Sema3C Promotes the Survival and Tumorigenicity of Glioma Stem Cells through Rac1 Activation

Abstract

SUMMARY Different cancer cell compartments often communicate through soluble factors to facilitate tumor growth. Glioma stem cells (GSCs) are a subset of tumor cells that resist standard therapy to contribute to disease progression. How GSCs employ a distinct secretory program to communicate with and nurture each other over the non-stem tumor cell (NSTC) population is not well defined. Here, we show that GSCs preferentially secrete Sema3C and coordinately express PlexinA2/D1 receptors to activate Rac1/NF-κB signaling in an autocrine/paracrine loop to promote their own survival. Importantly, Sema3C is not expressed in neural progenitor cells (NPCs) or NSTCs. Disruption of Sema3C induced apoptosis of GSCs, but not NPCs or NSTCs, and suppressed tumor growth in orthotopic models of glioblastoma. Introduction of activated Rac1 rescued the Sema3C knockdown phenotype in vivo. Our study supports targeting Sema3C to break this GSC-specific autocrine/paracrine loop to improve glioblastoma treatment, potentially with a high therapeutic index.

Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis

“…In contrast with our observations that suggest that sema3C is an inhibitor of tumor progression, sema3C expressed in tumors was reported to function as a protumorigenic factor (39)(40)(41). These observations are reminiscent of the similar protumorigenic activity displayed by p61-sema3E, which is the FPPC cleavage product of sema3E that gains the ability to activate the ErbB2 receptor and thus promotes tumor progression.…”

“…Several reports have characterized sema3C as a protumorigenic factor (39)(40)(41). These studies were conducted using wild-type, FPPC cleavable sema3C.…”

Cancer stem cells in glioblastoma

“…The A20 protein (TNFAIP3), a mediator of cell survival and the NF-κB pathway, is overexpressed in CSCs compared with NSTCs . Supporting these findings, Sema3C and its receptors, PlexinA2 and PlexinD1, are also coordinately expressed in CSCs and activate Rac1 and NF-κB in an autocrine/paracrine loop to promote CSC survival (Man et al 2014). GBM CSCs have also been shown to be highly dependent on Ephrin receptor signaling for survival and the maintenance of stem cell properties.…”

RBPJ maintains brain tumor–initiating cells through CDK9-mediated transcriptional elongation

“…The 4121 BTICs in which RBPJ was knocked down alone (cluster 1) or the same BTICs with both RBPJ knockdown and DAPT treatment (cluster 2) segregated along the principal component 3. Genes most significantly correlated with the BTICs in cluster 1 suggested enriched programs in vesicle trafficking and semaphorin signaling (Supplemental Figure 5), which we have recently shown regulates BTICs (17). In the BTIC cluster 2, the significantly correlated genes suggested increased activity in translation, ribosomal biogenesis, and intrinsic apoptotic pathway.…”