Metastatic brain tumors are a common and devastating complication of cancer, with high morbidity and mortality rates. They originate from tissues outside the brain, with spreading of cancer cells into the brain through the cardiovascular system and the establishment of metastatic lesions.

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In response to tumor-induced brain damage the CNS resident macrophages microglia are activated and monocytes infiltrate the tumor and become monocytes-derived macrophages (MDM); collectively termed "tumor-associated macrophages" (TAM). TAM are known to support tumor progression via CD38 glycoprotein.

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Another population of macrophages found in the tumor microenvironment is the border associated macrophages (BAM). BAMs are located at the central nervous system (CNS) borders, such as the ventricles and the leptomeninges, and include perivascular and meningeal BAM.

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These cells contribute to CNS homeostasis and brain pathologies in ways distinct from microglia.

 

Both BAMs and activated microglia express CD38,
thus we hypothesized that deficiency of CD38 in the brain would reduce BAMs' expression, thereby reducing metastasis progression in both the leptomeninges and the ventricles.

 

We also hypothesized that the deficiency of CD38 will reduce metastasis progression in the parenchyma via activated microglia.

 

To address these uestions, we use a genetic tracing mouse which enables us to distinguish between microglia and MDM and has a CD38 knockout. We use experimental brain metastases models, focusing on the metastatic lung cancer mouse model D122 and the metastatic melanoma mouse model RET.

 

Our results show that D122 mouse model with CD38 knockout is not different from WT D122 mouse model, but initial results might suggest a difference in the RET mouse model. Contrary to our hypothesis, CD38 knockout might result in bigger tumors.