Dottorato in Fisiopatologia Medica

Contatti

Supervisore

Maria Felice Brizzi

Tesi di dottorato

“Interleukin-3 boosts triple negative breast cancer stemness via miR-155-5p-driven Wnt/β-catenin pathway”

 

Triple negative breast cancer (TNBC) remains the most aggressive breast cancer subtypes with a very poor prognosis, currently deemed as an orphan disease still lacking effective therapeutic strategies. Our previous studies demonstrated that the Interleukin-3-Receptor-α (IL-3Rα) was highly expressed in TNBC. In the present study we aimed to dissect the mechanisms related to IL-3 -mediated biological action. Firstly, the clinical datasets analysis revealed that IL-3 was prevalently expressed in TNBC respect to different breast cancer subtypes and normal breast tissue. Interestingly, IL-3 expression correlated with the miR-155-5p production, a conserved process often involved in the pathogenesis of acute myeloid leukaemia (AML). However, among different TNBC cells subset, only Hs-578T and MDA-MB-436 cell lines was responsive to IL-3 in terms of miR-155-5p regulation. Indeed, IL-3 treatment induced STAT5 -mediated transcription of miR-155-5p in cancer cells. Furthermore, the action of miR-155-5p translated in APC and GSK-3β down-regulation impacting on β-catenin nuclear translocation and c-myc expression. These findings matched with the IL-3 -induced expansion of stem-like ALDH1A1 and CD44^high/CD24^low positive subpopulations and an enhanced tumor progression. Noteworthy, IL-3 stimulated the formation of cancer stem cells (CSCs) enriched mammospheres from which its release was most sustained, acting as autocrine-loop. On the other hand, the tumor suppressor PDCD4 was targeted and suppressed by the miR-155-5p further enhancing c-myc transcription. In conclusion, the aim of this study was to demonstrate the importance of pro-inflammatory factors as IL-3 in promoting the stemness maintenance, acting on miR-155-5p -targeted Wnt/β-catenin pathway and triggering tumor growth and metastatic spreading.

Attività di ricerca

1st year attended lessons:

Approaches to scientific reasearch:
- Livio Trusolino: Precision medicine in oncology: Putting drivers and targets in context
- Riccarda Granata: How to write a scientific paper
- Stefania Bruno: How to set up an in vivo experimental model
- Milena Maule:
(1) Fitting regression models: interpretation of regression coefficients, uncertainty measures and hypothesis testing;
(2) Regression models: from the linear model to the generalised linear models. Interpretation of interactions between predictors.

- Benedetta Bussolati: Scientific presentations

Pathophysiological basis of diseases:
- Franco Veglio: Update on physiology of hypertension
- Massimo Porta: Etiopathogenesis of diabetic retinopathy

- Gabriella Gruden: Physiopathology of diabetic nephropathy.
- Desireè Deandreis: Targets for functional imaging in medicine.
- Marilena Durazzo: Physiopathology of autoimmune hepatitis

2nd year attended lessons:

Pathophysiological basis of diseases: cardiovascular, metabolism and oncology

- Emanuela Arvat: Cancer survivors: pathophysiology of late-effects and challenges in their management
- Gabriella Gruden: Diabetic nephropathy
- Benedetta Bussolati: Extracellular vesicles and liquid biopsy
- Elisabetta Bugianesi: Impact of the metabolic syndrome on the digestive tract

3rd year attended lessons:

Pathophysiology and innovative therapeutic approaches of diseases

Emanuela Arvat: Cancer survivors: pathophysiology of late-effects and implication for translational application

Alberto Milan: Pathophysiology of cardiovascular hemodynamics and translational application

Renato Romagnoli: Therapeutic strategies for liver transplant

Paolo Mulatero: Genetic Forms of Hypertension

Luigi Biancone: Current and future directions of kidney transplantation

Benedetta Bussolati / Alessia Brossa: Extracellular vesicles and regenerative medicine

 

PRIZES AND AWARD

2023: Best Poster Presentation by a Young Scientist. 3rd EVita Symposium (Urbino, Semptember 13-15 2023).

2023: MOVE scholarship for participation to the MOVE Symposium, grant from EVita Society (Malaga, October 24-27 2023).

