Abstract
The cyclin-like protein SPY1 promotes proliferation and stemness of brain tumor–initiating cells.
Major finding: The cyclin-like protein SPY1 promotes proliferation and stemness of brain tumor–initiating cells.
Mechanism: Activation of CDK2 by SPY1 drives self-renewal in neural stem cells via symmetric cell division.
Impact: Noncanonical cell-cycle mechanisms affect stem cell maintenance and support tumor cell growth.
Despite widespread heterogeneity, primary brain tumors are thought to be similarly driven by a population of brain tumor-initiating cells (BTIC) that exhibit neural stem cell properties. Cell-cycle regulation has been implicated in maintaining the proper balance between the expansion and differentiation of progenitor cell pools, but the specific mechanisms that underlie BTIC growth and differentiation remain unknown. The developmentally regulated cyclin-like protein Speedy/RINGO cell-cycle regulator family member A (SPY1) can promote cell-cycle checkpoint bypass via noncanonical activation of cyclin-dependent kinases (CDK) and is upregulated in human cancers, prompting Lubanska and colleagues to assess the role that SPY1 plays in BTIC maintenance and glioma. SPY1 protein levels increased with brain tumor grade, and amplification of SPDYA, the gene that encodes SPY1, was detected in 143 of 222 (64%) gliomas. Moreover, SPDYA amplification and overexpression of the SPY1 binding partner CDK2 in gliomas was significantly correlated with reduced patient survival. In vitro, SPY1 depletion in glioblastoma cell lines or patient-derived glioma cells led to decreased proliferation and downregulation of factors associated with stemness, including CD133, a marker expressed by subpopulations of highly tumorigenic stem-like glioma cells. In support of a role for SPY1 in cellular fate determination, depletion of SPY1 led to reduced neurosphere formation in CD133-positive glioma cells, and overexpression of SPY1 enhanced neurosphere formation and progenitor cell marker levels in primary neural cells. Monitoring of single cells revealed that SPY1 knockdown increases asymmetric cell division, a mechanism that has been suggested to limit stem cell expansion. Importantly, depletion of cyclin E was unable to fully recapitulate SPY1-mediated changes in differentiation, suggesting that noncanonical CDK2 binding partners may be required for continued BTIC self-renewal. This work provides mechanistic insight as to how cell cycle–mediated growth characteristics contribute to BTIC maintenance and highlights a role for cyclin-like proteins in cancer.
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