Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, Bologna, 40126, Italy.
Pathology Unit, IRCCS Arcispedale Santa Maria Nuova, Via Amendola 2, 42122, Reggio Emilia, Italy.
Sci Rep. 2017 Oct 3;7(1):12568. doi: 10.1038/s41598-017-13002-1.
MYC-mediated cell competition is a cell-cell interaction mechanism known to play an evolutionary role during development from Drosophila to mammals. Cells expressing low levels of MYC, called losers, are committed to die by nearby cells with high MYC activity, called winners, that overproliferate to compensate for cell loss, so that the fittest cells be selected for organ formation. Given MYC's consolidated role in oncogenesis, cell competition is supposed to be relevant to cancer, but its significance in human malignant contexts is largely uncharacterised. Here we show stereotypical patterns of MYC-mediated cell competition in human cancers: MYC-upregulating cells and apoptotic cells were indeed repeatedly found at the tumour-stroma interface and within the tumour parenchyma. Cell death amount in the stromal compartment and MYC protein level in the tumour were highly correlated regardless of tumour type and stage. Moreover, we show that MYC modulation in heterotypic co-cultures of human cancer cells is sufficient as to subvert their competitive state, regardless of genetic heterogeneity. Altogether, our findings suggest that the innate role of MYC-mediated cell competition in development is conserved in human cancer, with malignant cells using MYC activity to colonise the organ at the expense of less performant neighbours.
MYC 介导的细胞竞争是一种细胞间相互作用的机制，已知在从果蝇到哺乳动物的发育过程中发挥着进化作用。表达低水平 MYC 的细胞，称为失败者，会被附近高 MYC 活性的细胞，称为胜利者，通过细胞凋亡来消灭，胜利者过度增殖以补偿细胞损失，从而选择最适合的细胞来形成器官。鉴于 MYC 在肿瘤发生中的巩固作用，细胞竞争应该与癌症有关，但它在人类恶性环境中的意义在很大程度上尚未被描述。在这里，我们在人类癌症中显示了典型的 MYC 介导的细胞竞争模式：MYC 上调的细胞和凋亡细胞确实在肿瘤-基质界面和肿瘤实质中反复出现。无论肿瘤类型和阶段如何，基质区细胞死亡量与肿瘤中 MYC 蛋白水平高度相关。此外，我们还表明，在人类癌细胞的异质共培养物中进行 MYC 调节足以颠覆它们的竞争状态，而与遗传异质性无关。总之，我们的发现表明，在人类癌症中，MYC 介导的细胞竞争在发育中的内在作用是保守的，恶性细胞利用 MYC 活性在器官中殖民，而牺牲表现较差的邻居。
