Reprogramming the brain microenvironment is a key step for organ colonization

Metastasis is the most frequent tumor affecting the brain and an unmet clinical need. Chemotherapies, targeted therapies and immunotherapies have a limited impact on the progression of the disease in most patients and local therapies (neurosurgery and radiation) are usually provided with palliative purposes.
The growth of metastatic cells in the brain modify the local environment. We hypothesized that identification of metastases-associated molecular alterations in the microenvironment might uncover important aspects of the biology of colonization and lead to novel therapeutic opportunities to benefit a higher number of patients.
STAT3 activation labels a subpopulation of reactive astrocytes (pSTAT3+ RA) in seven
experimental brain metastasis models and 89% of human brain metastases from different primary tumors. Genetic and pharmacologic targeting of STAT3 impairs the viability of brain metastasis even at advanced stages of colonization. pSTAT3+ RA are functionally different from other reactive astrocytes since they acquire stem-cell  like properties and are able to negatively influence adaptive immunity and promote pro-tumor macrophages/microglia. The use of a blood-brain barrier permeable, non-toxic and orally bioavailable STAT3 inhibitor reduces brain metastases in experimental models and lung adenocarcinoma patients.
I will provide a proof-of-concept for the development of therapies targeting reprogrammed cells from the microenvironment induced by the sustained presence of cancer cells in the brain. This finding applies to experimental and human brain metastases from breast cancer, lung cancer and melanoma suggesting that rain- specific therapies could be combined with others to improve the poor outcome of these patients.