Gene Expression Profiling of Olfactory Neuroblastoma Helps Identify Prognostic Pathways and Define Potentially Therapeutic Targets

Abstract

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years; all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months; 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams’ grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.

Single-cell transcriptomic landscape deciphers novel olfactory neuroblastoma subtypes and intratumoral heterogeneity

“…As a result, a total of N = 24686 ONB cancer cells were screened out and re-clustered into 7 malignant subgroups (Figure 2a) . According to a multi-omics study of ONB 9 , two subtypes of this tumor, namely Basal and Neural, could be distinguished by unique molecular expression patterns and distinct clinicopathological features, with possibly diverse cell origins from different layers of olfactory epithelium 10 . To validated this binary classification of ONB at single-cell resolution, we firstly evaluated the expression levels of Basal/Neural signatures provided in the multi-omics research (Table S4) , with subtype-specific expression assessed by scores displayed in feature-plots (Figure 2b) .…”

“…This study also illustrated the differences between normal OM cells and ONB malignant cells, so as to explore commonly expressed signatures and targets shared by all three subtypes. ONB expressed lower epithelial biomarkers like KRTs or EPCAM, and higher interstitial biomarkers like VIM, especially in Mesenchymal subtype tumors, suggesting that ONB underwent an EMT process 10 .…”

“…Although recently a few studies have attempted to develop molecular-based subtype classifications and analysis transcriptional pathways with prognostic values of ONB based on formalin-fixed paraffin-embedded (FFPE) tumor blocks or bulk tissue RNA-seq 9, 10 , the results failed to precisely decode the transcriptome features of this tumor, since bulk-RNA seq could only detect mixed bio-information contributed both by malignant and tumor-infiltrating TME cells. Moreover, the dynamic status and mutual interaction networks inside various cellular components also remained ill-defined.…”

SMAD9-MYCN positive feedback loop represents a unique dependency for MYCN-amplified neuroblastoma

“…TGF-beta/SMAD signaling plays an important role in tumor development, relapse, drug resistance and metastasis [35][36][37][38][39][40]. The 8 types of SMAD proteins constitute 3 functional groups: receptor-regulated SMADs (R-SMADs; which include SMAD2/3 and SMAD1/5/9), co-mediator SMAD (Co-SMAD; which include SMAD4) and inhibitory SMADs (I-SMADs; which includes SMAD6, 7).…”

Conservative management of orbital involvement in malignant tumors: is the paradigm evolving? A critical review

“…On the other side, in olfactory neuroblastoma (ONB) patients, the role of induction chemo, mainly with cisplatin and etoposide, is yet to be identified and requires further evaluation [14]. In a recent study on ONB, the genetic profiling of the tumors seemed to be more efficient in evaluating clinical outcomes than traditionally used parameters [15]. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.…”