Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Chiara Riganti - PI
Full professor of Biochemistry, Dept. of Oncology, University of Torino
- Prof. Chiara Riganti, MD (PI, full professor of biochemistry)
- Dr. Joanna Kopecka, PhD, tenure-track assistant professor
- Dr. Iris Chiara Salariglio, PhD, tenure-track assistant professor
- Dr. Simona Dobiasova, MSCA post-doc research fellow
- Dr. Giulianmichela Di Palma, MSc, PhD student
- Dr. Sabrina Digiovanni, MSc, PhD student
- Dr. Simona Fontana, MSc, PhD student
- Dr. Niloufar Jafari, PhD student
- Dr. Stefano Boetti, research fellow
- Dr. Angelo Meoli, research fellow
- Mr. Costanzo Costamagna, lab manager
RESEARCH ACTIVITY
New predictive biomarkers and therapeutic targets of tumor chemo-immunoresistance
Achieving a good efficacy of chemotherapy and an effective activation of the host immune system against the tumor are two major challenges still unresolved in patients with disseminated and metastatic tumors.
The main limitation to the efficacy of chemotherapy is multidrug resistance (MDR), a multiple cross-resistance towards different anticancer drugs. One of the main mechanisms of MDR is the overexpression of integral membrane transporters, belonging to the ATP binding cassette (ABC) transporters family, such as P-glycoprotein, MDR related proteins, breast cancer resistance protein, which efflux classical chemotherapeutic drugs as well as new “smart drugs” for targeted-therapies. All the pharmacological inhibitors of ABC transporters have failed in pre-clinical and clinical stages for their low specificity and high toxicity. Recent high-throughput screenings of pharmacological libraries progressively identified specific compounds, which were unexpectedly more effective in chemoresistant cells than in chemosensitive ones. However, the molecular basis of this paradoxical hypersensitivity- known as “collateral sensitivity” (CS) – are far from being understood.
Besides killing MDR cells, the successful tumor eradication depends on the ability of chemotherapy to kill tumor cells in a way detectable by the immune system, i.e. inducing an immunogenic cell death (ICD). Only specific drugs, like doxorubicin (Dox), mitoxantrone and oxaliplatin, have this property. Until now, there are not chemotherapeutic drugs and immunotherapy tools specifically designed for MDR tumors. Moreover, there are no chemosensitizing compounds with the dual property of inducing selective cytotoxicity (i.e. producing CS) in chemoresistant cells and re-activating the host immune system response (i.e. producing ICD) against them.
Our research group works on chemo-immunosensitive and chemo-immunoresistant tumor models (lung, prostate and breast cancer, malignant pleural mesothelioma, glioblastoma multiforme, multiple myeloma). We aim to:
- investigate the molecular and metabolic basis of chemo-immunoresistant phenotype, in order to identify new therapeutic targets and diagnostic/predictive markers;
- target ER stress proteins and mitochondrial homeostasis as vulnerabilities peculiar of chemo-immuno-resistant tumors that can be exploited to restore sensitivity to chemotherapy and immunotherapy in resistant cells.
- repurpose existing drugs or validate new ad hoc synthesized compounds, with the dual property of inducing CS and ICD in chemo-immunoresistant cancer cells.
Subline research a: Dissecting the endoplasmic reticulum-mitochondria network to overcome chemo-immuno-resistance in cancer cells
(Figura 1)
Research subline b: Disrupting the bad metabolic liaisons determining chemo-immuno-resistance (Figura 2)
A key factor determining chemo- and immune-resistance in non-small cell lung cancer is the ER stress-sensitive transcription factor CCAAT/Enhancer Binding Protein-β (C/EBP-β) that has two splicing isoforms: LAP and LIP that produce opposite effects and opposite metabolic rewiring via ncRNA-circuitries in murine embryonic fbroblasts. No data exists in cancer. We are investigating a series of competing endogenous RNAs (ceRNAs), predicted to control the splicing of C/EBP-β, to find new chemo-immunosenistizer strategy.
