Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra

  1. Juan Manuel Vazquez
  2. Maria T Pena
  3. Baaqeyah Muhammad
  4. Morgan Kraft
  5. Linda B Adams
  6. Vincent J Lynch  Is a corresponding author
  1. University of California, Berkeley, United States
  2. United States Department of Health and Human Services, United States
  3. University at Buffalo, State University of New York, United States

Abstract

The risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied Afrotherian lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives (Proboscideans), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch 2021). Unexpectedly, we also found that Xenarthrans (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: 1) several Xenarthran lineages independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; 2) the reduced cancer risk in the stem lineages of Xenarthra and Pilosa coincided with bursts of tumor suppressor gene duplications; 3) cells from sloths proliferate extremely slowly while Xenarthran cells induce apoptosis at very low doses of DNA damaging agents; and 4) the prevalence of cancer is extremely low Xenarthrans, and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in Xenarthrans and suggest they are a remarkably cancer resistant group of mammals.

Data availability

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

Article and author information

Author details

  1. Juan Manuel Vazquez

    Department of Integrative Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8341-2390
  2. Maria T Pena

    National Hansen's Disease Program, United States Department of Health and Human Services, Baton Rouge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Baaqeyah Muhammad

    Department of Biological Sciences, University at Buffalo, State University of New York, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Morgan Kraft

    Department of Biological Sciences, University at Buffalo, State University of New York, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Linda B Adams

    National Hansen's Disease Program, United States Department of Health and Human Services, Baton Rouge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vincent J Lynch

    Department of Biological Sciences, University at Buffalo, State University of New York, Buffalo, United States
    For correspondence
    vjlynch@buffalo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5311-3824

Funding

Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AAI15006)

  • Maria T Pena
  • Linda B Adams

National Institutes of Health (R56AG071860)

  • Vincent J Lynch

National Science Foundation (2028459)

  • Vincent J Lynch

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

Reviewing Editor

  1. Antonis Rokas, Vanderbilt University, United States

Version history

  1. Preprint posted: August 5, 2022 (view preprint)
  2. Received: August 9, 2022
  3. Accepted: December 7, 2022
  4. Accepted Manuscript published: December 8, 2022 (version 1)
  5. Version of Record published: January 3, 2023 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,103
    Page views
  • 126
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, 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)

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. Juan Manuel Vazquez
  2. Maria T Pena
  3. Baaqeyah Muhammad
  4. Morgan Kraft
  5. Linda B Adams
  6. Vincent J Lynch
(2022)
Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra
eLife 11:e82558.
https://doi.org/10.7554/eLife.82558

Share this article

https://doi.org/10.7554/eLife.82558

Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    Pengfei Guo, Rebecca C Lim ... Hui Zhang
    Research Article Updated

    The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4DCAF5 ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse Ezh2K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2K20R/K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation-dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to regulate the PRC2 activity and hematopoiesis.

    1. Cancer Biology
    Sen Qin, Yawei Xu ... Zheng Zhang
    Research Article

    Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.