Integration of physiological tissue models and machine learning to understand genomic instability from oncogene activation to cancer initiation

整合生理组织模型和机器学习，以了解从癌基因激活到癌症发生的基因组不稳定性

• 批准号: MR/W031442/1
• 负责人: Eva Petermann
• 金额: $ 122.62万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW031442%2F1
• 关键词: Integration; physiological; tissue; models; machine

Genes that cause abnormal growth of cells and development of cancer are called oncogenes. While oncogenes often arise from mutation of cellular genes, several types of viruses that can cause cancer, such as human papillomavirus (HPV), bring viral oncogenes into the cells they infect. Oncogenes can induce 'replication stress' (called oncogene-induced replication stress or Oi-RS), which is characterised by the frequent stalling or slowing of DNA replication when chromosomes are copied. This causes more mutations in the chromosomes, which is called genomic instability. While replication stress is common in established cancers, it has been discovered that it might also occur in pre-cancerous and early cancer tissues, leading to the hypothesis that Oi-RS is an initial driver of cancer but there is currently no direct evidence for this from existing experimental models of cancer development. Moreover, it is not known how early replication stress causes a healthy cell to become cancerous. Discovery of the initiating mechanisms leading to genomic instability and cancer would provide a vital step forward in understanding what causes cells to become cancerous and will be instrumental in improving early detection and treatment of cancer. We propose to use oncogenic HPV infection of human skin cells, the natural target cell of HPV, as a human tissue model system to analyse the precise steps from Oi-RS and genomic instability to cancer initiation. HPV causes >600,000 cancers per year worldwide that are characterised by high levels of genomic instability. Infection with high-risk types of HPV is a very useful model for Oi-RS and genomic instability during early cancer development, because viral oncogenes rapidly cause replication stress and genomic instability. To date however, no team has yet combined expertise to establish the precise pathways from HPV infection, replication stress and genomic instability, through to cancer formation in relevant human skin models. Our team comprises a tumour virologist, two cell biologists and a computational scientist. Together, we cross multiple biology disciplines from molecules to human tissue models and will bring diverse methods and technologies to investigate Oi-RS in a model of HPV infection. Our expertise ranges from molecular biochemistry and cell biology to computational biology and the application of artificial intelligence. Importantly, the individual partners all have a fundamental interest in how replication stress and genome instability contribute to cancer development. This project will for the first time bring together distinct backgrounds and disciplines to unravel the molecular events between Oi-RS, genomic instability, and cancer development. We will integrate single cell- and single molecule sequencing technology and machine learning-based detection of replication stress to interrogate the steps from early establishment of HPV in skin cells to the development of invasive cancer cells.

引起细胞异常生长和癌症发展的基因被称为致癌基因。虽然致癌基因通常是由细胞基因突变引起的，但几种可致癌的病毒，如人类乳头瘤病毒（HPV），会将病毒致癌基因带入它们感染的细胞。癌基因可以诱导“复制压力”（称为癌基因诱导的复制压力或Oi-RS），其特征是染色体复制时DNA复制经常停滞或减慢。这会导致更多的染色体突变，这被称为基因组不稳定性。虽然复制应激在已建立的癌症中很常见，但已经发现它也可能发生在癌前和早期癌症组织中，导致Oi-RS是癌症的初始驱动因素的假设，但目前尚无来自现有癌症发展实验模型的直接证据。此外，尚不清楚早期复制压力是如何导致健康细胞癌变的。发现导致基因组不稳定和癌症的启动机制将为理解导致细胞癌变的原因提供至关重要的一步，并将有助于改善癌症的早期发现和治疗。我们建议使用人类皮肤细胞（HPV的天然靶细胞）的致癌HPV感染作为人体组织模型系统来分析从Oi-RS和基因组不稳定性到癌症起始的精确步骤。HPV每年在全球范围内导致60万例癌症，其特征是高度的基因组不稳定性。高危型HPV感染是早期癌症发展过程中Oi-RS和基因组不稳定的一个非常有用的模型，因为病毒致癌基因迅速引起复制应激和基因组不稳定。然而，到目前为止，还没有一个团队结合专业知识，在相关的人类皮肤模型中建立从HPV感染、复制压力和基因组不稳定性到癌症形成的精确途径。我们的团队包括一名肿瘤病毒学家，两名细胞生物学家和一名计算科学家。我们将跨越从分子到人体组织模型的多个生物学学科，并将采用多种方法和技术来研究HPV感染模型中的Oi-RS。我们的专业范围从分子生物化学和细胞生物学到计算生物学和人工智能的应用。重要的是，个体合作伙伴都对复制压力和基因组不稳定性如何促进癌症发展有着根本的兴趣。该项目将首次汇集不同的背景和学科来揭示Oi-RS，基因组不稳定性和癌症发展之间的分子事件。我们将整合单细胞和单分子测序技术以及基于机器学习的复制压力检测，以询问从皮肤细胞中早期建立HPV到侵袭性癌细胞发展的步骤。

项目成果

Lead Time to Recurrence After Posttreatment Plasma and Saliva HPV DNA Testing in Patients With Low-Risk HPV Oropharynx Cancer

• DOI: 10.1001/jamaoto.2023.1730
• 发表时间: 2023-07-27
• 期刊: JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY
• 影响因子: 7.8
• 作者: Califano，Joseph;Yousef，Andrew;Mehanna，Hisham
• 通讯作者: Mehanna，Hisham

Conflicts with transcription make early replication late.

• DOI: 10.1016/j.molcel.2022.08.026
• 发表时间: 2022-09
• 期刊: Molecular cell
• 影响因子: 16
• 作者: E. Petermann

Lying low-chromatin insulation in persistent DNA virus infection.

• DOI: 10.1016/j.coviro.2022.101257
• 发表时间: 2022-08
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: C. S. Varghese;Joanna L. Parish;J. Ferguson