Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Miriam Martini - PI
Associate Professor, Univ. of Torino, Dept. of Molecular Biotechnology and Health Sciences.
Maria Chiara De Santis, senior postdoc
Andrea Costamagna, postdoc
Damiano Abbo, PhD student
Noemi Ghiglione, PhD student
Anastasia Bushunova, PhD student
Research activity
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer and is projected to become the second leading cause of cancer-related deaths worldwide by 2030. Despite advancements in diagnostic and treatment methods, the prognosis and early intervention for PDAC remain unsatisfactory. A comprehensive understanding of the molecular mechanisms governing the early stages of PDAC development is essential to devise improved prognostic and early intervention approaches.
Our laboratory focuses on pancreatic cancer biology, and we use a combination of approaches, including biochemistry, cell and molecular biology, and 3D cell culture models to define new signaling crosstalk mechanisms (Figure 1).
Studies using mouse models have indicated that PDAC originates from acinar cells in response to a mutation known as KrasG12D, a process termed acinar to ductal metaplasia (ADM). However, the specific mechanism by which mutant Kras induces ADM and contributes to PDAC development has not been fully elucidated. We have recently identified a connection between KrasG12D, ADM, and PDAC development through the involvement of the adaptor protein p130Cas. We demonstrated that p130Cas acts downstream of Kras, inducing the PI3K-AKT signaling pathway, thereby supporting its role in the early stages of PDAC development (Figure 2). We are currently studying more in depth this molecular mechanism in ductal-derived PDAC and its interaction with various subpopulations within the tumor microenvironment, as this knowledge could be pivotal in devising targeted therapeutic approaches for PDAC.
Resistance to chemotherapies represents a critical challenge for pancreatic cancer patients, thus novel therapeutic approaches for PDAC are desperately needed. A phenomenon that contributes to the dismal prognosis and chemoresistance is a unique characteristic of pancreatic cancer called desmoplasia, which results in reduced level of oxygen and nutrients. Deregulation of critical signaling pathways endows pancreatic cancer cell with specific features that support their survival in a harsh microenvironment. However, within this adversity, pancreatic cancer cells display remarkable adaptability through the deregulation of critical signaling pathways that confer specific traits supporting their survival. One such pathway that has garnered considerable attention in the context of pancreatic cancer is the mTOR signaling pathway. The hyperactivation of the mTORC1 pathway plays a pivotal role in the pathogenesis of PDAC, as it is essential for sustaining malignant growth and orchestrating a rewiring of cellular metabolism to meet the demands of rapid proliferation. The activation of mTORC1 is under the influence of various inputs, and amino acids play a particularly crucial role in driving its full activation. Among the recent discoveries in this area, we recently reported that PI(3,4)P2, a product of class II PI3K signaling, functions as a local repressor of mTORC1 signaling in response to fluctuations in glutamine levels (Figure 3). This newly uncovered interaction between PI(3,4)P2 and mTORC1 sheds light on the intricate regulatory mechanisms that enable pancreatic cancer cells to sense and respond to changes in nutrient availability. The tight control of mTORC1 activity through PI(3,4)P2 not only highlights the adaptability of cancer cells in harsh conditions but also presents a potential avenue for therapeutic intervention. Understanding these specific molecular interactions could pave the way for targeted therapies aimed at disrupting the survival strategies employed by pancreatic cancer cells and sensitizing them to existing treatments
Our research endeavors hold the promise of revolutionizing our understanding of pancreatic cancer biology, paving the way for novel and innovative treatment approaches to combat this formidable and life-threatening disease. Our primary focus lies in delving deep into the intricacies of the disease, aiming to shed new and illuminating light on its underlying mechanisms and vulnerabilities.
Specifically, we are committed to exploring alternative treatment strategies that can effectively challenge and overcome the resilience of pancreatic cancer. One of the key aspects we will investigate is the identification of new regulators within signaling pathways that play a crucial role in supporting the survival and growth of pancreatic cancer cells, especially during conditions of extreme nutrient deprivation, which is commonly observed in this particular type of cancer.
By deciphering the intricate signaling mechanisms that enable pancreatic cancer cells to thrive under harsh nutrient-deprived conditions, we aim to uncover potential therapeutic targets that can be harnessed to disrupt and debilitate the cancer cells, ultimately hindering their growth and progression. Our ultimate goal is to contribute to the validation of groundbreaking therapeutic strategies that hold the promise of significantly improving the prognosis and overall outcomes for patients with pancreatic cancer.
As it stands, pancreatic cancer is notoriously known for having one of the most unfavorable prognoses among all human cancers, with an alarmingly low 5-year survival rate of only 1%. However, we firmly believe that with our rigorous and cutting-edge research efforts, we can tip the scales in favor of the patients. By identifying and validating effective therapeutic approaches, we aspire to bring hope and a brighter future for those affected by this devastating disease.
The potential impact of our research extends far beyond the realms of pancreatic cancer. The insights gained from our investigations may have broader implications for cancer biology as a whole, offering valuable lessons and innovative strategies that could be adapted and applied to other challenging cancers as well.
In conclusion, through our dedicated pursuit of knowledge, our research aims to open up new avenues for understanding, diagnosing, and treating pancreatic cancer. By pushing the boundaries of scientific exploration, we aspire to contribute to the arsenal of weapons in the fight against this relentless disease, ultimately bringing renewed hope to patients, their families, and the medical community at large.
2020 Worldwide Cancer Research Grant
2023: AIRC (Associazione italiana ricerca sul cancro)-Individual Grants (IG).
De Santis MC, Gozzelino L, Margaria JP, Costamagna A, Ratto E, Gulluni F, Di Gregorio E, Mina E, Lorito N, Bacci M, Lattanzio R, Sala G, Cappello P, Novelli F, Giovannetti E, Vicentini C, Andreani S, Delfino P, Corbo V, Scarpa A, Porporato PE, Morandi A, Hirsch E, Martini M. Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer. Gut, 2022. doi: 10.1136/gutjnl-2021-325117.
Gozzelino L, Kochlamazashvili G, Baldassari S, Mackintosh AI, Licchetta L, Iovino E, Liu Y, Bennett CA, Bennett MF, Damiano JA, Zsurka G, Marconi C, Giangregorio T, Magini P, Kuijpers M, Maritzen T, Norata GD, Baulac S, Canafoglia L, Seri M, Tinuper P, Scheffer IE, Bahlo M, Berkovic SF, Hildebrand MS, Kunz WS, Giordano L, Bisulli F, Martini M*, Haucke V*, Hirsch E*, Pippucci T*. Defective lipid signaling caused by mTOR-activating ultra-rare variants in PIK3C2B underlies focal epilepsy. Brain. 2022. doi: 10.1093/brain/awac082.
Costamagna A, Natalini D, Leal MDPC, Simoni M, Gozzelino L, Cappello P, Novelli F, Ambrogio C, Defilippi P, Turco E, Giovannetti E, Hirsch E, Cabodi S, Martini M. Docking protein p130Cas regulates acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis. Gastroenterology, 2021. doi: 10.1053/j.gastro.2021.12.242.
Gulluni F*, Martini M*,#, De Santis MC*, Campa CC, Ghigo A, Margaria JP, Ciraolo E, Franco I, Ala U, Annaratone L, Di Salvatore D, Bertalot G, Viale G, Noatynska A, Compagno M, Sigismund S, Montemurro F, Thelen M, Fan F., Meraldi P, Marchiò C, Pece S, Sapino A, Chiarle R , Di Fiore PP and Hirsch E#. Mitotic spindle assembly and genomic stability in breast cancer require PI3K-C2A scaffolding function. CANCER CELL, 2017. doi: 10.1016/j.ccell.2014.11.007.
Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, Huang A, Wang Y, Nishtala M, Hall B, Rikova K, Zhao J, Hirsch E, Benes CH, Engelman JA. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. CANCER CELL, 2015. doi: 10.1016/j.ccell.2014.11.007.
Martini M, Russo M, Lamba S, Vitiello E, Crowley EH, Sassi F, Romanelli D, Frattini M, Marchetti A, Bardelli A(2013). Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis. CANCER RESEARCH, 2013. doi: 10.1158/0008-5472.CAN-12-3074
Bottos A*, Martini M*, Di Nicolantonio F, Comunanza V, Maione F, Minassi A, Appendino G, Bussolino F, Bardelli A. Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012. doi: 10.1073/pnas.1105026109
Martini M, Vecchione L, Siena S, Tejpar, Bardelli A. Targeted therapies: how personal should we go?. NATURE REVIEWS. CLINICAL ONCOLOGY, 2011. doi: 10.1038/nrclinonc.2011.164
Sartore-Bianchi A*, Martini M*, Molinari F*, Veronese S, Nichelatti M, Artale. S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. PIK3CA Mutations in Colorectal Cancer Are Associated with Clinical Resistance to EGFR-Targeted Monoclonal Antibodies. CANCER RESEARCH, 2009. doi: 10.1158/0008-5472.CAN-08-2466.
Di Nicolantonio F*, Martini M*, Molinari F*, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A. Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer. JOURNAL OF CLINICAL ONCOLOGY, 2008. doi: 10.1200/JCO.2008.18.0786
