Proteomic Insights into Metastatic Breast Cancer Response to Brain Cell-Secreted Factors

Abstract

AbstractThe most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2+ and triple negative breast cancers frequently metastasize to the brain and stay potentially dormant for years, clinging to the microvasculature, until favorable environmental conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection, diagnosis, and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain tissues and biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development, leading to slow progress in understanding the drivers of disease progression and response to therapy. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the growth and initial response of HER2+ breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment conditions were simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., human endothelial cells (HBEC5i), human astrocytes (NHA) and human microglia (HMC3) cells. Cytokine microarrays were used to investigate the cell secretomes and explore the mediators responsible for cell-cell communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The results of the study suggest that the exposure of SKBR3 cells to the brain secretomes altered their growth potential and drove them towards a state of quiescence. The cytokines, growth factors and enzymes detected in the brain cell-conditioned medium were supportive of mostly inflammatory conditions, indicating a collective functional contribution to cell activation, defense, inflammatory responses, chemotaxis, adhesion, angiogenesis, and ECM organization. The SKBR3 cells, on the other hand, secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell culture media, suggesting that upon exposure the SKBR3 cells were deprived of favorable environmental conditions required for optimal growth. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, providing insights into the cancer-host cell cross-talk that contributes to driving metastasized cancer cells into dormancy and into the opportunities that exist for developing novel therapeutic strategies that target the brain metastases of breast cancer.