Our research focuses on understanding the molecular mechanisms regulating tumor homeostasis and response to anti-cancer therapy. We approach this by modeling solid tumors in rodents and use such models for target and biomarker discovery and validation as well as to investigate molecular mechanisms which play a pivotal role regulating homeostasis. These include genotype-to-molecular phenotype connections, molecular and cellular heterogeneity and signaling to chromatin and transcription.
We mainly study the Glioblastoma Multiforme (GBM) and the Non-Small-Cell lung cancer (NSCLC), two unmet clinical needs with distinct challenges.
GBM is the most common primary brain tumor and it is incurable. Two major challenges affect GBM clinical management: its heterogeneity (which treatment will best fit this very patient?) and its resistance to available treatments (will the patient benefit in any way from the chosen therapy?). We are generating new GBM models reflecting GBM molecular subtypes at molecular level. To identify drug targets favoring patients’ response to the current standard of care, we exploit our models for state-of-art genetic screens in vivo. Specifically, we seek for synthetic lethal interactions between DNA damaging agents and the GBM transcriptome using in vivo CRISPR-based screening. At molecular level, we investigate the basis of GBM heterogeneity in vivo combining genetic and phenotypic tracing.
Kras-driven NSCLC are a leading cause of death with limited therapeutic options. The KRAS gene mutations are the most frequent genetic abnormalities both in primary and in metastatic lesions of NSCLC, notably to the central nervous system. In NSCLC, we aim to identify predictive biomarkers for metastasis and anti-metastatic treatments using mouse and rat models and identify novel factors regulating metastasis.
Identifying molecular fingerprinting and tumor-specific vulnerabilities conveys rapid translation in oncology and advances towards personalized medicine.
- Schmitt, M. J., Company, C., Dramaretska, Y., Barozzi, I., Göhrig, A., Kertalli, S., Großmann, M., Naumann, H., Sanchez-Bailon, M. P., Hulsman, D., Glass, R., Squatrito, M., Serresi, M., & Gargiulo, G. (2021). Phenotypic Mapping of Pathologic Cross-Talk between Glioblastoma and Innate Immune Cells by Synthetic Genetic Tracing. Cancer discovery, 11(3), 754–777.
- Serresi, M., Kertalli, S., Li, L., Schmitt, M. J., Dramaretska, Y., Wierikx, J., Hulsman, D., & Gargiulo, G. (2021). Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition. Science advances, 7(9), eabd7974.
- Ferone, G., Song, J. Y., Sutherland, K. D., Bhaskaran, R., Monkhorst, K., Lambooij, J. P., Proost, N., Gargiulo, G., & Berns, A. (2016). SOX2 Is the Determining Oncogenic Switch in Promoting Lung Squamous Cell Carcinoma from Different Cells of Origin. Cancer cell, 30(4), 519–532.
- Serresi, M., Gargiulo, G., Proost, N., Siteur, B., Cesaroni, M., Koppens, M., Xie, H., Sutherland, K. D., Hulsman, D., Citterio, E., Orkin, S., Berns, A., & van Lohuizen, M. (2016). Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer. Cancer cell, 29(1), 17–31.
- Gargiulo, G., Serresi, M., Cesaroni, M., Hulsman, D., & van Lohuizen, M. (2014). In vivo shRNA screens in solid tumors. Nature protocols, 9(12), 2880–2902.
- Lancini, C., van den Berk, P. C., Vissers, J. H., Gargiulo, G., Song, J. Y., Hulsman, D., Serresi, M., Tanger, E., Blom, M., Vens, C., van Lohuizen, M., Jacobs, H., & Citterio, E. (2014). Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells. The Journal of experimental medicine, 211(9), 1759–1777.
- Gargiulo, G., Cesaroni, M., Serresi, M., de Vries, N., Hulsman, D., Bruggeman, S. W., Lancini, C., & van Lohuizen, M. (2013). In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis. Cancer cell, 23(5), 660–676.
- Di Micco, R., Sulli, G., Dobreva, M., Liontos, M., Botrugno, O. A., Gargiulo, G., dal Zuffo, R., Matti, V., d'Ario, G., Montani, E., Mercurio, C., Hahn, W. C., Gorgoulis, V., Minucci, S., & d'Adda di Fagagna, F. (2011). Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nature cell biology, 13(3), 292–302.