Mouse models mimicking the transition from a common form of lung cancer to a more aggressive one may help scientists develop future strategies to prevent this transformation.

模擬從一種常見之肺癌轉變為一種，更具侵襲性肺癌的小鼠模型，可能有助於科學家們開發，未來阻止這種轉變的對策。

圖1. 研究人員們開發了，模擬於小鼠中，從肺腺癌到小細胞肺癌之組織結構轉變的實驗模型。

Researchers developed experimental models that mimic the histological transformation from lung adenocarcinoma to small cell lung cancer in mice.

Lung adenocarcinoma (LUAD), the most common form of lung cancer, is already a challenging disease. It is currently the leading cause of cancer death in the United States. In response to therapies that inhibit their genetic drivers, LUAD cells may undergo transformation as a mechanism of resistance and begin to exhibit traits of a more aggressive and difficult-to-treat cancer type known as small cell lung cancer (SCLC). 

肺腺癌(LUAD)是最常見的肺癌形式，早已是一種具有挑戰性的疾病。目前在美國，它是癌症死亡的主要原因。在對抑制其遺傳驅動因子之療法作出反應上，LUAD細胞可能經歷一種，作為抵抗機制的轉變。因此，開始展現更具侵襲性及難以治療，被通稱為小細胞肺癌(SCLC)之癌腫類型的諸多特徵。

To gain deeper insight into the mechanisms underlying this problematic transition, Eric Gardner, a lung cancer biologist at Weill Cornell Medicine, and his colleagues developed mouse models that recapitulated the process.

為了獲得，潛藏於該有問題之轉變背後機制的更深入洞察力，美國康乃爾大學威爾康奈爾醫學院的肺癌生物學家，Eric Gardner及其同僚們開發了，重現此變化過程的小鼠模型。

The researchers found that the lung cell type that gives rise to LUAD is typically unaffected by mutations in one of the oncogenes driving SCLC. However, when the team inhibited an oncogenic driver for LUAD and deleted specific tumor suppressor genes, a subset of LUAD cells converted into a stem-like state.

此些研究人員發現，引起LUAD的肺細胞類型，通常不受到於驅動SCLC之致癌基因之一，諸多突變的影響。然而，當該團隊抑制LUAD的一個致癌驅動因子，及剔除若干特定的腫瘤抑制基因時，部分LUAD細胞轉變成一種，幹細胞樣的狀態。

Under these conditions, the cells were plastic enough to respond to the cancer gene driving the SCLC transformation, the team reported in Science.

該團隊於《科學》期刊中述說，在此些條件下，這些細胞具有足於，對驅動SCLC轉變之該種癌細胞，作出反應的可塑性。

Gardner’s team first focused their efforts on the challenging task of creating mouse strains that could recapitulate the complex transformation in a simplified model. “It took three years to make these mice, and then it took another two to three years to actually model this process,” said Gardner. 

首先，Gardner的團隊將其諸多嘗試著重於，在一種簡化的模型中，創造能重現該複雜轉變之小鼠品種的挑戰性任務上。Gardner宣稱：「創造此些小鼠，花了三年時間。之後又花了兩到三年時間，來實際模擬此變化過程。」

The design of these genetically engineered mice was inspired by other mouse models for different lung cancer types. “I didn’t really develop anything that new so much as I took a little bit of this, a little bit of that, and brought it together,” he explained.

此些遺傳工程改造之小鼠的構思，受到不同肺癌類型之其他小鼠模型的啟發。他解釋：「我並沒有真正開發出任何新的東西，而是我拿了一點這個，一點那個，然後把它放在一起。」

The resulting mouse strains had mechanisms to turn on the expression of cancer genes involved in either LUAD or SCLC in specific cell types, for example. 

譬如，這些從而產生的小鼠品種具有，在特定細胞類型中，開啟涉及LUAD 或SCLC之癌基因表現的機制。

Researchers also labelled the mouse tumor cells with a fluorescent protein to track their course and used single-cell RNA sequencing to characterize gene expression throughout the transformation. 