POSTERS AND SPEAKS

2023: Oral communication: “Circulating extracellular vesicles derived from tumor endothelial cells hijack the local and systemic anti-tumor immune response: Role of mTOR/ G-CSF pathway”. 1st MOVE symposium (Malaga, October 24-27 2023).

2023: Poster presentation: “Circulating extracellular vesicles derived from tumor endothelial cells hijack the local and systemic anti-tumor immune response: Role of mTOR/ G-CSF pathway”. 3rd EVita Symposium (Urbino, Semptember 13-15 2023).

2022: Poster Presentation: “IL-3 signalling in the tumour microenvironment shapes the immune response via tumour endothelial cell-derived extracellular vesicles”. 62nd annual Meeting of the Italian Cancer Society: “The exciting path from preclinical research to clinical application” (Venice, November 16-18, 2022).

LICENSES AND CERTIFICATIONS

2024: Laboratory Animal Science (mouse/rat) - BERLIN, EU Function A, D (formerly FELASA B) from Humboldt-Universität zu Berlin.

2024: Biomedical Summer School – Medical University of Vienna.

PhD VISITING:

01/07/2024 - 01/10/2024: Medical University of Vienna

Center for Biomedical Research and Translational Surgery, Cardiovascular Institute, Medical University of Vienna

Establishment of a new mouse model of Ischemia-Reperfusion Injury (IRI) and Myocardial infarction (MI) to test the cardioprotective effects of serum derived- extracellular vescicles (EVs) from patients affected by Coronary Artery Disease (CAD)

Papers:

Sarcinella, A.; Femminò, S.; Brizzi, M.F. Extracellular Vesicles: Emergent and Multiple Sources in Wound Healing Treatment. Int. J. Mol. Sci. 2023, 24, 15709. https://doi.org/10.3390/ijms242115709

Koni M, Lopatina T, Grange C, Sarcinella A, Cedrino M, Bruno S, Buffolo F, Femminò S, Camussi G, Brizzi MF. Circulating extracellular vesicles derived from tumor endothelial cells hijack the local and systemic anti-tumor immune response: Role of mTOR/G-CSF pathway. Pharmacol Res. 2023 Sep;195:106871. doi: 10.1016/j.phrs.2023.106871. Epub 2023 Jul 26. PMID: 37506784.

Lopatina T, Sarcinella A, Brizzi MF. Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion. Cancers (Basel). 2022 Aug 20;14(16):4020. doi: 10.3390/cancers14164020. PMID: 36011012; PMCID: PMC9406972.

Salemme V, Vedelago M, Sarcinella A, Moietta F, Piccolantonio A, Moiso E, Centonze G, Manco M, Guala A, Lamolinara A, Angelini C, Morellato A, Natalini D, Calogero R, Incarnato D, Oliviero S, Conti L, Iezzi M, Tosoni D, Bertalot G, Freddi S, Tucci FA, De Sanctis F, Frusteri C, Ugel S, Bronte V, Cavallo F, Provero P, Gai M, Taverna D, Turco E, Pece S, Defilippi P. p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response. Nat Commun. 2023 May 11;14(1):2350. doi: 10.1038/s41467-023-37824-y. PMID: 37169737; PMCID: PMC10175288.

Gibello L, D'Antico S, Salafia M, Senetta R, Pomatto MAC, Orlando G, Sarcinella A, Lopatina T, Quaglino P, Lorenzi M, Verzini F, Camussi G, Brizzi MF. First pilot case-control interventional study using autologous extracellular vesicles to treat chronic venous ulcers unresponsive to conventional treatments. Pharmacol Res. 2023 Apr;190:106718. doi: 10.1016/j.phrs.2023.106718. Epub 2023 Mar 5. PMID: 36878306.

Koni M, Castellano I, Venturelli E, Sarcinella A, Lopatina T, Grange C, Cedrino M, Femminò S, Cossu-Rocca P, Orrù S, D'Ascenzo F, Cotellessa I, Tampieri C, Debernardi C, Cugliari G, Matullo G, Camussi G, De Miglio MR, Brizzi MF. Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target. Cancers (Basel). 2022 Aug 13;14(16):3918. doi: 10.3390/cancers14163918. PMID: 36010912; PMCID: PMC9406043.