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- Title
A combined experimental-computational approach uncovers a role for the Golgi matrix protein Giantin in breast cancer progression.
- Authors
Ghannoum, Salim; Fantini, Damiano; Zahoor, Muhammad; Reiterer, Veronika; Phuyal, Santosh; Leoncio Netto, Waldir; Sørensen, Øystein; Iyer, Arvind; Sengupta, Debarka; Prasmickaite, Lina; Mælandsmo, Gunhild Mari; Köhn-Luque, Alvaro; Farhan, Hesso
- Abstract
Our understanding of how speed and persistence of cell migration affects the growth rate and size of tumors remains incomplete. To address this, we developed a mathematical model wherein cells migrate in two-dimensional space, divide, die or intravasate into the vasculature. Exploring a wide range of speed and persistence combinations, we find that tumor growth positively correlates with increasing speed and higher persistence. As a biologically relevant example, we focused on Golgi fragmentation, a phenomenon often linked to alterations of cell migration. Golgi fragmentation was induced by depletion of Giantin, a Golgi matrix protein, the downregulation of which correlates with poor patient survival. Applying the experimentally obtained migration and invasion traits of Giantin depleted breast cancer cells to our mathematical model, we predict that loss of Giantin increases the number of intravasating cells. This prediction was validated, by showing that circulating tumor cells express significantly less Giantin than primary tumor cells. Altogether, our computational model identifies cell migration traits that regulate tumor progression and uncovers a role of Giantin in breast cancer progression. Author summary: The Golgi is a specialised structure inside cells that functions as a factory where molecules necessary for diverse cell functions are modified and sorted for transport. One of the proteins that maintains the physical structure of the Golgi is called Giantin. We found that breast cancer patients whose tumors have lower Giantin die earlier compared to patients with higher Giantin tumors. To find an explanation, we induced Golgi fragmentation in breast cancer cells by depleting Giantin. Interestingly, we found that Giantin depletion alters the migratory and invasive properties of those cells. To understand the implications of altered migration and invasion, we run computer simulation of tumor growth and progression with and without Giantin depletion. Our simulations predicted that Giantin-depleted tumors, while smaller, are nevertheless capable of seeding more cells inside the circulatory system. This is a precondition for the formation of metastases in distant organs, which is the major factor that determines mortality in breast cancer patients. To validate our model prediction, we showed that breast cancer cells that have enter the circulatory system have lower Giantin that the tumors in the breast where the cancer was originated. In summary, our combination of modeling and experimental validation provides a possible explanation for poor survival of breast cancer patients with low Giantin levels.
- Publication
PLoS Computational Biology, 2023, Vol 19, Issue 4, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1010995