PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo

TLDR

Medulloblastomas are childhood cerebellar tumors that harbor perivascular stem cells thought to drive recurrence after radiation, and these cellular features resemble human disease. The study used multiple mouse models to investigate how key tumor cell types respond to therapy. Bulk tumor cells undergo p53‑dependent apoptosis after radiation, whereas nestin‑positive perivascular stem cells survive by activating PI3K/Akt, arresting in a p53‑dependent manner, and re‑entering the cycle at 72 h; PTEN loss promotes Akt activation and nodular morphology, and Akt inhibition sensitizes these stem cells to radiation‑induced death.

Abstract

Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.