PDF(Pubmed)
Abstract：
Several classification systems have been developed to define tumor subtypes in colorectal cancer (CRC). One system proposes that tumor heterogeneity derives in part from distinct cancer stem cell populations that co-exist as admixtures of varying proportions. However, the lack of single cell resolution has prohibited a definitive identification of these types of stem cells and therefore any understanding of how each influence tumor phenotypes. Here were report the isolation and characterization of two cancer stem cell subtypes from the SW480 CRC cell line. We find these cancer stem cells are oncogenic versions of the normal Crypt Base Columnar (CBC) and Regenerative Stem Cell (RSC) populations from intestinal crypts and that their gene signatures are consistent with the \"Admixture\" and other CRC classification systems. Using publicly available single cell RNA sequencing (scRNAseq) data from CRC patients, we determine that RSC and CBC cancer stem cells are commonly co-present in human CRC. To characterize influences on the tumor microenvironment, we develop subtype-specific xenograft models and we define their tumor microenvironments at high resolution via scRNAseq. RSCs create differentiated, inflammatory, slow growing tumors. CBCs create proliferative, undifferentiated, invasive tumors. With this enhanced resolution, we unify current CRC patient classification schema with TME phenotypes and organization.
摘要：
已经开发了几种分类系统来定义结直肠癌（CRC）中的肿瘤亚型。一个系统提出,肿瘤异质性部分地源自作为不同比例的混合物共存的不同癌症干细胞群。然而,由于缺乏单细胞分辨率,这阻碍了对这些类型干细胞的明确鉴定,因此无法理解每种干细胞对肿瘤表型的影响.这里报道了来自SW480CRC细胞系的两种癌症干细胞亚型的分离和表征。我们发现这些癌症干细胞是来自肠道隐窝的正常隐窝碱基柱状（CBC）和再生干细胞（RSC）群体的致癌版本，并且它们的基因签名与“混合物”和其他CRC分类系统一致。使用公开可用的来自CRC患者的单细胞RNA测序（scRNAseq）数据，我们确定RSC和CBC癌干细胞通常共存于人类CRC中。为了表征对肿瘤微环境的影响，我们开发了亚型特异性异种移植模型,并通过scRNAseq以高分辨率定义其肿瘤微环境.RSCs产生分化,炎症，肿瘤生长缓慢。CBCs产生增殖，未分化,侵袭性肿瘤.有了这种增强的分辨率，我们将当前CRC患者分类模式与TME表型和组织统一起来.
