# Integrative systems‐level analysis reveals a contextual crosstalk between hypoxia and global metabolism in human breast tumors

## TL;DR

This study shows that hypoxia and metabolism in breast tumors interact in complex ways, with hypoxia strongly linked to metabolic changes and tumor aggressiveness.

## Contribution

The study reveals a contextual crosstalk between hypoxia and global metabolism in breast tumors using systems-level analysis of over 2000 samples.

## Key findings

- Hypoxia is strongly associated with metabolic aggression and deregulation, especially in M3 metabolic type tumors.
- The correlation between hypoxia and metabolic pathways varies by metabolic type, with M1 showing the most sensitivity.
- Hypoxia may contribute to immune evasion in M3 tumors, suggesting broader implications for cancer biology and therapy.

## Abstract

Hypoxia is known to induce reprogramming of glucose metabolism in cancer. However, the impact of hypoxia on global metabolism remains poorly understood. Here, using the systems approach, we evaluated the potential crosstalk between hypoxia and global metabolism using data from > 2000 breast tumors. Tumor samples were scored for hypoxia and 90 metabolic pathways, and these metrics were subjected to an analysis pipeline. Hypoxia showed a very strong association with metabolic aggression and an overall contextual relationship with metabolism. Out of three (M1, M2, and M3) metabolic types in breast cancer, M3 exhibited the strongest relationship with hypoxia; that is, high hypoxic tumors were also metabolically deregulated. Further, the overall correlation pattern between hypoxia and metabolic pathway scores was specific to each type, with M1 showing maximal sensitivity to hypoxia, followed by M2 and then M3. Experimental validation using metabolic inhibitors on cell lines with high or low hypoxia scores further confirmed the metabolic type‐dependence of hypoxia. In addition, evaluation of the impact of hypoxia on cancer pathways other than metabolic ones revealed a potential role of hypoxia in immune evasive characteristic of M3 tumors. Overall, the results suggest a complex interplay between hypoxia and metabolism in the context of human breast tumors, with potential implications for both basic cancer biology and breast cancer therapy.

Breast tumor samples scored for metabolic deregulation (M1 to M3) were given a hypoxia score (HS). The highest HS occurred in patients with strongest metabolic deregulation (M3), supporting tumor aggressiveness. HS correlated with the highest number of metabolic pathways in M1. This suggests hypoxia to be an early event in metabolic deregulation. The overall crosstalk between hypoxia and metabolism was found to be contextual.