2025-2027
Project title: GBM4EPI- Development of glioblastoma and blood-tumour barrier models for investigating the combination therapy of anticancer agents and efflux pump inhibitors. Source: HORIZON-MSCA-2023-PF-01-01
2024-2028
Project title: How ncRNAs control (immuno)metabolism in lung cancer: new biomarkers of chemoimmune-resistance, new druggable targets. Source: AIRC (Italian Association for Cancer Research; IG29250 - “Investigator Grant 2023” program)
2024-2026
Project title: Inducing BRCAness in pancreatic cancer by modulating a glycolytic branch
Source: MUR – Ministero del’Università e della Ricerca – Bando PRIN 2022
2023-2024
Project title: Novel DNA alkylating agents as immune-sensitizers in malignant pleural mesothelioma. Source: PharmaMar research contract
Project title: Novel PI3K-delta inhibitors as chemo-immune-sensitizers in thoracic cancers. Source: iOnctura research contract
La Vecchia S, Fontana S, Salaroglio IC, Anobile DP, Digiovanni S, Akman M, Jafari N, Godel M, Costamagna C, Corbet C, Kopecka J, Riganti C. Increasing membrane polyunsaturated fatty acids sensitizes non-small cell lung cancer to anti-PD-1/PD-L1 immunotherapy. Cancer Lett 2024, 604: 217221
Salaroglio IC, Stefanova D, Teixeira RG, Oliveira NFB, Ahmed A, Fusi F, Tzankova V, Yordanov Y, Machuqueiro M, Saponara S, Valente A, Riganti C. A novel combinatory treatment against a CDDP-resistant non-small cell lung cancer based on a Ruthenium(II)-cyclopentadienyl compound. Pharmacol Res 2024, 208: 107353
Akman M, Monteleone C, Doronzo G, Godel M, Napoli F, Merlini A, Campani V, Nele V, Balmas E, Chontorotzea T, Fontana S, Digiovanni S, Barbu FA, Astanina E, Jafari N, Salaroglio IC, Kopecka J, De Rosa G, Mohr T, Bertero A, Righi L, Novello S, Scagliotti GV, Bussolino F, Riganti C. TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer. J Exp Clin Cancer Res. 2024;43(1):219
Anobile DP, Salaroglio IC, Tabbò F, La Vecchia S, Akman M, Napoli F, Bungaro M, Benso F, Aldieri E, Bironzo P, Kopecka J, Passiglia F, Righi L, Novello S, Scagliotti GV, Riganti C. Autocrine 17-β-estradiol/estrogen receptor-α loop determines the response to immune-checkpoint inhibitors in non-small cell lung cancer. Clin Cancer Res. 2023 Jun 7:CCR-22-3949. doi: 10.1158/1078-0432.CCR-22-3949
Salaroglio IC, Belisario DC, Akman M, La Vecchia S, Godel M, Anobile DP, Ortone G, Digiovanni S, Fontana S, Costamagna C, Rubinstein M, Kopecka J, Riganti C. Mitochondrial ROS drive resistance to chemotherapy and immune-killing in hypoxic non-small cell lung cancer. J Exp Clin Cancer Res 2022, 41:243; doi: 10.1186/s13046-022-02447-6
Kopecka J, Salaroglio IC, Perez-Ruiz E, Sarmento-Ribeiro AB, Saponara S, De Las Rivas J, Riganti C. Hypoxia as a driver of resistance to immunotherapy. Drug Resist Update 2021, 18: 100787. doi: 10.1016/j. drup.2021.100787.
Salaroglio IC, Kopecka J, Napoli F, Pradotto M, Maletta F, Costardi L, Gagliasso M, Milosevic V, Ananthanarayanan P, Bironzo P, Tabbò F, Cartia CF, Passone E, Comunanza V, Ardissone F, Rufini E, Bussolino F, Righi L, Novello S, Di Maio M, Papotti M, Scagliotti GV, Riganti C. Potential diagnostic and prognostic role of micro-environment in malignant pleural mesothelioma. J Thor Oncol 2019, 14(8):1458-1471; doi: 10.1016/j.jtho.2019.03.029
Alexa-Stratulat T, Pešić M, Čipak Gašparović A, Trougakos IP, Riganti C.. What sustains the multidrug resistance phenotype beyond ABC eflux transporters? Looking beyond the tip of the iceberg. Drug Resist Update 2019, 46:100643. doi: 10.1016/j.drup.2019.100643
Castella B, Kopecka J, Sciancalepore P, Mandili G, Foglietta M, Mitro N, Caruso D, Novelli F, Riganti C*, Massaia M*. Mechanisms of phosphoantigen release and Vγ9Vδ2 T-cell activation by dendritic cells. Nat Commun 2017, 8:15663 * co-last authors. doi: 10.1038/ncomms15663
Salaroglio IC, Panada E, Moiso E, Buondonno I, Provero P, Rubinstein M, Kopecka J, Riganti C. PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Mol Cancer 16:e91, 2017; doi: 10.1186/s12943-017-0657-0
Riganti C, Kopecka J, Panada E, Barak S, Rubinstein M. The Role of C/EBP-β LIP in Multidrug Resistance. J Natl Cancer Inst 2015, 107(5): djv046; doi: 10.1093/ jnci/djv046
