CD271+ Cells Are Diagnostic and Prognostic and Exhibit Elevated MAPK Activity in SHH Medulloblastoma

Abstract

The extensive heterogeneity both between and within the medulloblastoma subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH medulloblastoma subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH medulloblastoma using IHC analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271 and CD271 cells revealed molecularly distinct, coexisting cellular subsets, both and MAPK/ERK signaling was upregulated in the CD271 population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels, whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH medulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271 SHH medulloblastoma cells. This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271 cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHH medulloblastoma. .

An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

“…Similar results were obtained for PAX3 and PAX6 in an independent MB patient sample cohort (Fig. 1e ), and are in stark contrast to the very high OTX2 levels observed in Group 3 and Group 4 MB 33 . Of note, PAX3 and PAX6 expression showed no significant correlation with MYC , which is highly expressed or amplified in Group 3 MB tumors (Supplementary Fig.…”

“…2e ) 37 , while OTX2 levels were very high in Group 3 MB tumors (Supplementary Fig. 3a ) 33 , 37 . As observed in the transcript data, PAX3 levels were highest in the WNT MB tumors, and PAX6 levels were elevated in the SHH MB subgroup (Fig.…”

Neurotrophin Signaling in Medulloblastoma

“…In fact, it was recently demonstrated, through immunohistochemical analysis and transcriptome data across 763 primary tumors, that p75NTR is a novel potential diagnostic and prognostic marker for SHH MB. The ERK/MAPK pathway was upregulated in p75NTR-positive tumors, and inhibiting MAPK signaling reduced stem/progenitor cell proliferation, survival, as well as migration [139]. A summary of findings from studies investigating neurotrophin signaling in MB is presented in Table 1.…”

“…Higher overall survival [118] Favorable outcome [120] High expression in SHH MB [121] Unknown Potential diagnostic and prognostic marker for SHH group [138,139] Unknown ↑ increase; ↓ decrease.…”

Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions

“…The prognoses of SHH-activated MBs are less favorable; SHH-MBs have an intact blood-brain barrier (BBB) and are less responsive to chemotherapy compared to WNT-MBs (22,26,27). Many SHH-MBs are age-dependent, with those aged ≥17 months more likely to harbor SMO and PTCH1 mutations (18,(28)(29)(30)(31)(32). Subgroup-driven clinical trials are currently underway to assess the efficacy of SHH pathway inhibitors such as vismodegib at diagnosis or in recurrent or refractory SHH-activated tumors.…”