Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma
Abstract
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.
Data availability
-
Copy number changes (average and single cell) and matching transcriptomes of HCCs and T-ALLs isolated from Mad2 p53 conditional double knockout micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63689).
-
Cytogenetic aberrations in Hepatocellular adenoma and carcinomaPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63100).
-
Hepatocellular adenoma/carcinoma from Mad2 deficient hepatocytesPublicly available at the NCBI Sequence Read Archive (accession no: SRA191233).
Article and author information
Author details
Funding
National Institute for Health Research (CA084179)
- Lee A Albacker
- Ying Yue
- Stephanie H Davis
- Peter K Sorger
National Institute for Health Research (CA139980)
- Lee A Albacker
- Ying Yue
- Stephanie H Davis
- Peter K Sorger
KWF Kankerbestrijding (2012-RUG-5549)
- Floris Foijer
- Bjorn Bakker
H2020 European Research Council (ERC advanced ROOTS)
- Diana C Spierings
- Peter M Lansdorp
European Molecular Biology Organization (Longterm fellowship)
- Floris Foijer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Angelika Amon, Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States
Ethics
Animal experimentation: All animals were kept in pathogen-free housing under guidelines approved by the Center for Animal Resources and Comparative Medicine at Harvard Medical School or at the Wellcome Trust Sanger Institute. Animal protocols were approved by the Massachusetts Institute of Technology, Harvard Medical School Committees on Animal Care (IACUC numbers I04272 and IS00000178), UK Home Office, and UMCG animal facility (DEC 6369).
Version history
- Received: August 23, 2016
- Accepted: March 18, 2017
- Accepted Manuscript published: March 20, 2017 (version 1)
- Version of Record published: April 21, 2017 (version 2)
Copyright
© 2017, Foijer 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
-
- 2,302
- Page views
-
- 435
- Downloads
-
- 45
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
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)
Further reading
-
- Cancer Biology
- Medicine
Nondestructive pathology based on three-dimensional (3D) optical microscopy holds promise as a complement to traditional destructive hematoxylin and eosin (H&E) stained slide-based pathology by providing cellular information in high throughput manner. However, conventional techniques provided superficial information only due to shallow imaging depths. Herein, we developed open-top two-photon light sheet microscopy (OT-TP-LSM) for intraoperative 3D pathology. An extended depth of field two-photon excitation light sheet was generated by scanning a nondiffractive Bessel beam, and selective planar imaging was conducted with cameras at 400 frames/s max during the lateral translation of tissue specimens. Intrinsic second harmonic generation was collected for additional extracellular matrix (ECM) visualization. OT-TP-LSM was tested in various human cancer specimens including skin, pancreas, and prostate. High imaging depths were achieved owing to long excitation wavelengths and long wavelength fluorophores. 3D visualization of both cells and ECM enhanced the ability of cancer detection. Furthermore, an unsupervised deep learning network was employed for the style transfer of OT-TP-LSM images to virtual H&E images. The virtual H&E images exhibited comparable histological characteristics to real ones. OT-TP-LSM may have the potential for histopathological examination in surgical and biopsy applications by rapidly providing 3D information.
-
- Cancer Biology
- Microbiology and Infectious Disease
Investigating the human fallopian tube (FT) microbiota has significant implications for understanding the pathogenesis of ovarian cancer (OC). In this large prospective study, we collected swabs intraoperatively from the FT and other surgical sites as controls to profile the microbiota in the FT and to assess its relationship with OC. Eighty-one OC and 106 non-cancer patients were enrolled and 1001 swabs were processed for 16S rRNA gene PCR and sequencing. We identified 84 bacterial species that may represent the FT microbiota and found a clear shift in the microbiota of the OC patients when compared to the non-cancer patients. Of the top 20 species that were most prevalent in the FT of OC patients, 60% were bacteria that predominantly reside in the gastrointestinal tract, while 30% normally reside in the mouth. Serous carcinoma had higher prevalence of almost all 84 FT bacterial species compared to the other OC subtypes. The clear shift in the FT microbiota in OC patients establishes the scientific foundation for future investigation into the role of these bacteria in the pathogenesis of OC.