Mario Leonardo Squadrito RicercatoreMedicina
Liver metastases arising from different types of tumors are associated with unfavorable prognosis and are often the cause of death in cancer patients. Whereas primary tumors are often surgically resettable, liver metastases can be definitively removed only in a minor number of cases. Moreover, most cancer therapies, including chemotherapy, immunotherapy and targeted therapy, show reduced efficacy when patients develop liver metastases. Therefore, it is of pivotal importance understanding the factors that promote metastatic dissemination and developing therapeutic strategies aimed at reducing the seeding of cancer cells.
In the last years, cancer immunotherapy has been recognized as an effective therapeutic option for a variety of cancer types. However, local and systemic immunosuppressive circuits thwart the efficacy of such treatments and thus only a minority of patients experience long-term clinical benefits. To improve cancer therapies, our group has been exploiting innovative cell-engineering strategies that activate immune responses to tumors.
Our current research aims at developing gene-engineering techniques that by targeting liver macrophages activate the immune system, limit metastatic spreading, and leverage conventional cancer therapy, such as cancer immunotherapy and targeted therapy. To this aim, we have engineered lentiviral vectors that convey powerful cytokines, such as interferon-alpha, or tumor antigens, to the liver. Furthermore, we are employing genetic interventions to overexpress or knockout genes of interest in liver macrophages to study their contribution to tumor progression.
High tittering lentiviral vector production, as well as cell-specific transcription and post-transcription regulatory sequences in the vector design ensure high targeting efficacy and specificity. Innovative liver-targeting genetic engineering provides a new therapeutic intervention to thwart metastatic spreading in patients at risk and enable systemic immune activation to revert tumor progression.
2012: PhD degree at the San Raffaele University, Milan, Italy and the Open University, UK.
2008: Master degree in Pharmaceutical Biotechnology (110/110 summa cum laude), University of L’Aquila, Italy.
2006: Bachelor degree in Biotechnology (110/110 summa cum laude), University of L’Aquila, Italy.
September 2018 – present: Project leader at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Targeted Cancer Gene Therapy Unit. Prof. Luigi Naldini
2012 – August 2018: Postdoc at the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland. Laboratory of angiogenesis and tumor-microenvironment, Prof. Michele De Palma.
2009 – 2012: PhD student at the San Raffaele Research Institute, Telethon Institute for Gene Therapy (TIGET) Milan, Italy. Supervisor: Prof. Michele De Palma; second supervisor: Prof. Luigi Naldini.
- Keklikoglou I, Cianciaruso C, Güç E, Squadrito ML, Spring LM, Tazzyman S, Lambein L, Poissonnier A, Ferraro GB, Baer C, Cassará A, Guichard A, Iruela-Arispe ML, Lewis CE, Coussens LM, Bardia A, Jain RK, Pollard JW, De Palma M. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Biol, 2019 Feb;21(2):190-202.
- Squadrito ML#, Hansen SK, Cianciaruso C, De Palma M#. EVIR: Chimeric receptors that enhance dendritic cell cross-dressing with tumor antigens. Nature Methods, 2018 Mar;15(3):183-186.
- Baer C*, Squadrito ML*#, Laoui D, Thompson D, Hansen SK, Kiialainen A, Hoves S, Ries CH, Ooi CH, De Palma M#. Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity. Nat Cell Biol. 2016 Jul;18(7):790-802.
- Squadrito ML, De Palma M. A niche role for periostin and macrophages in glioblastoma. Nat Cell Biol. 2015 Feb;17(2):107-9.
- Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD, Lyle R, Ibberson M, De Palma M. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 2014 Sep 11;8(5):1432-46.
- Escobar G, Moi D, Ranghetti A, Ozkal-Baydin P, Squadrito ML, Kajaste-Rudnitski A, Bondanza A, Gentner B, De Palma M, Mazzieri R, Naldini L. Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression. Sci Transl Med. 2014 Jan 1;6(217):217ra3.
- Squadrito ML, Etzrodt M, De Palma M, Pittet MJ. MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol. 2013 Jul;34(7):350-9.
- Squadrito ML, Pucci F, Magri L, Moi D, Gilfillan GD, Ranghetti A, Casazza A, Mazzone M, Lyle R, Naldini L, De Palma M. miR-511-3p modulates genetic programs of tumor-associated macrophages. Cell Rep. 2012 Feb 23;1(2):141-54.
- Takeda Y, Costa S, Delamarre E, Roncal C, Leite de Oliveira R, Squadrito ML, Finisguerra V, Deschoemaeker S, Bruyère F, Wenes M, Hamm A, Serneels J, Magat J, Bhattacharyya T, Anisimov A, Jordan BF, Alitalo K, Maxwell P, Gallez B, Zhuang ZW, Saito Y, Simons M, De Palma M, Mazzone M. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature. 2011 Oct 9;479(7371):122-6.
- Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, De Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 2011 Jan 18;19(1):31-44.
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