MDA 4SCR6.1042 (Unit 1954)
The University of Texas MD Anderson Cancer Center
Department of Genomic Medicine
My lab has strong interest in translational medicine. The research program is focused on studying pancreatic cancer, a deadly disease characterized by a silent onset and a very poor prognosis. Although mainly focused on a single disease, our interests are broad and span over three major areas of investigation.
Dissection of complexity and functional tumor heterogeneity. A long-standing concept in cancer biology is that tumors are extremely complex and characterized by extraordinary intratumor heterogeneity. This complexity inherent in tumors has important implications, as it underscores the adaptability of cancer cells when exposed to external perturbations. To unravel adaptive mechanisms and understand the contributions of different subclones on tumor growth and treatment response, we recently developed Clonal Replica Tumors (CRTs), an innovative and powerful platform to study heterogeneous populations of cells and their clonal dynamics in vivo. Leveraging the identical clonal composition of orthotopic cohorts derived from human pancreatic cancers, CRTs enables longitudinal studies aim to comprehensively capture the clonal dynamics during tumor growth, dissemination and response to therapy. This powerful approach allows also the investigation of the interactions existing between cancer cells and their microenvironment and how tumor cells shape their environment over time and in response to pharmacological treatments.
Early determinants of tumor progression. Inflammation is one of the major risk factors for pancreatic cancer. When occurring in the context of pancreatitis, mutations of KRAS, the most frequent driver oncogene of pancreatic cancer, lead to accelerated tumor development through the sequential occurrence of metaplastic and dysplastic lesions, and eventually overt PDAC. Interested in characterizing the effects of inflammation on normal pancreatic epithelial cells and how these effects cooperate with the activation of oncogenic KRAS to provide fitness and evolutionary advantages to the mutated cells, the long-term objectives of this project are to generate molecular signatures that can be used as biomarkers of progression as well as the identification of new therapeutic strategies to slow down tumor development.
Energetic metabolism of drug resistance.
Several studies, including ours, have suggested that tumor cells with features of cancer stem cells are typically resistant to conventional therapies due to their quiescence, the activation of alternative checkpoints and high expression of multidrug resistance-associated proteins. However, little has been done to understand the metabolic requirements of these cells. Recently, analyzing hundreds of post-operative specimens derived from patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant chemoradiation, we found that tumor cells surviving treatment are characterized by high mitochondrial mass and rely on oxidative metabolism for their survival. Understanding of the molecular programs responsible for this metabolic reprogramming is key to develop new approaches to eradicate residual disease and counteract the emerging of drug resistance in cancer.
Education & Training
M.D. - University of Turin School of Medicine (Italy) - 2000