Understanding the effect of chemotherapy on tumour heterogeneity and metastatic ability in colorectal cancer

“化疗仍然是转移性结直肠癌（CRC）的主要治疗方法，可以将总生存期延长至两年以上。然而，超过一半的患者可能对标准化疗方案无反应，并且免疫疗法对大多数患者显示出有限的疗效。因此，需要更详细地了解化疗如何重塑CRC转移，以改善治疗选择。肿瘤的异质性和可塑性有助于治疗逃避。我们的目标是通过研究化疗诱导的转录异质性和可塑性对CRC转移的影响，更好地了解化疗如何在单细胞水平上改变恶性细胞和肿瘤微环境（TME）。使用单核多组数据，我们已经确定了化疗治疗和未经治疗的CRC肝转移共同的恶性细胞状态。这些亚群，包括癌症特异性状态和让人想起正常结肠的细胞层次结构，在治疗过的肿瘤和未经治疗的肿瘤之间显示出相似的丰度，但在治疗后从干细胞样细胞转移。差异表达和途径分析表明，治疗和未治疗的肿瘤之间的转录相似性，与一些富集的干扰素反应信号在治疗初治肿瘤。这可能表明，恶性细胞的可塑性，使他们能够恢复到治疗前state.In TME，我们检测到化疗治疗后的骨髓和T细胞亚群的水平显着差异。为了研究治疗重塑的微环境与恶性细胞之间的关系，我们对患者转移样品进行了空间转录组学分析。我们将确定化疗是否改变了癌细胞状态与特定TME群体的共定位，这将为细胞间通讯分析提供信息。这将有助于我们识别驱动不同恶性状态的候选信号因子。为了模拟化疗对细胞状态转变的影响，我们将用化疗治疗专利衍生的类器官，并生成单细胞时间序列数据。这将阐明可以靶向限制向抗性细胞状态转变的调控和/或信号传导因子。"

"Chemotherapy remains the mainstay treatment for metastatic colorectal cancer (CRC), which can prolong overall survival to more than two years. However, over half of patients may be unresponsive to standard chemotherapy regimes and immunotherapies show limited efficacy for most patients. Consequently, a more detailed understanding of how chemotherapy remodels CRC metastases is required for improving therapeutic options. Tumour heterogeneity and plasticity contribute to therapy evasion. We aim to better understand how chemotherapy alters both malignant cells and the tumour microenvironment (TME) at the single-cell level, by investigating the impact of chemotherapy-induced transcriptional heterogeneity and plasticity on CRC metastasis.Using single-nucleus multiome data, we have identified malignant cell states common to both chemotherapy-treated and therapy-naïve CRC liver metastases. These subpopulations, including cancer-specific states and cell hierarchies reminiscent of the normal colon, show similar abundance between treated and therapy-naïve tumours, with a shift away from stem-like cells following treatment. Differential expression and pathway analyses suggest transcriptional similarity between treated and untreated tumours, with some enrichment of interferon response signalling in therapy-naïve tumours. This may indicate that the plasticity of malignant cells enables their reversion to a pre-treatment state.In the TME, we detect significant differences in levels of myeloid and T cell subsets following chemotherapy treatment. To investigate the relationship between the therapy-remodelled microenvironment and malignant cells, we have performed spatial transcriptomics analysis of patient metastasis samples. We will determine whether chemotherapy alters the co-localisation of cancer cell states with specific TME populations, which will inform cell-cell communication analyses. This will help us identify candidate signalling factors driving distinct malignant states.To model the effect of chemotherapy on cell state transitions, we will treat patent-derived organoids with chemotherapy and generate single-cell time series data. This will elucidate regulatory and/or signalling factors that can be targeted to restrict transitions into resistant cell states."