Matthew Dankner1,2,3, Maxime Caron4, Tariq Al-Saadi3,5, WenQing Yu3, Véronique Ouellet6, Rima Ezzeddine2,7, Sarah M Maritan1,2,3, Matthew G Annis2, Phuong Uyen Le3,5, Javad Nadaf4,5, Noah S Neubarth2,8, Paul Savage9, Dongmei Zuo2, Charles P Couturier3,5, Jean Monlong4, Haig Djambazian4, Huda Altoukhi3,10, Guillaume Bourque4, Jiannis Ragoussis4, Roberto J Diaz3,5, Morag Park1,2,3,7,11, Marie-Christine Guiot2,3,5,11, Stephanie Lam3,12, Kevin Petrecca3,5, Peter M Siegel1,2,3,7,8. 1. Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. 2. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. 3. McGill Faculty of Medicine, McGill University, Montreal, Quebec, Canada. 4. McGill University Genome Centre, Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 5. Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada. 6. Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. 7. Department of Biochemistry, McGill University, Montreal, Quebec, Canada. 8. Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada. 9. Department of Surgery, University of Toronto, Toronto, Ontario, Canada. 10. Department of Radiation Oncology, McGill University, Montreal, Quebec, Canada. 11. Department of Pathology, McGill University, Montreal, Quebec, Canada. 12. Department of Diagnostic Radiology, McGill University, Montreal, Quebec, Canada.
Abstract
BACKGROUND: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival. METHODS: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues. RESULTS: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain. CONCLUSIONS: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.
BACKGROUND: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival. METHODS: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues. RESULTS: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain. CONCLUSIONS: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.
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