1. Cancer Biology
  2. Cell Biology

Activation of Hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin

  1. Qi Deng
  2. Ping Li
  3. Manju Che
  4. Jiajia Liu
  5. Soma Biswas
  6. Gang Ma
  7. Lin He
  8. Zhanying Wei
  9. Zhenlin Zhang
  10. Yingzi Yang
  11. Huijuan Liu  Is a corresponding author
  12. Baojie Li  Is a corresponding author
  1. Shanghai Jiao Tong University, China
  2. Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China
  3. Harvard School of Dental Medicine, United States
https://doi.org/10.7554/eLife.50208
Share this article
Cite this article
  1. Qi Deng
  2. Ping Li
  3. Manju Che
  4. Jiajia Liu
  5. Soma Biswas
  6. Gang Ma
  7. Lin He
  8. Zhanying Wei
  9. Zhenlin Zhang
  10. Yingzi Yang
  11. Huijuan Liu
  12. Baojie Li
(2019)
Activation of Hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin
eLife 8:e50208.
https://doi.org/10.7554/eLife.50208
  2. Download BibTeX
  3. Download .RIS

Abstract

Indian Hedgehog (IHH) signaling, a key regulator of skeletal development, is highly activated in cartilage and bone tumors. Yet deletion of Ptch1, encoding an inhibitor of IHH receptor Smoothened (SMO), in chondrocyte or osteoblasts does not cause tumorigenesis. Here, we show that Ptch1 deletion in mice Prrx1+ mesenchymal stem/stromal cells (MSCs) promotes MSC proliferation and osteogenic and chondrogenic differentiation but inhibits adipogenic differentiation. Moreover, Ptch1 deletion led to development of osteoarthritis-like phenotypes, exostoses, enchondroma, and osteosarcoma in Smo-Gli1/2-dependent manners. The cartilage and bone tumors are originated from Prrx1+ lineage cells and express low levels of osteoblast and chondrocyte markers, respectively. Mechanistically, Ptch1 deletion increases the expression of Wnt5a/6 and leads to enhanced b-Catenin activation. Inhibiting Wnt/b-Catenin pathway suppresses development of skeletal anomalies including enchondroma and osteosarcoma. These findings suggest that cartilage/bone tumors arise from their early progenitor cells and identify the Wnt/b-Catenin pathway as a pharmacological target for cartilage/bone neoplasms.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Qi Deng

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Ping Li

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Manju Che

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Jiajia Liu

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Soma Biswas

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1427-2678

  6. Gang Ma

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Lin He

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Zhanying Wei

    Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Zhenlin Zhang

    Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Yingzi Yang

    Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3933-887X

  11. Huijuan Liu

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    liuhj@sjtu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  12. Baojie Li

    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
    For correspondence
    libj@sjtu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3913-1062

Funding

National Natural Science Foundation of China (81373210)

  • Baojie Li

National Natural Science Foundation of China (81520108012)

  • Baojie Li

National Natural Science Foundation of China (91542120)

  • Baojie Li

National Key Research and Development Program of China (2017YFA0103602)

  • Baojie Li

Schaefer Research Scholarship

  • Baojie Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse work was carried out following the recommendations from the NationalResearch Council Guide for the Care and Use of Laboratory Animals, with the protocols approved by the Institutional Animal Care and Use Committee of Shanghai, China [SYXK (SH) 2011-0112]. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Copyright

© 2019, Deng 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

  • 3,553
    views
  • 739
    downloads
  • 95
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

  1. Qi Deng
  2. Ping Li
  3. Manju Che
  4. Jiajia Liu
  5. Soma Biswas
  6. Gang Ma
  7. Lin He
  8. Zhanying Wei
  9. Zhenlin Zhang
  10. Yingzi Yang
  11. Huijuan Liu
  12. Baojie Li
(2019)
Activation of Hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin
eLife 8:e50208.
https://doi.org/10.7554/eLife.50208

Share this article

https://doi.org/10.7554/eLife.50208

Categories and tags

Research organism

Further reading

    1. Cancer Biology

    Non-destructive in situ monitoring of structural changes of 3D tumor spheroids during the formation, migration, and fusion process

    Ke Ning, Yuanyuan Xie ... Ling Yu
    Research Article

    For traditional laboratory microscopy observation, the multi-dimensional, real-time, in situ observation of three-dimensional (3D) tumor spheroids has always been the pain point in cell spheroid observation. In this study, we designed a side-view observation petri dish/device that reflects light, enabling in situ observation of the 3D morphology of cell spheroids using conventional inverted laboratory microscopes. We used a 3D-printed handle and frame to support a first-surface mirror, positioning the device within a cell culture petri dish to image cell spheroid samples. The imaging conditions, such as the distance between the mirror and the 3D spheroids, the light source, and the impact of the culture medium, were systematically studied to validate the in situ side-view observation. The results proved that placing the surface mirror adjacent to the spheroids enables non-destructive in situ real-time tracking of tumor spheroid formation, migration, and fusion dynamics. The correlation between spheroid thickness and dark core appearance under light microscopy and the therapeutic effects of chemotherapy doxorubicin and natural killer cells on spheroids’ 3D structure was investigated.

    1. Cancer Biology

    NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

    Ismail M Meraz, Mourad Majidi ... Jack A Roth
    Research Article

    Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11mt/aPD1R tumors but was synergistic in KRASwt/aPD1S H1299. NPRL2 also showed a significant antitumor effect on KRASmt/aPD1R LLC2 syngeneic-tumors. The antitumor effect was correlated with increased infiltration of human cytotoxic-T, HLA-DR+DC, CD11c+DC, and downregulation of myeloid and regulatory-T cells in TME. Antitumor effect was abolished upon in-vivo depletion of CD8-T, macrophages, and CD4-T cells whereas remained unaffected upon NK-cell depletion. A distinctive protein-expression profile was found after NPRL2 treatment. IFNγ, CD8b, and TBX21 associated with T-cell functions were significantly increased, whereas FOXP3, TGFB1/B2, and IL-10RA were strongly inhibited by NPRL2. A list of T-cell co-inhibitory molecules was also downregulated. Restoration of NPRL2 exhibited significantly slower tumor growth in humanized-mice, which was associated with increased presence of human cytotoxic-T, and DC and decreased percentage of Treg, MDSC, and TAM in TME. NPRL2-stable cells showed a substantial increase in colony-formation inhibition and heightened sensitivity to carboplatin. Stable-expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR signaling. Taken-together, NPRL2 gene-therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen-presentation and cytotoxic immune-cell activation.

    1. Biochemistry and Chemical Biology
    2. Cancer Biology

    Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth

    Flavie Coquel, Sing-Zong Ho ... Philippe Pasero
    Research Article

    Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or inhibit checkpoint kinases involved in the DNA damage response. Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the plant, Psoralea corylifolia, that synergistically inhibit cancer cell proliferation. Bakuchiol inhibited DNA replication and activated the checkpoint kinase CHK1 by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand break repair by inhibiting the checkpoint kinase CHK2 and DNA end resection. The combination of bakuchiol and isobavachalcone synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted NOD/SCID mice. The synergistic effect of inhibiting DNA replication and CHK2 signaling identifies a vulnerability of cancer cells that might be exploited by using clinically approved inhibitors in novel combination therapies.