Mechanism allowing pancreatic cancer cells to survive and proliferate in the absence of nutrients identified
An international study published in the journal Nature Signal Transduction and Targeted Therapy, which involved the multidisciplinary collaboration of several centres in Italy, including Sapienza University of Rome, revealed for the first time the mechanism of survival and neoplastic progression of this tumour, paving the way for new therapeutic approaches
Biologically, cancer cells are under constant stress: their microenvironment is low in oxygen and particularly low in nutrients. This is particularly true of pancreatic cancer, one of the most dreaded and often treatment-resistant neoplasms of our time. How pancreatic cancer can maintain a high proliferation rate in the absence of nutrients is still unknown.
An international study published in the journal Nature Signal Transduction and Targeted Therapy, and involving multidisciplinary collaboration between several centres in Italy, including Sapienza University of Rome, revealed for the first time the mechanism of survival and progression of this tumour, paving the way for new therapeutic approaches.
According to the researchers, this is due to the lack of expression of a small non-coding RNA molecule (microRNA) called miR-15a, which is normally expressed in the healthy pancreas but is often lost during the early stages of neoplastic transformation. The miR-15a acts as a molecular brake that keeps the levels of the Fra-2 protein, a transcription factor that is crucial for the tumour's response to stress, at a constant low level.
In the absence of miR-15a, tumour cells stimulated by nutrient deficiency are free to express the transcription factor Fra-2, which cascades to activate the transcription of genes crucial for their survival. Among the target genes of Fra-2 is the IGF1-receptor, which is responsible for the proliferative stimulus.
“The discovery of this mechanism”, says Gian Luca Rampioni Vinciguerra, the study's first name and a researcher at the Department of Clinical and Molecular Medicine of Sapienza," improves our understanding of the disease and provides a useful rationale for the design of therapies. In our models, pancreatic cancer under nutrient deprivation becomes dependent on the activation of the IGF1 receptor and therefore extremely sensitive to its pharmacological inhibition, which becomes a very effective weapon against tumour growth".
The work was initiated by Professor Carlo Maria Croce (The Ohio State University, USA), the most cited Italian scientist in the world according to Top Italian Scientists, who has made fundamental discoveries in the field of cancer genetics throughout his long career. The research also benefited from the multidisciplinary collaboration of several centres in Italy, including Sapienza University of Rome, the Universities of Modena and Reggio Emilia, and the Centro di Riferimento Oncologico of Aviano.
References:
Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma - Gian Luca Rampioni Vinciguerra, Marina Capece, Luca Reggiani Bonetti, Giovanni Nigita, Federica Calore, Sydney Rentsch, Paolo Magistri, Roberto Ballarin, Fabrizio Di Benedetto, Rosario Distefano, Roberto Cirombella, Andrea Vecchione, Barbara Belletti, Gustavo Baldassarre, Francesca Lovat & Carlo M. Croce - Signal Transduction and Targeted Therapy 2024. https://doi.org/10.1038/s41392-024-01740-4
Further Information
Gian Luca Rampioni Vinciguerra
Department of Clinical and Molecular Medicine
gianluca.rampionivinciguerra@uniroma1.it
Friday, 23 February 2024