PI3K: A master regulator of brain metastasis‐promoting macrophages/microglia

Abstract

Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis‐promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan‐PI3K Class I inhibitor with a good blood‐brain‐barrier penetrance, reduced their metastasis‐promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re‐educates the metastasis‐promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers

“…LPCAT1 gene expression may play a key role in promoting BM via the PI3K pathway [36]. Furthermore, prior studies of BM in breast cancer and melanoma have also illustrated the importance of PI3K pathway upregulation [37][38][39]. Finally, the specific fusion partner may also play a role, potentially due to differing protein conformations.…”

Molecular and cellular mechanisms underlying brain metastasis of breast cancer

“…1b(h, i)). Pharmacological inhibition of PI3K activity was found to attenuate the expression of these genes as well as the infiltration of metastatic breast cancer cells in the brain of mice [33].…”

“…The activation of PI3K was detected in a large proportion (77%) of brain metastases in breast cancer patients [33], and activation of PI3K-Akt signaling in such metastases has been associated with a poor survival outcome [34,35]. The PI3K-Akt signaling pathway contributes to upregulation of the expression of immunosuppressive or metastasis-promoting genes such as those for PD-L1, cytotoxic T lymphocyte-associated protein 4 (CTLA4), colony-stimulating factor 1 (CSF1), and the CSF1 receptor (CSF1R) in cancer cells or microglia in the microenvironment of brain metastases [33] (Fig. 1b(h, i)).…”

Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

“…The spectrum of activated microglial phenotypes in brain tumours ranges from "classical" M1 proinflammatory cells capable of releasing proinflammatory cytokines and eliciting a T cell response, to "alternative" M2 anti-inflammatory cells which promote tumour growth, angiogenesis and invasion [21][22][23][24][25]. Thus, targeting the anti-inflammatory microglial population [26][27][28], and/or enhancing the activity of the proinflammatory population [29], may provide a new treatment approach for brain metastases. However, better models are required to improve understanding of the functional activity of microglia in the microenvironment around brain tumour cells.…”