Unlike healthy tissues, tumours thrive in low-oxygen environments, often acquiring the ability to resist treatment and spread to other sites in the body. Despite being a well-known cause of therapy resistance and metastasis, the impact of low oxygen, known as hypoxia, on tumour cells is poorly understood. As reported today in Nature Genetics, researchers have discovered molecular hallmarks of hypoxia in the first-ever pan-cancer analysis of low oxygen in human tumours, with a special focus on prostate cancer.
The study, which was partially funded by the TFRI, investigated more than 8,000 human tumours across 19 different cancer types, including prostate tumours from the Canadian Prostate Cancer Genome Network (CPC-GENE). The authors discovered common markers of hypoxia that could help predict cancer aggressiveness and better inform treatment decisions for each patient.
These findings, which include several genes more commonly mutated in hypoxic cancers and new information about hypoxia-related patterns of tumour evolution, make up the largest resource available for hypoxia research.
“If we look at any single aspect of cancer, we only gain a partial understanding of this complex disease. But here we’ve exploited a wealth of human tumour data to gain a more comprehensive understanding,” says Vinayak Bhandari, lead author of this study and PhD Candidate at the University of Toronto, who is conducting research at the Ontario Institute for Cancer Research (OICR). “By tying together our new understanding of the environment in which tumours develop with detailed evaluation of genetic changes, we created a biological signature that highlights patients who may benefit from more therapy.”
The markers observed in this study also open new opportunities for researchers to develop therapies that target hypoxia-related treatment resistance and metastasis across many types of cancer, including prostate cancer.
“Understanding common genomic traits across cancer types is critically important to the future of cancer diagnosis and treatment,” says Dr. Paul Boutros (University of California, Los Angeles), a former TFRI New Investigator and senior investigator of the study. “We were initially motivated by the inability to differentiate between aggressive and non-aggressive prostate cancers, but our findings provide insights into how treatments might be developed for many tumour types.”
“Hypoxia was previously associated with aggressive disease, but the mechanisms by which it drives this process in human tumours was poorly understood from a genetic angle,” says Professor Robert Bristow (Manchester Cancer Research and University of Manchester), who is also a former TFRI-funded researcher. “We can now start to exploit these findings into novel clinical trials to target hypoxia and abnormal genetics at the same time.”
Molecular landmarks of tumor hypoxia across cancer types
Vinayak Bhandari, Christianne Hoey, Lydia Y. Liu, Emilie Lalonde, Jessica Ray, Julie Livingstone, Robert Lesurf, Yu-Jia Shiah, Tina Vujcic, Xiaroyong Huang, Shadrielle M. G. Espiritu, Lawrence E. Heisler, Fouad Yousif, Vincent Huang, Takafumi N. Yamaguchi, Cindy Q. Yao, Veronica Y. Sabelnykova, Michael Fraser, Melvin L. K. Chua, Theodorus van der Kwast, Stanley K. Liu, Paul C. Boutros & Robert G. Bristow
This work was partially supported by a Terry Fox New Frontiers Program Project Grant in Research pipeline for hypoxia-directed precision cancer medicine