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細(xì)胞起源和遺傳、表觀遺傳和微環(huán)境因素導(dǎo)致小兒顱內(nèi)室管膜瘤的腫瘤內(nèi)異質(zhì)性

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Intra-cranial ependymoma (EPN) accounts for approximately 10% of pediatric brain tumors. The current therapeutic strategies have not significantly improved prognosis, which is still dismal in nearly 40% of patients. Major challenges for treatment are chemorefractoriness of EPN, tendency to recur, and high intra-tumoral heterogeneity (ITH). It is increasingly emerging that stalled neurodevelopmental programs driven by cancer stem cells (CSCs)/progenitor cells are at the root of oncogenesis and ITH of pediatric brain tumors, including EPN. This is the first review that examines how genetic and heritable epigenetic alterations and environmental selection forces drive ITH of pediatric intra-cranial EPN in the perspective of the CSC model. This review also summarizes how improvement in the single-cell technology has deepened the comprehension of the complexity, cell-of-origin, and developmental trajectories of EPN, paving the way for novel therapeutic options.

顱內(nèi)室管膜瘤 (EPN) 約占小兒腦腫瘤的 10%。目前的治療策略并沒有顯著改善預(yù)后，近 40% 的患者預(yù)后仍然不佳。治療的主要挑戰(zhàn)是 EPN 的化學(xué)難治性、復(fù)發(fā)傾向和高腫瘤內(nèi)異質(zhì)性 (ITH)。越來越多的跡象表明，由癌癥干細(xì)胞 (CSC)/祖細(xì)胞驅(qū)動的停滯的神經(jīng)發(fā)育計劃是小兒腦腫瘤（包括 EPN）的腫瘤發(fā)生和 ITH 的根源。這是第一篇從 CSC 模型的角度研究遺傳和可遺傳的表觀遺傳改變和環(huán)境選擇力如何驅(qū)動兒科顱內(nèi) EPN 的 ITH 的綜述。

細(xì)胞工廠

Despite the enormously increased understanding of the molecular drivers and biology of EPN, the treatment standards have essentially remained static over recent years. Gross total resection is still the strongest predictor of outcome [220]. The role for chemotherapy in young children to protect them from the side effects of radiation therapy is still debated [221,222], whereas no survival advantage with the use of chemotherapy in recurrent EPN has been found [223] despite intensive investigation.

At present, 108 clinical trials are ongoing in pediatric EPN (ClinicalTrials.gov [224], accessed on 22 November 2021), however, they do not take into account EPN variants. Moving forward, the next challenge is to go beyond tumor control and to include EPN molecular classification in treatment decisions so as to adapt therapeutic strategies based on risk stratification, reducing therapy-induced morbidity in low-risk patients, while intensifying treatment for high-risk patients [225]. Development of new treatments for patients with EPN, especially in the pediatric cohort, meets several challenges, including low investment by pharmaceutical companies and low incidence of patients with rare cancers, that hamper testing of new compounds in prospective clinical trials [212]. The establishment of appropriate preclinical models, which mirror the distinct EPN subgroups and even the distinct EPN subpopulations, is critical for drug testing and identification of drug response biomarkers [226]. Although there are many preclinical studies in EPN models [74,199,227,228], few studies have hitherto compared drug sensitivities in heterogeneous subpopulations of EPN cell lines [78,79,216].

scRNA-seq has just begun to be applied to translational research in EPN. Future studies are warranted to increase the number of EPN specimens dissected at the single-cell level, to sample anatomically and temporally distinct regions in order to address tumor heterogeneity and evolution at recurrence, with the ultimate goal to discover EPN sub-type specific drivers and druggable pathways. In addition, the diverse and complex extrinsic interactions of EPN cells with the tumor microenvironment should also be prospectively evaluated.

細(xì)胞轉(zhuǎn)瓶

Although single-cell genomics have shown the complex intercellular variability that governs EPN biology and challenges the response to treatment, they have also evidenced coalescing commonalities shared across subgroups of tumors and even across tumors of disparate histologies. For instance, Neuronal-Precursor-like programs are strictly correlated in PF-EPN and ST-EPN, and share transcriptional overlaps with the Neuronal-Precursor-like cell programs described in GBM [165,229]. Likewise, the mesenchymal signatures in PF-EPN and ST-EPN are similar to that reported in GBM. In addition, the astro-ependymal program in PF-EPN resembles the astrocyte-like programs in both DIPG and GBM [165,190]. In addition to scRNA-seq, integrative proteogenomics analyses have identified common biological processes between and among PBTs of seven histological types, including HGG, and EPN, which suggests that tumors of disparate histologies may share common therapeutic vulnerabilities [230].

In conclusion, not only has scRNA-seq highlighted the bewildering heterogeneity of EPN, but it may also contribute to defining subtype- and subgroup-specific molecular vulnerabilities and new options for therapeutic interventions. Moreover, the observation that some transcriptomic signatures cross histological boundaries among EPN groups and even amongst disparate pediatric tumors suggests that some treatment opportunities may be effective in a larger group of diseases than that might have been expected.

