Abstract

   Breast cancer is the most common type of cancer in women. It is also
   the 2^nd most common cause of brain metastases (BrM), with 30-50% of
   breast cancer patients developing BrM over the course of their disease.
   Despite aggressive therapy and novel systemic treatment options,
   prognosis for these patients remains poor. The objectives of our work
   were to identify the underlying genomic and transcriptomic signatures
   that characterise early BrM establishment in patients with breast
   cancer, and to identify brain-intrinsic molecular mechanisms critical
   to BrM development. We performed transcriptomic and genomic profiling
   on fresh frozen (FF) brain metastases tumour samples of patients who
   required surgical resection of an intracranial metastatic early (<3
   years from initial diagnosis) or late (>3 years from initial diagnosis)
   in the disease course. Findings were validated by immunohistochemistry
   and immunofluorescence staining for genes of interest in BrM, matched
   primary breast tumour samples, and healthy brain tissue. The findings
   were complemented with scRNA sequencing studies to resolve cellular
   contributions of individual cell types and subtypes and uncover
   specific cell-type interactions in BrM establishment. In patients with
   early metastatic disease, pathway enrichment analysis identified TGF-β
   pathway upregulation, which stimulates epithelial-to-mesenchymal
   transition, integrin-mediated invasion, recruitment and activation of
   cancer-associated fibroblasts. We identified collagen-extracellular
   matrix interactions as key oncogenic features of the metastatic tumour
   microenvironment. We have selected lead candidates that can play
   significant role in early colonisation of breast cancer cells to the
   brain from the primary breast tumour and enhance tumorigenesis. These
   markers will be challenged in an in vivo brain metastasis model to
   attenuate the establishment of metastatic disease. Our goal is to
   identify a modifiable marker that could be clinically targeted to
   prevent the establishment of brain metastases in patients diagnosed
   with breast cancer.
     __________________________________________________________________

   Articles from Neuro-Oncology Advances are provided here courtesy of
   Oxford University Press
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