研究人員們也使用螢光蛋白標記了，此些小鼠腫瘤細胞，來追蹤其進程。並使用了單細胞RNA排序，來表示出整個轉變中，基因表現的特徵。

The models revealed that lung alveolar epithelial cells that give rise to LUAD are sensitive to mutations in the oncogene coding for the epidermal growth factor receptor (EGFR), but are resistant to transformation driven by overexpression of Myc, one of the cancer genes leading to SCLC.

此些模型揭露了，引發LUAD之肺泡上皮細胞對於，在為表皮生長因子受體(EGFR)指定遺傳碼之致癌基因中的突變體，是敏感的。不過對於，由導致SCLC的癌基因之一，Myc過度表現所驅動的轉變，具有抵抗力。

Conversely, pulmonary neuroendocrine cells, the cells of origin for SCLC, are responsive to Myc overexpression, but not to EGFR mutations.

相反地，肺神經內分泌細胞(SCLC的起源細胞)對Myc過度表現有反應，不過對EGFR突變體沒有反應。

Gardner and his colleagues explored the mechanisms that rendered alveolar epithelial cells susceptible to the oncogenic effects of Myc.

Gardner及其同僚們探索了，使肺泡上皮細胞變得，易受Myc致癌基因之影響的機制。

The researchers discovered that by deleting specific tumor suppressor genes—some previously linked to SCLC—and blocking EGFR function, a subset of the alveolar epithelial cells transformed into stem-like cells that are sensitive to both EGFR and Myc.

此些研究人員發現，藉由剔除特定的腫瘤抑制基因(其中一些，先前與 SCLC被聯繫起來)及阻斷EGFR蛋白質的功能。一部分肺泡上皮細胞轉變成，對EGFR及Myc敏感的幹細胞樣細胞。

This plasticity allowed these cells to transform into Myc-driven SCLC neuroendocrine tumor cells. “This represents . . . a fundamental switch in the oncogenic driver program,” said Gardner. 

該種可塑性使此些細胞得以轉變成，Myc驅動的SCLC神經內分泌腫瘤細胞。Gardner宣稱：「這代表著…在致癌驅動因子編碼指令序列中的一種根本轉變。」

The advantage of this system is that it enables researchers to turn on and off the expression of lineage-specific oncogenic drivers, according to Hideo Watanabe, a genomic scientist studying lung cancer lineages at the Icahn School of Medicine at Mount Sinai who did not participate in this study. “It’s a very elegant [and] laborious way to look at this [transition],” he said. 

根據美國紐約州西奈山伊坎醫學院，未參與該項研究之研究肺癌種系的基因體科學家，Hideo Watanabe的說法，此方法的優點是，這使研究人員們能開啟及關閉，種系特異性之致癌驅動因子的表現。他宣稱：「這是一種探究此轉變，極佳卻費力的方式。」

Watanabe added that these mouse models may help scientists identify potential biomarkers activated during the transition from LUAD to SCLC, which could be monitored in patients to guide treatment decisions.

Watanabe附言，此些小鼠模型可能有助於科學家們識別，在從LUAD到SCLC的轉變中，被激活之能在患者中被監測，以引導治療決定的潛在生物標記。

However, he cautioned that researchers still need to determine how accurately the molecular processes in the model reflect LUAD to SCLC transformation in human lung cancer. Moreover, he noted, this might represent just one of many transition mechanisms, given the heterogeneity of lung cancer. 

不過他警告，研究人員們仍需要確定，該於此模型中之分子變化過程，如何精確反映於人類肺癌中，LUAD到SCLC的轉變。此外他特別指出，鑒於肺癌的異質性，這可能只是諸多轉變機制之一。

Watanabe believes that there's a long way to go before these findings have direct clinical implications. Yet, he added that the study offers foundational information that may help scientists develop future strategies for preventing this transformation in patients. 

Watanabe認為，在此些發現具有直接臨床意義之前，有漫長的路要走。不過他附言，該項研究提供了，能有助於科學家們開發，於患者中，防止此種轉變之未來對策的基本資訊。

網址：https://www.the-scientist.com/

翻譯：許東榮