD as a consequence of KRAS activation, copy number gain or gene amplifications – and mutations in ARID1A, among other alterations. This linear model is currently under debate, Nota et al suggest that genomic instability and specifically the phenomenon of chromothripsis in early stages, may play an important role in the genetics of APD.

Several groups have demonstrated the importance of differentiation as a safety mechanism against cellular transformation and how de-differentiated cells are more prone to transformation. In this direction, the inflammatory response such as that occurring during pancreatitis can induce de-differentiation of acinar cells and their subsequent trans-differentiation to ductal cells, through a process called acinoductal metaplasia (ADM). This is a reversible process, but if chronified it can induce cell transformation. Supporting this hypothesis, our laboratory has demonstrated how the c-MYC oncogene is able to induce a de-differentiated state, repressing the acinar program and promoting cell transformation.

My group is interested in exploring how c-MYC recognizes different epigenetic contexts -normal vs. tumor- and executes different genetic programs. To bind to DNA and induce transcription of its target genes, c-MYC heterodimerizes with the ubiquitous transcription factor MAX to recognize specific sequences in DNA called E-boxes. There are more than 25,000 c-MYC binding sites in the genome. We now know that the differential recognition of these sites depends on the epigenetic context – defined by the combination of different histone marks – which constitutes a prerequisite for c-MYC binding. The presence of CpG islands and transcription activator tags (H3K4me3, H3K79me and H3ac) define the high-affinity sites of c-MYC, which we termed “euchromatic islands”, whereas low-affinity sites are defined by the H4K16ac tag. c-MYC requires specific chromatin remodelers to recognize the different tags and to be recruited to chromatin. In this regard, our group described a novel co-factor of c-MYC, the chromatin remodeler BPTF (Bromodomain PHD finger transcription factor), required for its recruitment to chromatin, transcriptional activity and c-MYC-dependent tumor development. Our interest is to extend these results and explore the role of c-MYC and BPTF during acinar transformation and de-differentiation processes in addition to their role as a therapeutic target in KRAS-driven APD models. Beyond the therapeutic potential of BPTF, several studies support the importance of chromatin modifiers and remodelers as therapeutic targets. To address this challenge we are interested in the genetic screening of new therapeutic targets using sgRNA libraries for CRISPR/Cas9 in collaboration with Dr. Sandra Rodriguez who heads the Cytogenetics Unit at CNIO in order to explore possible synergies with current treatments in APD.

BPTF and chromatin remodelers as new therapeutic targets in pancreatic carcinoma. Fondo de Investigaciones Sanitarias (FIS). Principal Researcher. PI18/01080. Duration: January 2019-December 2022.

BPTF as a therapeutic target and regulator of cell plasticity in pancreatic ductal adenocarcinoma. ASEICA +QUEUNTRAIL. Principal Researcher. Duration January 2020-December 2020.

Thematic network of cooperative research in cancer. Instituto de Salud Carlos III. Collaborator. RD12/0036/0034. Duration: 2013 – 2016.

Development of BPTF-MYC functional inhibitors for anticancer therapy. ROCHE. Collaborator. Duration: 2013 – 2015 .

Transcriptional control of acinar cell differentiation and pancreatic cancer. MINECO. Collaborator. SAF2011-29530. Duration: 2012 – 2014.

CANCERALIA-Development of novel diagnostic and therapeutic approaches to improve patients outcome in lung and pancreatic tumors. EU-FP7. Collaborator. 259737. Duration: 2011 – 2014.

FIS PI22/00492 Title: Chromatin remodelers as therapeutic immuno-modulators in pancreatic ductal adenocarcinoma. Duration until January 2025

Blanco-García, Leyla, Yolanda Ruano, Raquel Blanco Martínez-Illescas, Rocío Cubo, Paula Jiménez Sánchez, Sanchez-Arévalo Lobo, V.J., Erica Riveiro Falkenbach, Pablo Ortiz Romero, María C. Garrido, and José L. Rodríguez Peralto. 2023. pTERT C250T Mutation: A Potential Biomarker of Poor Prognosis in Metastatic Melanoma. Heliyon 9 (8): e18953. (2023). https://doi.org/10.1016/j.heliyon.2023.e18953. PMCID: PMC10440525

Arconada-Luque, Elena Jiménez-Suarez, Jaime Pascual-Serra, Raquel Nam-Cha, Syong Hyun Moline, Teresa Cimas, Francisco J. Fliquete, Germán Ortega-Muelas, Marta Roche, Olga Fernández-Aroca, Diego M.Velasco, Raúl Muñoz García-Flores, Natalia Garnés-García, Cristina Sánchez-Fdez, Adrián Matilla-Almazán, Sofía, Sanchez-Arévalo Lobo, V.J. Hernández-Losa, Javier Belandia, Borja Pandiella, Atanasio Esparís-Ogando, Azucena Cajal, Santiago Ramón y  Cajal, Peso, Luis del Sánchez-Prieto, Ricardo Ruiz-Hidalgo, María José. ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology. Cancers 14, 3509 (2022).  https://doi.org/10.3390/cancers14143509. PMCID: PMC9316148. Q1

Velasco, R. M.; Sánchez, P. J.; García, A. G.; Martínez-Illescas, R. B.; Senovilla, Á. P.; Yagüe, M. L.; Trento, A.; García-Martin, R. M.; Navarro, D.; Sainz, B.; Peralto, J. L. R.; Sánchez-Arévalo Lobo, V.J. Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR). Cancers 2022, 14 (6), 1518. https://doi.org/10.3390/cancers14061518. PMID: 35326669

Velasco, R. M., García, A. G., Sánchez, P. J., Sellart, I. M. & Sánchez-Arévalo Lobo VJ. Tumour microenvironment and heterotypic interactions in pancreatic cancer. J Physiol Biochem 1–14 (2022) doi:10.1007/s13105-022-00875-8. PMID: 35102531

Rodríguez Gil Y, Jimenez Sánchez, P., Muñoz Velasco, R., García Garcia, A. & Sánchez-Arévalo Lobo VJ (2021). Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic. Int J Mol Sci 22, 2077. DOI:10.3390/ijms22042077. PMID: 33669845