癌症发生过程中从多细胞到单细胞的退行性演变
The degenerative evolution from multicellularity to unicellularity during cancer
摘要：
理论推理表明，人类癌症可能是由于敲低了为维持后生动物多细胞性而进化的遗传限制，然而，这需要一个关键的测试。使用基于异种移植的实验进化，我们首次在基因组和转录组水平上表征了肿瘤从开始到转移的完整生命史，并观察到一组多细胞相关基因上通常功能丧失突变的转移驱动正选择，这进一步得到了临床肿瘤样本的大规模外显子组数据的支持。随后的表达分析显示，主要是多细胞相关基因的表达下调，这形成了一个不断发展的表达谱接近胚胎干细胞，细胞类型与单细胞生命的最大特征。理论推测预测，在后生动物多细胞出现时出生的基因往往是癌症驱动因素，我们使用严格的生物地层学分析对癌症基因普查所注释的基因的出生率进行了验证。此外，在人类患者的典型肿瘤中，功能丧失的肿瘤抑制因子的数量通常超过活化的癌基因。这些数据共同表明，与获得新基因是主流的典型生物进化不同，癌症代表了功能丧失驱动的退化进化回到单细胞基态。这种癌症演变模型可以解释临床上巨大的肿瘤遗传异质性，尽管有不同的环境要求，但原发性肿瘤中的远距离器官转移是如何起源的，并对设计有效的癌症治疗方法产生影响。
英文摘要：
Theoretical reasoning suggests that human cancer may result from knocking down the genetic constraints evolved for maintenance of the metazoan multicellularity, which, however, requires a critical test. Using xenograft-based experimental evolution we characterized for the first time the full life history from initiation to metastasis of a tumor at the genomic and transcriptomic levels, and observed metastasis-driving positive selection for generally loss-of-function mutations on a set of multicellularity-related genes, which is further supported by large-scale exome data of clinical tumor samples. Subsequent expression analysis revealed mainly expression down-regulation of multicellularity-related genes, which form an evolving expression profile approaching that of embryonic stem cells, the cell type with the most characteristics of unicellular life. The theoretical conjecture predicts that genes born at the emergence of metazoan multicellularity tend to be cancer drivers, which we validated using a rigorous phylostratigraphy analysis on the birth rate of genes annotated by Cancer Gene Census. Also, the number of loss-of-function tumor suppressors often predominates over activated oncogenes in a typical tumor of human patients. These data collectively suggest that, different from typical organismal evolution in which gain of new genes is the mainstream, cancer represents a loss-of-function-driven degenerative evolution back to the unicellular ground state. This cancer evolution model may explain the enormous tumoral genetic heterogeneity in the clinic, underlie how distant-organ metastases originate in primary tumors despite distinct environmental requirements, and hold implications for designing effective cancer therapy.
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