The blood-brain barrier regulates brain tumor growth through the SLC36 amino acid transporter Pathetic in Drosophila.

Tumors adapt their metabolism to sustain increased proliferation, rendering them particularly vulnerable to fluctuations in nutrient availability. However, the role of the tumor microenvironment in modulating sensitivity to nutrient restriction (NR) remains poorly understood. Using a Drosophila brain dedifferentiation neural stem cell (NSC) tumor model induced by Prospero (Pros) inhibition, we show that tumor sensitivity to NR is governed by the blood-brain barrier (BBB) glia. We found that the SLC36 amino acid transporter Pathetic (Path) regulates brain branched-chain amino acids (BCAAs) levels. Under NR, while wild-type buffers against low nutrient levels by upregulating Path, tumor glia down-regulate Path. Furthermore, Path is specifically required by the tumor (but not wildtype) BBB; its downregulation causes reduced cell cycle progression of BBB glial cells and, in turn, restricts NSC tumor growth. Path influences BBB glial cell cycle via the BCAA-mTor-S6K pathway, and its expression is controlled by Ilp6 levels and the Insulin/PI3K pathway. Overexpression of Path is sufficient to counteract the inhibitory effects of NR on tumor growth. These findings suggest that Path levels at the glial niche BBB play a key role in determining tumor sensitivity to NR.