A reactive species reactions module for integration into genome-scale metabolic models for improved insights: Application to cancer

Subasree Sridhar; Prerna Bhalla; Justin Kullu; Sriya Veerapaneni; Swagatika Sahoo; Nirav Bhatt; G K Suraishkumar

doi:10.1016/j.ymben.2023.08.006

A reactive species reactions module for integration into genome-scale metabolic models for improved insights: Application to cancer

Metab Eng. 2023 Nov:80:78-93. doi: 10.1016/j.ymben.2023.08.006. Epub 2023 Sep 7.

Authors

Subasree Sridhar¹, Prerna Bhalla², Justin Kullu², Sriya Veerapaneni², Swagatika Sahoo³, Nirav Bhatt⁴, G K Suraishkumar⁵

Affiliations

¹ Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building - 1 and 2, Indian Institute of Technology Madras, Chennai, 600 036, India; Centre for Integrative Biology and Systems medicinE, Indian Institute of Technology Madras, Chennai, 600 036, India.
² Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building - 1 and 2, Indian Institute of Technology Madras, Chennai, 600 036, India.
³ Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, 600 036, India.
⁴ Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building - 1 and 2, Indian Institute of Technology Madras, Chennai, 600 036, India; Centre for Integrative Biology and Systems medicinE, Indian Institute of Technology Madras, Chennai, 600 036, India; Robert Bosch Centre for Data Science and Artificial Intelligence, Indian Institute of Technology Madras, Chennai, 600 036, India. Electronic address: niravbhatt@iitm.ac.in.
⁵ Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building - 1 and 2, Indian Institute of Technology Madras, Chennai, 600 036, India. Electronic address: gk@iitm.ac.in.

PMID: 37689259
DOI: 10.1016/j.ymben.2023.08.006

Abstract

Reactive species (RS) play significant roles in many disease contexts. Despite their crucial roles in diseases including cancer, the RS are not adequately modeled in the genome-scale metabolic (GSM) models, which are used to understand cell metabolism in disease contexts. We have developed a scalable RS reactions module that can be integrated with any Recon 3D-derived human metabolic model, or after fine-tuning, with any metabolic model. With RS-integration, the GSM models of three cancers (basal-like triple negative breast cancer (TNBC), high grade serous ovarian carcinoma (HGSOC) and colorectal cancer (CRC)) built from Recon 3D, precisely highlighted the increases/decreases in fluxes (dysregulation) occurring in important pathways of these cancers. These dysregulations were not prominent in the standard cancer models without the RS module. Further, the results from these RS-integrated cancer GSM models suggest the following decreasing order in the ease of ferroptosis-targeting to treat the cancers: TNBC > HGSOC > CRC.

Keywords: Cancer metabolism; Ferroptosis; Genome-scale metabolic models; Reactive species.

MeSH terms

Genome
Humans
Triple Negative Breast Neoplasms* / genetics