Abstract

Basal subtype cancers are deadly malignancies but the molecular events driving tumor lethality are not completely understood. Ataxia-telangiectasia group D complementing gene (ATDC, also known as TRIM29), is highly expressed and drives tumor formation and invasion in human bladder cancers but the factor(s) regulating its expression in bladder cancer are unknown. Molecular subtyping of bladder cancer has identified an aggressive basal subtype, which shares molecular features of basal/squamous tumors arising in other organs and is defined by activation of a TP63-driven gene program. Here, we demonstrate that ATDC is linked with expression of TP63 and highly expressed in basal bladder cancers. We find that TP63 binds to transcriptional regulatory regions of ATDC and KRT14 directly, increasing their expression, and that ATDC and KRT14 execute a TP63-driven invasive program. In vivo, ATDC is required for TP63-induced bladder tumor invasion and metastasis. These results link TP63 and the basal gene expression program to ATDC and to aggressive tumor behavior. Defining ATDC as a molecular determinant of aggressive, basal cancers may lead to improved biomarkers and therapeutic approaches.

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Acknowledgments

The authors would like to thank Andrew Ewald for assistance with the 3D invasion and imaging systems used in this study.

Funding

This work was funded by grants from the University of Michigan Cancer Center Core Grant CA046592-26S3, NIH K08 CA201335 (PLP), BCAN YIA (PLP), ASCO YIA (PLP), and NIH R01 CA17483601 (DMS).

Author information

Affiliations

  1. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Phillip L. Palmbos
    • , Yin Wang
    • , Alan J. Kelleher
    • , McKenzie L. Ahmet
    •  & Erica R. Gumkowski
  2. Rogel Cancer Center, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Phillip L. Palmbos
    • , Yin Wang
    • , Armand Bankhead III
    • , Samuel D. Welling
    • , Brian Magnuson
    • , Jacob Leflein
    • , Guadalupe Lorenzatti Hiles
    • , Ethan V. Abel
    • , Michele L. Dziubinski
    • , Sumithra Urs
    •  & Mats E. Ljungman
  3. Department of Biostatistics, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Armand Bankhead III
    •  & Brian Magnuson
  4. Department of Computational Medicine and Bioinformatics, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Armand Bankhead III
  5. Department of Surgery, NYU Langone Health, New York, NY, 10016, USA

    • Lidong Wang
    •  & Diane M. Simeone
  6. Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA

    • Lidong Wang
    •  & Diane M. Simeone
  7. Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Huibin Yang
    •  & Mats E. Ljungman
  8. Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Guadalupe Lorenzatti Hiles
    •  & Mark L. Day
  9. Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    • Michele L. Dziubinski
  10. Department of Pathology, NYU Langone Health, New York, NY, 10016, USA

    • Diane M. Simeone

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https://doi.org/10.1038/s41388-018-0646-9