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Abstract Brain metastasis from breast cancer (BCBM) are lethal tumors occurring in 10-15% of IV stage breast cancers against which only limited therapeutic options are available. A critical hindrance to the design of novel therapeutic approaches is the narrow set of preclinical models to study BCBM pathophysiology, chiefly those resembling the stem-like population which is thought be the main source of BCBM dissemination and progression. We aimed to isolate patient-derived metastasis-initiating cells (MICs) to furnish novel preclinical models of metastatization. MICs were cultured as stem-enriching tumorspheres, which we characterized in term of i) brain/breast/stem markers expression ii) tumorigenicity, iii) growth and in vitro/in vivo self-renewal, iv) adhesion to organ-specific endothelium, v) metastatic potential and vi) drug responsiveness. Further, we transcriptionally profiled MIC-driven organ-specific metastasis. Patient-derived MICs expressed epithelial markers while the expression of brain markers was poor, coherently with their epithelial origins. About 90% of MICs were positive to the expression of the putative stem cell markers CD15, CD24 and CD44, while CD133 and ALDH1A1 were less represented. MICs were grown indefinitely in stem cell medium and successfully formed spheres in serial clonogenic assays, suggesting their endowment with stem-like traits. Similarly, their ability to form tumors when orthotopically injected in mice brain was maintained upon serial transplantation and under in vivo limiting dilution conditions. The representative PR60 MICs showed metastatic potential to mice brain and bones upon either intracardiac or intranipple transplantation. Of note, independently of the route of injection, this metastatization pattern wholly mirrored the clinical course of the patient they had been derived from. PR60-driven brain metastasis also recapitulated patient tumor histology, cytoarchitecture and marker expression. Further confirming their brain-tropism, PR60 MICs preferentially adhered to human brain compared to non-brain endothelium under shear stress mimicking in vivo hemodynamic conditions. Transcriptomically, PR60 MICs displayed high correlation with the BCBM of origin but retain the ability to form intra-nipple tumors resembling patient primitive breast tumor. PR60-derived brain and bone metastasis reveal a distinct expression profile suggesting that PR60 MICs can colonize different organs rewiring their transcriptomic landscape. Compared to the whole tumor of origin, MICs revealed an up-regulation of drug resistance signatures, which are often linked with stem-like traits, and that were functionally validated by a high throughput drug screening. Altogether, we established a robust and versatile MIC model that reliably mirrors the brain metastasis of origin and mimics the different steps of brain metastatic dissemination for in vitro and in vivo studies. This model has the potential to provide further knowledge for future therapy development for BCBM management. Citation Format: Stefania Faletti, Cristina Richichi, Daniela Osti, Elena Ceccacci, Massimiliano Del Bene, Camilla Cerutti, Giovanni Bertalot, Monica Patanè, Bianca Pollo, Giuliana Pelicci. Establishment of patient-derived brain metastasis initiating cells as a novel preclinical model of breast cancer metastatization abstract. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₁): Abstract nr B007.
Faletti et al. (Mon,) studied this question.