NOTCH Signaling Regulates Asymmetric Cell Fate of Fast- and Slow-Cycling Colon Cancer–Initiating Cells

Abstract

Colorectal cancer cells with stem-like properties, referred to as colon cancer initiating cells (CCIC), have high tumorigenic potential. While CCIC can differentiate to promote cellular heterogeneity, it remains unclear whether CCIC within a tumor contain distinct subpopulations. Here we describe the co-existence of fast-cycling and slow-cycling CCIC, which can undergo asymmetric division to generate each other, highlighting CCIC plasticity and interconvertibility. Fast-cycling CCIC express markers such as LGR5 and CD133, relying on MYC for their proliferation, whereas slow-cycling CCIC express markers such as BMI1 and hTERT and are independent of MYC. NOTCH signaling promotes asymmetric cell fate, regulating the balance between these two populations. Overall, our results illuminate the basis for CCIC heterogeneity and plasticity by defining a direct interconversion mechanism between slow-cycling and fast-cycling CCIC.

Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

“…More recently, it was reported that Lgr5 showed promise as a biomarker for colorectal CSCs [9, 11, 12]. Moreover, increasing evidence has shown that Lgr5 is involved in the Wnt/β-catenin pathway, which plays a key role in maintaining CSC self-renewal and tumorigenic ability [13-15].…”

Asymmetric Division Promotes Therapeutic Resistance in Glioblastoma Stem Cells

“…Established GBM xenografts (T4121, T3832, BT84, BT73 and L1) were previously reported (Bao et al, 2006;Cusulin et al, 2015;Schonberg et al, 2015;Srinivasan et al, 2016) and were obtained via a material transfer agreement from Duke University, University of Florida, and the University of Calgary, where they were originally established under IRB-approved protocols that facilitated the generation of xenografts in a de-identified manner from excess tissue taken from consented patients. For experimental studies, GBM cells were dissociated from established xenografts under Cleveland Clinic-approved Institutional Animal Care and Use Committee protocols.…”

“…Asymmetric cell division (ACD) is a cellular mechanism to generate heterogeneity while simultaneously maintaining a stem cell population (Venkei and Yamashita, 2018). ACD has been observed in multiple advanced cancers Lathia et al, 2011;Srinivasan et al, 2016;Wang et al, 2016), yet its functional contribution to tumorigenesis is not well understood. As ACD can enrich fate-determining molecules in one daughter cell, we hypothesized that this cellular mechanism may be leveraged in CSCs to generate therapeutically resistant progeny by concentrating pro-survival molecules to one daughter cell at the expense of the other.…”

Transcriptional Regulation of the Intestinal Cancer Stem Cell Phenotype

“…Using small-molecule inhibitors and short hairpin RNA-mediated knock-down, it has been demonstrated that Notch prevents apoptosis of colon cancer-initiating cells (CCICs) and is critical for self-renewal [46]. Moreover, the Notch pathway supports slow-cycling BMI1+ CCICs, by promoting their self-renewal, tumorigenicity and chemoresistance in tumor xenografts [47].…”