eDyNAmiC - SCRIPPS

EDyNAmiC(染色体外DNA与癌症) 人类基因排列在23对染色体上，但在癌症中，促癌基因可以从染色体中解放出来，重新定位到环状、染色体外的DNA片段(EcDNA)上。这些ecDNA不遵循正常的染色体遗传规则，使肿瘤能够获得比其他情况下更高水平的致癌基因，并允许癌症以一种进化和改变其基因组的方式逃避治疗，其速度对人类细胞来说是不可想象的。EcDNA环状结构的改变也改变了致癌基因的调控和表达方式，进一步促进了侵袭性肿瘤的生长。这些独特的特征使含有ecDNA的癌症特别侵袭性强，难以治疗。肿瘤携带ecDNA的癌症患者的生存期明显较短。尽管ecDNA在50多年前就被首次发现，但它的关键重要性直到最近才被曝光，而且这个问题的规模是巨大的。近一半的人类癌症类型中都存在ecDNA，而且可能高达所有癌症患者的三分之一。目前对ecDNA是如何形成、如何发挥作用、如何在细胞内移动、如何进化以抵抗治疗、如何影响免疫系统以及如何有效靶向的集体目前缺乏了解。我们汇聚了一支由癌症生物学家、遗传学家、计算机科学家、进化生物学家、数学家、临床医生和患者权益倡导者组成的国际公认的开拓性跨学科团队，大胆创造新的见解和资源，并为癌症的重大挑战之一提供变革性的解决方案。一个由经验丰富和富有成效的ecDNA研究人员组成的核心团队将与ecDNA和癌症领域的新研究人员合作，为这一艰巨的挑战带来全新的视角和方法。通过连接来自癌症基因组学、酵母遗传学、表观基因组学、人工基因组合成、纵向患者跟踪、组合和机器学习算法、数学建模、免疫生物学和创新化学的尖端和多样化的方法和见解，我们将对ecDNA在癌症中的作用产生新的理解，我们将找到新的方法来治疗不可治疗的药物。这一大胆的方案由7个工作包和承诺的国际基础设施组成，产生了在任何其他类型的筹资机制下根本不可能实现的新的、不同寻常的合作。我们的计划致力于促进大胆的创新解决方案，以解决癌症中最棘手的问题之一和癌症患者面临的最大挑战之一。

eDyNAmiC (extrachromosomal DNA in Cancer) Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago, the critical importance of ecDNA has only recently come to light, and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form, how they function, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted are lacking. We bring together an internationally recognized, pioneering interdisciplinary team of cancer biologists, geneticists, computer scientists, evolutionary biologists, mathematicians, clinicians, and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancer’s Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, combinatorial and machine learning algorithms, mathematical modelling, immunobiology, and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer, and we will find new ways to drug the undruggable. This bold programme, which consists of 7 work packages and a committed international infrastructure, generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients.