PDF(Pubmed)
Abstract：
UNASSIGNED: Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed.
UNASSIGNED: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.
UNASSIGNED: The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.
UNASSIGNED: The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
UNASSIGNED: To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.
UNASSIGNED: The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.
UNASSIGNED: The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
摘要：
■基因组完整性对生物体的生存至关重要。DNA错配修复（MMR）基因（例如，MLH1，MSH2，MSH6和PMS2）在维持基因组完整性的DNA损伤应答途径中起关键作用。MMR基因的种系突变可导致Lynch综合征或体质错配修复缺陷综合征，导致以微卫星不稳定性（MSI-H）和高突变负担为特征的癌症的终生风险增加。尽管免疫疗法已被批准用于MMR缺陷（MMRd）癌症患者，整体回应率需要提高，需要其他管理选择。
■为了更好地了解MMRd癌症的生物学特性，阐明免疫调节的抗性机制，并为这个高危人群开发疫苗和治疗性测试平台，我们从Msh2缺陷小鼠模型中开发的肠道肿瘤中产生了类器官和原位小鼠模型，并进行了详细的表征。
■显示类器官是具有干细胞特征的上皮来源，具有MSI-H和染色体不稳定性的高移码突变频率，以及肿瘤内和肿瘤间的异质性。使用盲肠内植入源自类器官的肿瘤碎片的原位模型显示进行性肿瘤生长，导致腺癌的发展，并伴有粘液性特征和肝脏和淋巴结的远处转移。
■已建立的具有MSI-H癌症特征的类器官可用于研究MMRd癌症生物学。原位模型，随着其远处转移和表达移码肽，适用于评估基于新抗原的疫苗或抗癌药物与其他疗法的组合的功效。
■为了更好地了解MMRd癌症的生物学特性，阐明免疫调节的抗性机制，并为这个高危人群开发疫苗和治疗性测试平台，我们从Msh2缺陷小鼠模型中开发的肠道肿瘤中产生了类器官和原位小鼠模型，并进行了详细的表征。
■显示类器官是具有干细胞特征的上皮来源，具有MSI-H和染色体不稳定性的高移码突变频率，以及肿瘤内和肿瘤间的异质性。使用盲肠内植入源自类器官的肿瘤碎片的原位模型显示进行性肿瘤生长，导致腺癌的发展，并伴有粘液性特征和肝脏和淋巴结的远处转移。
■已建立的具有MSI-H癌症特征的类器官可用于研究MMRd癌症生物学。原位模型，随着其远处转移和表达移码肽，适用于评估基于新抗原的疫苗或抗癌药物与其他疗法的组合的功效。
