A combined experimental-computational approach uncovers a role for the Golgi matrix protein Giantin in breast cancer progression

Abstract

Few studies so far have investigated the impact of different cell migration traits on tumor progression. 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 induced by depletion of Giantin, a Golgi matrix protein, the downregulation of which correlates with poor patient survival. Applying the migration and invasion traits of Giantin depleted 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.

Initial refinement of data from video‐based single‐cell tracking

“…This information holds significant prognostic value by providing indications of cellular response and potential outcomes associated with specific interventions. For instance, it can contribute to the identification of distinct migration and persistence values that may correlate with the rate of intravasation [46].…”

“…Such data can also have direct interest in special studies. [46] for example, argue for the importance of acquiring such data for better understanding tumor growth rate and size.…”

The Golgi complex is a regulatory hub for homologous recombination-mediated DNA repair

“…Interestingly, other members of the Golgin family have also been reported to alter HR repair rates (Adamson et al, 2012) and phosphorylation of DDR signalling protein, H2AX (Paulsen et al, 2009). Numerous studies have also implicated the role of the Golgins in cancer progression (Baschieri et al, 2015;Bhat et al, 2017;Bui et al, 2021;Ghannoum et al, 2022) and although further studies are required to clarify their role, these observations raise the intriguing possibility that this protein family can be integral for DDR regulation. Taking in the wide array of novel double-localising proteins identified in our study and their respective roles in important cellular processes such as membrane trafficking, cell cycle and DNA damage response, our results propose a high degree of interconnectivity between the secretory membrane system and nuclear compartment.…”

“…Interestingly, other members of the Golgin family have also been reported to alter HR repair rates (Adamson et al, 2012) and phosphorylation of DDR signalling protein, H2AX (Paulsen et al, 2009). Numerous studies have also implicated the role of the Golgins in cancer progression (Baschieri et al, 2015; Bhat et al, 2017; Bui et al, 2021; Ghannoum et al, 2022)and although further studies are required to clarify their role, these observations raise the intriguing possibility that this protein family can be integral for DDR regulation.…”

“…Interestingly, similarly to Giantin, other members of the Golgin family have also been reported to HR rates 28 and DDR signalling protein 29 . Furthermore, numerous studies have also implicated the role of Giantin and the Golgins in cancer progression 14,35–37 and although further studies are required to clarify their role, these observations raise the intriguing possibility that this protein family can be integral for DDR regulation.…”