Targeting aneuploidy in breast cancer

Federico Gulluni - PI

Assistant professor, University of Turin, Medical Faculty, Dept. of Molecular Biotechnology and Health Sciences, Italy

Ping Zhang PhD student (co-tutor)
Roberta Rubino PhD student (co-tutor)
Emanuele Fantastico Postgraduate fellow

Research activity

Aneuploidy, characterized by an abnormal number of chromosomes, is a well-established characteristic linked to cancer development. Unlike normal cells, which usually maintain a stable and predictable number of chromosomes (euploid), cancer cells frequently exhibit an erratic count (aneuploid). The objective of our research is to comprehend the significance of aneuploidy in cancer and to determine whether it presents vulnerabilities that can be targeted for treatment. Specifically, recent studies suggest that certain drugs, by making cancer cells even more aneuploid than they already are, might push them past a point of no return, causing catastrophic errors during cell division and ultimately leading to cell death (Figure 1).

Thinking of it like fixing a malfunctioning assembly line in a factory, the introduction of changes that make the process even more chaotic may reach a breaking point, causing the entire system to fail. In cancer cells, this failure is known as mitotic catastrophe (Figure 2). In our research focused on breast cancer, we explore the deficiency of phosphoinositide kinases, including PI3K-C2α. When these kinases are dysfunctional, they disrupt the normal arrangement and segregation of chromosomes during cell division, resulting in genomic instability. Our particular focus lies on two phosphoinositides (PIs) generated during this process: PI(3,4)P2 and its precursor PI(4)P, both playing a crucial role in concluding the cell division process. Essentially, our research suggests that disturbing the production of specific phosphoinositides during mitosis can prompt a rapid merging of cells in the initial phases of cell division. This results in an unusual increase in chromosome count, inducing chromosomal instability (CIN) and rendering cancer cells more susceptible to drugs targeting the cell division apparatus (Figure 2).

Moreover, disrupting the early stages of cell division in cancer cells, thus inducing CIN, may potentially trigger the expression of neoantigens derived from genomic instability itself. These neoantigens can activate the body’s natural defense against cancer – the immune response. Concurrently, CIN can activate signaling pathways that modulate the immune response, including the cGASSTING pathway. Therefore, we are adopting a dual strategy: 1) utilizing drugs to enhance aneuploidy in tumors, combined with drugs targeting chromosome segregation, to induce a catastrophic failure in cell division; and 2) identifying cancer vulnerabilities resulting from the activation of cGAS-STING-dependent responses to chromosomal instability (CIN) and the subsequent immune modulation associated with cancer progression (Figure 3). Through this dual-strategy approach, our goal is to enhance the efficacy of treatments in suppressing the growth of breast cancer cells.

FUTURE RESEARCH PLANS

Our upcoming research aims to unravel the intricate processes that lead to aneuploidy during the early stages of cell division in breast cancer. Our main objective is to investigate the molecular mechanisms orchestrating this phenomenon, employing genetic modifications and pharmacological interventions. The focus will be on manipulating key proteins, particularly phosphoinositide kinases and phosphatases, crucial in mitotic cell division. Concurrently, our future plans involve exploring the potential connection of these events to immune system alterations, specifically through the activation of the cGASSTING pathway. Furthermore, we seek to determine whether heightened aneuploidy renders breast cancer cells more susceptible to specific inhibitors targeting essential cell division checkpoints, such as the spindle assembly checkpoint (SAC) or cyclin-dependent kinases (CDKs). Essentially, our main goal is to unravel the complex coordination of cellular processes contributing to aneuploidy induction in breast cancer, with the ultimate objective of paving the way for potential breakthroughs in treatment strategies.

