TFRI-funded researchers in Montreal have discovered how cancers that metastasize to the brain are able to invade distantly into the surrounding tissue, making them more likely to grow back after surgical resection. These findings, published in Neuro-Oncology (January 2021), highlight the prognostic potential of measuring the invasion pattern of metastatic brain cancers and pave the way for the development of personalized cancer treatments that take this important factor into account.
To make this finding, the team analyzed tissue samples of surgically resected brain metastases, dividing them into two groups based on the cancer’s “invasion pattern”: minimally invasive brain metastases, which display limited or no invasion into surrounding brain tissue, and highly invasive brain metastases, that exhibit marked invasion of cancer cells into the surrounding brain.
The team used a large cohort of patient brain metastasis specimens to demonstrate that patients with highly invasive brain metastases exhibited a greater probability of experiencing postoperative local recurrence and shortened overall survival compared to those with minimally invasive lesions.
Their subsequent analyses showed that the cancer cells that had aggressively invaded surrounding tissue overexpressed a specific protein called cold-inducible RNA-binding protein (CIRBP), and that CIRBP plays an important role in the cancer cells’ ability to grow invasively in the brain.
“This study not only revealed how these cancer cells invade surrounding tissue, but also showed us that invasive growth drives poor outcomes in patients with surgically resected brain metastases,” said Matthew Dankner, an MD/PhD student at McGill University and the paper’s first author. “These findings have direct implications for practicing neurosurgeons, neuropathologists, and radiation oncologists in the clinical management of patients with brain metastases.”
Currently, patients with surgically resected brain metastases are uniformly treated with post-operative radiotherapy. While radiotherapy reduces the risk of the cancer coming back, it has significant side-effects that dramatically impact quality of life.
These new findings suggest that patients with minimally invasive brain metastases may not need this treatment at all.
To test this theory, the team is setting up a clinical trial that compares patients with minimally invasive brain metastases receiving radiotherapy against patients who merely undergo observation. The goal of this trial is to learn whether these patients can forego receiving this aggressive treatment that does not provide them with benefit.
“We hope that the findings from these clinical trials will contribute to a paradigm shift in how we treat brain metastases, towards a personalized strategy rather than a one-size-fits-all approach,” says Dankner.
The group is also continuing to pursue laboratory studies with unique patient-derived mouse models of brain metastases that will enable further investigations into the molecular and metabolic underpinnings that promote the establishment and growth of minimally and highly invasive brain metastases.
Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases
Matthew Dankner, Maxime Caron, Tariq Al-Saadi, WenQing Yu, Véronique Ouellet, Rima Ezzeddine, Sarah M. Maritan, Matthew G. Annis, Phuong Uyen Le, Javad Nadaf, Noah S. Neubarth, Paul Savage, Dongmei Zuo, Charles P. Couturier, Jean Monlong, Haig Djambazian, Huda Altoukhi, Guillaume Bourque, Jiannis Ragoussis, Roberto J. Diaz, Morag Park, Marie-Christine Guiot, Stephanie Lam, Kevin Petrecca, and Peter M. Siegel
This study is partially funded by a Terry Fox New Frontiers Program Project Grant in Targeting Metabolic Vulnerabilities in Cancer