Spheroids formation during epithelial ovarian cancer progression correlates with peritoneal organ colonization, disease recurrence, and poor prognosis. Although cancer progression has been demonstrated to be associated with and driven by metabolic changes within transformed cells, possible associations between metabolic dynamics and metastatic morphological transitions remain unexplored. To address this problem, we performed quantitative proteomics to identify protein signatures associated with three distinct morphologies (2D monolayers and two geometrically individual three-dimensional spheroidal states) of the high-grade serous ovarian cancer line OVCAR-3. Integrating the protein states onto genome-scale metabolic models allowed us to construct context-specific metabolic models for each morphological stage of the OVCAR-3 cell line and systematically evaluate their metabolic functionalities. We obtained disease-driving metabolic reaction modules using these models and elucidated gene knockout strategies to reduce metabolic alterations associated with disease progression. We explored the DrugBank database to mine pharmacological agents and evaluated the effect of drugs in impairing cancer progression. Finally, we experimentally validated our predictions by confirming the ability of one of our predicted drugs: the neuraminidase inhibitor oseltamivir, to disrupt the metastatic spheroidal morphologies without any cytotoxic effect on untransformed stromal mesothelial monolayers.
Aim: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with high heterogeneity, rapid progression, and paucity of treatment options. The most effective chemotherapeutic drug used to treat TNBC is doxorubicin (Doxo) which is an anthracycline antibiotic. However, Doxo treatment alters cytosolic calcium dynamics leading to drug-resistance condition. The aim of this study is to capture the alterations in the activity of various calcium channels and pumps during Doxo treatment and their consequences on cytosolic calcium dynamics that ultimately result in drug resistance. Methods: In the present study, a mathematical model is proposed to capture the complex dynamical landscape of intracellular calcium during Doxo treatment. This study provides an insight into Doxo remodeling of calcium dynamics and associated drug-resistance effect. The model was first analyzed analytically and then explored through numerical simulation using techniques like global sensitivity analysis, parameter recalibration, etc. Results: The model is used to predict the potential combination therapy for Doxo that can overcome Doxo associated drug resistance. The results show targeting the dysregulated Ca2+ channels and pumps might provide efficient chemotherapy in TNBC. It was also observed that the indispensability of calcium influx rate is paramount in the Doxo drug resistance. Finally, three drugs were identified from existing literature that could be used as a combination therapy along with Doxo. Conclusions: The investigation highlights the importance of integrating the calcium signaling of various calcium regulating compounds for their effective anti-tumor effects deliverance along with chemotherapeutic agents. The results from this study might provide a new direction to the experimental biologists to explore different combination therapies with Doxo to enhance its anti-tumor effect.
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