FUNDING ID (PAST 5 YEARS)

2023 – 2027 MFAG. Targeting aneuploidy for breast cancer therapeutics.
2023 – 2025 PRIN 2022. Characterization of extracellular vesicle biogenesis and content in Hepatocellular Carcinoma: circulating biomarkers of tumorigenesis and progression.
2020 – 2021 PEZCOLLER FOUNDATION-SIC. Defining The Role of PI3K-C2α as a New Prognostic Marker in Breast Cancer Progression.
2017 – 2019 AIRC/FIRC FELLOWSHIP FOR ITALY. Study of the role of PtdIns(3,4)P2 and PI3K-C2α in breast cancer

SELECTED PUBLICATIONS

Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer. Li H, Prever L, Hsu MY, Lo WT, Margaria JP, De Santis MC, Zanini C, Forni M, Novelli F, Pece S, Di Fiore PP, Porporato PE, Martini M, Belabed H, Nazare M, Haucke V, Gulluni F*, Hirsch E*. Adv Sci (Weinh). 2022 Mar;9(9):e2103249. doi: 10.1002/advs.202103249.
PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation. Gulluni F, Prever L, Li H, Krafcikova P, Corrado I, Lo WT, Margaria JP, Chen A, De Santis MC, Cnudde SJ, Fogerty J, Yuan A, Massarotti A, Sarijalo NT, Vadas O, Williams RL, Thelen M, Powell DR, Schueler M, Wiesener MS, Balla T, Baris HN, Tiosano D, McDermott BM Jr, Perkins BD, Ghigo A, Martini M, Haucke V, Boura E, Merlo GR, Buchner DA, Hirsch E. Science. 2021 Dec 10;374(6573):eabk0410. doi: 10.1126/science.abk0410.
Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer. Li H, Prever L, Hirsch E, Gulluni F. Cancers (Basel). 2021 Jul 14;13(14). doi: 10.3390/cancers13143517.
Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction. Tiosano D*, Baris HN*, Chen A*, Hitzert MM*, Schueler M*, Gulluni F*, Wiesener A, Bergua A, Mory A, Copeland B, Gleeson JG, Rump P, van Meer H, Sival DA, Haucke V, Kriwinsky J, Knaup KX, Reis A, Hauer NN, Hirsch E, Roepman R, Pfundt R, Thiel CT, Wiesener MS, Aslanyan MG, Buchner DA. PLoS Genet. 2019 Apr;15(4):e1008088. doi: 10.1371/ journal.pgen.1008088.
Class II PI3K Functions in Cell Biology and Disease. Gulluni F, De Santis MC, Margaria JP, Martini M, Hirsch E. Trends Cell Biol. 2019 Apr;29(4):339-359. doi: 10.1016/j.tcb.2019.01.001.
Cytokinetic Abscission: Phosphoinositides and ESCRTs Direct the Final Cut. Gulluni F, Martini M, Hirsch E. J Cell Biochem. 2017 Nov;118(11):3561-3568. doi: 10.1002/jcb.26066.
Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module. Wang H, Lo WT, Vujičić Žagar A, Gulluni F, Lehmann M, Scapozza L, Haucke V, Vadas O. Mol Cell. 2018 Jul 19;71(2):343- 351.e4. doi: 10.1016/j.molcel.2018.06.042.
Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function. Gulluni F, Martini M, De Santis MC, Campa CC, Ghigo A, Margaria JP, Ciraolo E, Franco I, Ala U, Annaratone L, Disalvatore 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, Hirsch E. Cancer Cell. 2017 Oct 9;32(4):444- 459.e7. doi: 10.1016/j.ccell.2017.09.002.
PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Franco I*, Gulluni F*, Campa CC*, Costa C*, Margaria JP, Ciraolo E, Martini M, Monteyne D, De Luca E, Germena G, Posor Y, Mafucci T, Marengo S, Haucke V, Falasca M, Perez-Morga D, Boletta A, Merlo GR, Hirsch E. Dev Cell. 2014 Mar 31;28(6):647-58. doi: 10.1016/j.devcel.2014.01.022.
Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Posor Y, Eichhorn-Gruenig M, Puchkov D, Schöneberg J, Ullrich A, Lampe A, Müller R, Zarbakhsh S, Gulluni F, Hirsch E, Krauss M, Schultz C, Schmoranzer J, Noé F, Haucke V. Nature. 2013 Jul 11;499(7457):233-7. doi: 10.1038/nature12360.

Ultimo aggiornamento: 11/11/2024