1. Cancer Biology
Download icon

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

  1. Blake Ferguson
  2. Herlina Y Handoko
  3. Pamela Mukhopadhyay
  4. Arash Chitsazan
  5. Lois Balmer
  6. Grant Morahan
  7. Graeme J Walker  Is a corresponding author
  1. QIMR Berghofer Medical Research Institute, Australia
  2. Harry Perkins Institute of Medical Research, Australia
Research Article
  • Cited 4
  • Views 1,116
  • Annotations
Cite this article as: eLife 2019;8:e42424 doi: 10.7554/eLife.42424

Abstract

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the 'usual suspects' by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.

Article and author information

Author details

  1. Blake Ferguson

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Herlina Y Handoko

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Pamela Mukhopadhyay

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Arash Chitsazan

    QIMR Berghofer Medical Research Institute, Herston, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Lois Balmer

    Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Grant Morahan

    Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Graeme J Walker

    QIMR Berghofer Medical Research Institute, Herston, Australia
    For correspondence
    Graeme.Walker@qimr.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9392-8769

Funding

Melanoma Research Alliance (Investigator Grant Award Number: 346859 2015-2018)

  • Graeme J Walker

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations Australian code of Practice for the care and use of animals for scientific purposes.. All of the animals were handled according to approved institutional animal care and use committee of the Queensland Institute of Medical research. The protocol was approved by the Committee (A98004M). No surgery was performed. Animals were sacrificed when tumours reached 10mm in diameter, or animals were otherwise distressed.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: October 2, 2018
  2. Accepted: January 25, 2019
  3. Accepted Manuscript published: January 25, 2019 (version 1)
  4. Version of Record published: March 21, 2019 (version 2)

Copyright

© 2019, Ferguson 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

  • 1,116
    Page views
  • 218
    Downloads
  • 4
    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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    Yogev Sela et al.
    Short Report

    Cancer patients often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells on spatial grounds. We developed PIC-IT, a photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size – including single-metastatic cells – which are largely inaccessible otherwise. In a murine pancreatic cancer model, transcriptional profiling of spontaneously arising microcolonies revealed phenotypic heterogeneity, functionally reduced propensity to proliferate and enrichment for an inflammatory-response phenotype associated with NF-κB/AP-1 signaling. Pharmacological inhibition of NF-κB depleted microcolonies but had no effect on macrometastases, suggesting microcolonies are particularly dependent on this pathway. PIC-IT thus enables systematic investigation of metastatic heterogeneity. Moreover, the technique can be applied to other biological systems in which isolation and characterization of spatially distinct cell populations is not currently feasible.

    1. Cancer Biology
    2. Genetics and Genomics
    Iris E Glykofridis et al.
    Research Article Updated

    Germline mutations in the Folliculin (FLCN) tumor suppressor gene cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing carriers to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanism by which FLCN prevents kidney cancer remains unknown. Here, we show that disrupting FLCN in human renal tubular epithelial cells (RPTEC/TERT1) activates TFE3, upregulating expression of its E-box targets, including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, the absence of FLCN or its binding partners FNIP1/FNIP2 induces interferon response genes independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence immune responses. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.