盡管對 EPN 的分子驅(qū)動因素和生物學(xué)的了解大大增加，但近年來治療標(biāo)準(zhǔn)基本上保持不變。總切除仍然是結(jié)果的最強(qiáng)預(yù)測指標(biāo) [ 220 ]?；熢谟變褐斜Ｗo(hù)他們免受放射治療副作用的作用仍然存在爭議 [ 221 , 222 ]，盡管進(jìn)行了深入研究，但在復(fù)發(fā)性 EPN 中使用化療并未發(fā)現(xiàn)生存優(yōu)勢 [ 223 ]。

目前，兒童 EPN 正在進(jìn)行 108 項(xiàng)臨床試驗(yàn)（ClinicalTrials.gov [ 224 ]，于 2021 年 11 月 22 日訪問），但是，它們沒有考慮 EPN 變體。展望未來，下一個挑戰(zhàn)是超越腫瘤控制，將 EPN 分子分類納入治療決策，以便根據(jù)風(fēng)險分層調(diào)整治療策略，減少低風(fēng)險患者的治療引起的發(fā)病率，同時加強(qiáng)對高風(fēng)險患者的治療患者 [ 225]。為 EPN 患者開發(fā)新的治療方法，特別是在兒科隊(duì)列中，遇到了一些挑戰(zhàn)，包括制藥公司的低投資和罕見癌癥患者的低發(fā)病率，這阻礙了在前瞻性臨床試驗(yàn)中測試新化合物 [ 212 ]。建立適當(dāng)?shù)呐R床前模型，反映不同的 EPN 亞組甚至不同的 EPN 亞群，對于藥物檢測和藥物反應(yīng)生物標(biāo)志物的鑒定至關(guān)重要 [ 226 ]。盡管 EPN 模型中有許多臨床前研究 [ 74 , 199 , 227 , 228]，迄今為止很少有研究比較 EPN 細(xì)胞系異質(zhì)亞群中的藥物敏感性 [ 78 , 79 , 216 ]。

PETG血清培養(yǎng)基瓶

scRNA-seq 剛剛開始應(yīng)用于 EPN 的轉(zhuǎn)化研究。未來的研究有必要增加在單細(xì)胞水平解剖的 EPN 標(biāo)本的數(shù)量，對解剖學(xué)和時間上不同的區(qū)域進(jìn)行采樣，以解決腫瘤異質(zhì)性和復(fù)發(fā)時的演變，最終目標(biāo)是發(fā)現(xiàn) EPN 亞型特異性驅(qū)動因素和成藥途徑。此外，還應(yīng)前瞻性地評估 EPN 細(xì)胞與腫瘤微環(huán)境的多樣化和復(fù)雜的外在相互作用。

盡管單細(xì)胞基因組學(xué)已經(jīng)顯示出控制 EPN 生物學(xué)并挑戰(zhàn)治療反應(yīng)的復(fù)雜細(xì)胞間變異性，但它們也證明了腫瘤亞組甚至不同組織學(xué)腫瘤之間共享的共同點(diǎn)。例如，神經(jīng)元前體樣程序在 PF-EPN 和 ST-EPN 中嚴(yán)格相關(guān)，并且與 GBM [ 165 , 229 ] 中描述的神經(jīng)元前體樣細(xì)胞程序共享轉(zhuǎn)錄重疊。同樣，PF-EPN 和 ST-EPN 中的間充質(zhì)特征與 GBM 中報道的相似。此外，PF-EPN 中的星形室管膜程序類似于 DIPG 和 GBM 中的星形膠質(zhì)細(xì)胞樣程序 [ 165 , 190]。除了 scRNA-seq，綜合蛋白質(zhì)組學(xué)分析已經(jīng)確定了包括 HGG 和 EPN 在內(nèi)的七種組織學(xué)類型的 PBT 之間的共同生物學(xué)過程，這表明不同組織學(xué)的腫瘤可能具有共同的治療漏洞 [ 230 ]。

總之，scRNA-seq 不僅突出了 EPN 令人眼花繚亂的異質(zhì)性，而且還可能有助于定義亞型和亞組特異性的分子脆弱性以及治療干預(yù)的新選擇。此外，觀察到一些轉(zhuǎn)錄組特征在 EPN 組之間甚至在不同的兒科腫瘤中跨越組織學(xué)界限，這表明一些治療機(jī)會可能對比預(yù)期更大的疾病組有效。

關(guān)鍵詞：intra-tumoral heterogeneity,ependymoma,genetics,epigenetics,tumor microenvironment, cancer stem cells, single cell RNA seq,H3K27me3,H3K27M 瘤內(nèi)異質(zhì)性,室管膜瘤,遺傳學(xué), 表觀遺傳學(xué),腫瘤微環(huán)境,癌癥干細(xì)胞,單細(xì)胞RNA序列,H3K27me3, H3K27M

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6100/htm