結腸類器官的遺傳編輯提供了鋸齒狀癌發生的分子特異性和原位性臨床前模型

今天與大家一起來學習於2018年4月17日發表在Gut（IF=16.658）上的一篇文章：Genetic editing of colonicorganoids provides a molecularly distinct and orthotopic preclinical model ofserrated carcinogenesis《結腸類器官的遺傳編輯提供了鋸齒狀癌發生的分子特異性和原位性臨床前模型》。

下面對這篇文章進行簡要介紹：

OBJECTIVE:

Serratedcolorectal cancer (CRC) accounts for approximately 25% of cases and includestumours that are among the most treatment resistant and with worst outcomes.This CRC subtype is associated with activating mutations in themitogen-activated kinase pathway gene,BRAF, and epigeneticmodifications termed the CpG Island Methylator Phenotype, leading to epigeneticsilencing of key tumour suppressor genes. It is still not clear which(epi-)genetic changes are most important in neoplastic progression and we beginto address this knowledge gap herein.

目的：

鋸齒狀結直腸癌（CRC）約佔結直腸癌病例的25％，其中包括耐藥性最強且預後最差的腫瘤。這種CRC亞型與有絲分裂原活化激酶通路基因BRAF中的激活突變和CpG島甲基化表型的表觀遺傳修飾相關，導致關鍵腫瘤抑制基因的表觀遺傳沉默。目前尚不清楚哪些（epi）基因改變在腫瘤進展中最重要，我們開始著手解決這方面的知識缺口。

DESIGN:

We use organoidculture combined with CRISPR/Cas9 genome engineering to sequentially introducegenetic alterations associated with serrated CRC and which regulate the stemcell niche, senescence and DNA mismatch repair.

設計：

我們使用與CRISPR / Cas9基因工程相結合的類器官培養技術依次引入與鋸齒狀CRC有關的基因改變，並調節幹細胞巢、衰老和DNA錯配修復。

RESULTS:

Targeted biallelicgene alterations were verified by DNA sequencing. Organoid growth in theabsence of niche factors was assessed, as well as analysis of downstreammolecular pathway activity. Orthotopic engraftment of complex organoid lines,but notBrafV600Ealone, quickly generatedadenocarcinoma in vivo with serrated features consistent with human disease.Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatelliteinstability. Sphingolipid metabolism genes are differentially regulated in bothour mouse models of serrated CRC and human CRC, with key members of thispathway having prognostic significance in the human setting.

結果：

通過DNA測序證實了靶向雙等位基因的改變。評估缺乏生態因子的類器官生長情況，並且分析下游分子途徑活性。複雜類器官系的原位植入，但不是單獨的BrafV600E，在體內迅速產生具有與人類疾病一致的鋸齒狀特徵的腺癌。必需DNA錯配修復酶Mlh1的缺失導致微衛星序列不穩定。鞘磷脂代謝基因在我們的鋸齒狀CRC小鼠模型和人類CRC中均有差異性調節，該通路的核心成員在人類環境中具有預測意義。

CONCLUSION:

We generate rapid,complex models of serrated CRC to determine the contribution of specificgenetic alterations to carcinogenesis. Analysis of our models alongside patientdata has led to the identification of a potential susceptibility for thistumour type.

結論：

我們製作快速、複雜的鋸齒狀CRC模型以確定特定基因改變對致癌的作用。 我們的模型與患者數據一起分析，引起對這種腫瘤類型潛在易感性的鑒定。

KEYWORDS:

cancer genetics;colorectal cancer; gene mutation; methylation; oncogenes

關鍵詞：

腫瘤遺傳學; 結直腸癌; 基因突變;甲基化;癌基因

補充說明：organoid的具體意思

來源於Wikipedia（維基百科）：Anorganoidisa miniaturized and simplified version of an organ produced in vitro in threedimensions that shows realistic micro-anatomy. They are derived from one or afew cells from a tissue, embryonic stem cells or induced pluripotent stemcells, which can self-organize in three-dimensional culture owing to theirself-renewal and differentiation capacities. The technique for growingorganoids has rapidly improved since the early 2010s, and it was named by TheScientist as one of the biggest scientific advancements of 2013.[ Organoids areused by scientists to study disease and treatments in a laboratory.

類器官是體外產生的器官微型和簡化形式，在三維情況下可顯示出其真實的顯微解剖。 它們來自組織中的一個或幾個細胞、胚胎幹細胞或者誘導的多能幹細胞，由於其自我更新和分化能力強，它們可以在三維立體培養中自我組織。自2010年初以來，種植類器官技術迅速發展，並被科學家評為2013年最大科學進展之一。科學家使用類器官在實驗室研究疾病及其治療方法。

喜歡這篇文章嗎？立刻分享出去讓更多人知道吧！