Intra-organismal evolution, cancer, and the challenges of an asexually reproducing immortal soma

多细胞性依赖于细胞间的合作，易受欺骗细胞的影响。一旦欺骗细胞在多细胞生物体中进化，合作的崩溃可能表现为癌症。大多数物种都能够通过经历生殖单细胞瓶颈，使下一代免于潜在的癌症，从而从物理上逃离这些逐渐进化的欺骗细胞。然而，某些物种，如某些专性无性繁殖的真涡虫，缺乏单细胞瓶颈，而是通过分裂繁殖。这种基于分裂的繁殖需要一个不朽的索马，它可能允许欺骗细胞在进化过程中发展。这表明，永生的无性真涡虫可能已经进化出了极端的肿瘤抑制机制，以应对欺骗细胞进化带来的挑战。然而，人们对涡虫的肿瘤抑制机制知之甚少，也没有理论模型来探索这种无性繁殖模式如何影响永生生物体内自私的细胞进化。在这篇论文中，我将在分析癌症以分离潜在的致癌基因和肿瘤抑制因子之前，驱动无性繁殖的真涡虫的癌症并使它们进化。此外，我将测试是否单独的创新的涡虫无性持续包含干细胞，进化自私的行为和高的内部有机体的竞争力。最后，我将建立一个理论框架，用于模拟生物体内和生物体间的竞争如何相互作用，以选择不朽生物体内的细胞行为。综上所述，这项研究有可能分离出允许极端抗癌的基因，并探索永生生物体内细胞合作的理论局限性。BBSRC优先领域：“整个生命过程中的健康老龄化”，“终身健康和福祉”，“体内技术”。

Multicellularity is dependent on cellular cooperation and is susceptible to cheating cells. Once cheating cells evolve within a multicellular organism, the breakdown in cooperation can manifest as cancer. Most species are able to physically escape these progressively evolving cheating cells by undergoing a reproductive single cell bottleneck that frees the next generation from potential cancer. However, some species such as certain obligate asexual planarians, lack a single cell bottleneck and instead reproduce by fission. Such fission-based reproduction necessitates an immortal soma which may allow cheating cells to develop over evolutionary time. This suggests that immortal asexual planarians may have evolved extreme tumour suppressive mechanisms to deal with the challenges posed by cheating cell evolution. However, little is known about the tumour suppressive mechanisms of planarians, and there are no theoretical models exploring how this asexual mode of reproduction may impact selfish cell evolution within the body of immortal organisms. In this thesis, I will drive cancer in asexual planarians and allow them to evolve before analysing the cancers to isolate potential oncogenes and tumour suppressors. Additionally, I will test whether separate innovations of planarian asexuality consistently contain stem cells that evolve selfish behaviour and high intra-organismal competitiveness. Finally, I will build a theoretical framework for modelling how intra-organismal and inter-organismal competition interact to select for cell behaviour within immortal organisms. Taken together, this research has the potential to isolate genes allowing for extreme cancer resistance as well as explore the theoretical limitations of cell cooperation within immortal organisms.BBSRC priority areas: "Healthy ageing across the lifecourse", "Lifelong Health and Wellbeing", "In vivotechniques".