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      Generation of a squamous cell carcinoma mouse model for lineage tracing of BMI1+ cancer stem cells

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          Summary

          BMI1-expressing cancer stem cells (CSCs) play a key role in the development, progression, therapy resistance, recurrence, and metastasis of head and neck squamous cell carcinoma (HNSCC). Here, we present a chemically-induced HNSCC mouse model, genetically and pathologically similar to human HNSCC. This protocol describes how to use genetic lineage tracing based on the Cre-loxP recombination strategy, which allows us to study the regulation and targeting of BMI1 + CSCs in primary tumors and lymph node metastases.

          For complete details on the use and execution of this protocol, please refer to Chen et al. (2017) and Jia et al. (2020)

          Graphical abstract

          Highlights

          • •

            A protocol for inducing squamous cell carcinoma (SCC) in mice

          • •

            In vivo lineage tracing of BMI1 + cancer stem cells in primary tumors

          • •

            In vivo lineage tracing of BMI1 + cancer stem cells in metastatic lymph nodes

          • •

            Immunostaining and immunohistochemistry for pathology analysis

          Abstract

          BMI1-expressing cancer stem cells (CSCs) play a key role in the development, progression, therapy resistance, recurrence, and metastasis of head and neck squamous cell carcinoma (HNSCC). Here, we present a chemically-induced HNSCC mouse model, genetically and pathologically similar to human HNSCC. This protocol describes how to use genetic lineage tracing based on the Cre-loxP recombination strategy, which allows us to study the regulation and targeting of BMI1 + CSCs in primary tumors and lymph node metastases.

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          Most cited references4

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          A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

          Linda Madisen, Theresa Zwingman, Susan M. Sunkin … (2009)
          The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universal responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in a number of Cre-driver lines, including novel Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.
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            Bmi1 is expressed in vivo in intestinal stem cells.

            Eugenio Sangiorgi, Mario R. Capecchi (2008)
            Bmi1 plays an essential part in the self-renewal of hematopoietic and neural stem cells. To investigate its role in other adult stem cell populations, we generated a mouse expressing a tamoxifen-inducible Cre from the Bmi1 locus. We found that Bmi1 is expressed in discrete cells located near the bottom of crypts in the small intestine, predominantly four cells above the base of the crypt (+4 position). Over time, these cells proliferate, expand, self-renew and give rise to all the differentiated cell lineages of the small intestine epithelium. The induction of a stable form of beta-catenin in these cells was sufficient to rapidly generate adenomas. Moreover, ablation of Bmi1(+) cells using a Rosa26 conditional allele, expressing diphtheria toxin, led to crypt loss. These experiments identify Bmi1 as an intestinal stem cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than one molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis.
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              Targeting BMI1(+) Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma.

              Demeng Chen, Mansi Wu, Yang Li … (2017)
              Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC, and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here we show through lineage tracing and genetic ablation that BMI1(+) CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC. This model and primary human HNSCC samples contain highly tumorigenic, invasive, and cisplatin-resistant BMI1(+) CSCs, which exhibit increased AP-1 activity that drives invasive growth and metastasis of HNSCC. Inhibiting AP-1 or BMI1 sensitized tumors to cisplatin-based chemotherapy, and it eliminated lymph node metastases by targeting CSCs and the tumor bulk, suggesting potential regimens to overcome resistance to treatments and eradicate HNSCC metastasis.
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                Author and article information

                Contributors
                Demeng Chen
                Cun-Yu Wang
                Journal
                Journal ID (nlm-ta): STAR Protoc
                Journal ID (iso-abbrev): STAR Protoc
                Title: STAR Protocols
                Publisher: Elsevier
                ISSN (Electronic): 2666-1667
                Publication date PMC-release: 18 April 2021
                Publication date Collection: 18 June 2021
                Publication date (Electronic): 18 April 2021
                Volume: 2
                Issue: 2
                Electronic Location Identifier: 100484
                Affiliations
                [1 ]Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510030, China
                [2 ]Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA
                [3 ]Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510030, China
                [4 ]Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
                [5 ]Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
                Author notes
                [∗ ]Corresponding author chendm29@ 123456mail.sysu.edu.cn
                [∗∗ ]Corresponding author cwang@ 123456dentistry.ucla.edu
                [6]

                Technical contact

                [7]

                Lead contact

                Article
                Publisher Item ID: S2666-1667(21)00191-X Publisher ID: 100484
                DOI: 10.1016/j.xpro.2021.100484
                PMC ID: 8081985
                PubMed ID: 33982017
                SO-VID: d8ca5065-aca8-4ba1-ab84-9e76db6916e9
                Copyright © © 2021 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Subject: Protocol

                Keywords: cancer,microscopy,model organisms,stem cells
                Data availability:
                Keywords: cancer, microscopy, model organisms, stem cells

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