Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis
- Shengjing Hospital of China Medical University, China
- Shengjing hospital of China Medical University, China
- Tongji Medical College, China
- Xijing Hospital of Fourth Military Medical University, China
- Cancer Hospital of China Medical University, China
- Cancer Center of Dalian Medical University, China
- Dalian University of Technology, China
Abstract
Tumor metastasis remains the main cause of breast cancer-related deaths, especially delayed breast cancer distant metastasis. The current study assessed the frequency of CD44-/CD24- breast cancer cells in 576 tissue specimens for associations with clinicopathological features and metastasis and investigated the underlying molecular mechanisms. The results indicated that higher frequency (≥19.5%) of CD44-/CD24- cells was associated with delayed postoperative breast cancer metastasis. Furthermore, CD44-/CD24- triple negative breast cancer (TNBC) cells spontaneously converted into CD44+/CD24- cancer stem cells (CSCs) with properties similar to CD44+/CD24- CSCs from primary human breast cancer cells and parental TNBC cells in terms of stemness marker expression, self-renewal, differentiation, tumorigenicity and lung metastasis in vitro and in NOD/SCID mice. RNA sequencing identified several differentially expressed genes (DEGs) in newly converted CSCs and RHBDL2, one of the DEGs, expression was up-regulated. More importantly, RHBDL2 silencing inhibited the YAP1/USP31/NF-κB signaling and attenuated spontaneous CD44-/CD24- cell conversion into CSCs and their mammosphere formation. These findings suggest that the frequency of CD44-/CD24- tumor cells and RHBDL2 may be valuable for prognosis of delayed breast cancer metastasis, particularly for TNBC.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Foundation for Innovative Research Groups of the National Natural Science Foundation of China (#81572609)
- Caigang Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Renata Pasqualini, Rutgers University, United States
Ethics
Animal experimentation: The experimental protocol was approved by the Animal Research and Care Committee of China Medical University (Shenyang, China) and followed the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Female BALB/c nude mice (6 weeks old) were obtained from Human Silaikejingda Laboratory Animals (Changsha, China) and housed in a specific pathogen-free facility with free access to autoclaved food and water. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering. The current study was approved by the Ethics Committee of all three hospital review board review boards ((Project identification code: Project identification code: 2018PS304K, date on 03/05/2018 2018PS304K, date on 03/05/2018))
Version history
- Received: December 3, 2020
- Accepted: July 25, 2021
- Accepted Manuscript published: July 28, 2021 (version 1)
- Version of Record published: August 6, 2021 (version 2)
Copyright
© 2021, Qiao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,148
- Page views
-
- 270
- Downloads
-
- 9
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis
eLife 10:e65418.
https://doi.org/10.7554/eLife.65418
Further reading
-
- Cancer Biology
- Cell Biology
Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during rat Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective Schwann cell migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased Schwann cell collective migration and increased clustering of Schwann cells within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.
-
- Cancer Biology
- Structural Biology and Molecular Biophysics
Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl’s activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.
