Experimental oncology
Preclinical models of cancer
This unit is interested in studying the processes underlying the formation and progression of haematological and solid tumours, with a particular interest for elucidating adaptive mechanisms that tumour cells ordain to establish a supporting tumour microenvironment.
In this respect, group specific interest lies in the tumorigenic functions of hypoxia inducible transcription factors (HIFs), which are implicated in regulating adaptive responses to hypoxic conditions in physiological and pathological conditions. HIF factors were initially identified as critical regulators of neo-angiogenesis, but more recently have been implicated in several other processes involved in tumour progression, such as metabolic switches occurring in conditions of low oxygen concentrations and high proliferation rates, cancer stem cell maintenance, cell migration and cell invasion. Moreover, HIF factors are currently being recognized as important regulators of tumour cell-microenvironment interactions.
Research activity
The unit study the function of these genes both in haematological malignancies, where their functions have been less studied, as well as in solid tumours. The group has identified novel pathways leading to the activation of HIF factors in sub-types of acute myeloid leukaemia, chronic lymphocytic leukaemia, and breast cancer, and they found that in different tumour contexts HIF factors play different and sometimes opposite functions, such as regulating cell migration or adhesion to stroma and retention in protective niches. Current interest is to elucidate the role of these genes in new tumour contexts and to better understand their regulation upon specific microenvironmental stimuli.
Magliulo D, Bernardi R. HIF-α factors as potential therapeutic targets in leukemia. Expert Opin Ther Targets. 2018, 22:917-928.
Ponente M, Campanini L, Cuttano R, Piunti A, Delledonne GA, Coltella N, Valsecchi R, Villa A, Cavallaro U, Pattini L, Doglioni C, Bernardi R. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes. JCI Insight. 2017 Feb 23; 2(4): e87380.
Soncini M, Corna G, Moresco M, Coltella N, Restuccia U, Maggioni D, Raccosta L, Lin CY, Invernizzi F, Crocchiolo R, Doglioni C, Traversari C, Bachi A, Bernardi R, Bordignon C, Gustafsson JÅ, Russo V. 24- Hydroxycholesterol participates in pancreatic neuroendocrine tumor development. Proc. Natl. Acad. Sci. USA 2016 Oct 11;113(41):E6219-E6227.
Migliavacca J, Percio S, Valsecchi R, Ferrero E, Spinelli A, Ponzoni M, Tresoldi C, Pattini L, Bernardi R*, Coltella N*. Hypoxia inducible factor-1a regulates a pro-invasive phenotype in acute monocytic leukemia. Oncotarget. 2016 Aug 16;7(33):53540-53557.
Valsecchi R, Coltella N, Belloni D, Ponente M, Ten Hacken E, Scielzo C, Scarfò L, Bertilaccio MT, Brambilla P, Lenti E, Martinelli Boneschi F, Brendolan A, Ferrero E, Ferrarini M, Ghia P, Tonon G, Ponzoni M, Caligaris Cappio F, Bernardi R. HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment. Blood 2016 Apr 21;127(16):1987-97.
Coltella N, Valsecchi R, Ponente M, Ponzoni M, Bernardi R. Synergistic leukemia eradication by combined treatment with retinoic acid and HIF inhibition by EZN-2208 (PEG-SN38) in preclinical models of PML-RARα and PLZF-RARα driven leukemia. Clin Cancer Res. 2015 Aug 15;21(16):3685-94.
Guarnerio J, Riccardi L, Taulli R, Maeda T, Wang G, Hobbs RM, Song MS, Sportoletti P, Bernardi R, Bronson RT, Castillo-Martin M, Cordon-Cardo C, Lunardi A, Pandolfi PP. A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells. Cancer Discov. 2015 Apr;5(4):396-409.
Percio S, Coltella N, Grisanti S, Bernardi R, Pattini L. A HIF-1 network reveals characteristics of epithelial-mesenchymal transition in acute promyelocytic leukemia. Genome Med. 2014; 6(12): 84.
Bernardi R, Gianni L. Hallmarks of triple negative breast cancer emerging at last? Cell Res. 2014 Aug; 24(8): 904–905.
Guarnerio J, Coltella N, Ala U, Tonon G, Pandolfi PP, Bernardi R. Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis. Stem Cell Reports 2014 May 15;2(6):794-809.
Coltella N, Percio S, Valsecchi R, Cuttano R, Guarnerio J, Ponzoni M, Pandolfi PP, Melillo G, Pattini L, Bernardi R. HIF factors cooperate with PML-RARα to promote acute promyelocytic leukemia progression and relapse. EMBO Mol Med. 2014 May;6(5):640-50.
