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Helicobacter pylori accelerates KRAS-dependent gastric dysplasia

Valerie P. O’Brien, Amanda Koehne, Julien Dubrulle, Armando E. Rodriguez, Christina K. Leverich, Paul Kong, Jean S. Campbell, Robert H. Pierce, James R. Goldenring, Eunyoung Choi, View ORCID ProfileNina R. Salama
doi: https://doi.org/10.1101/2020.10.06.328518
Valerie P. O’Brien
1Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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Amanda Koehne
2Fred Hutchinson Cancer Research Center, Comparative Medicine Shared Resource, Seattle, WA, USA
3Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
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Julien Dubrulle
4Fred Hutchinson Cancer Research Center, Genomics and Bioinformatics Shared Resource, Seattle, WA, USA
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Armando E. Rodriguez
1Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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Christina K. Leverich
1Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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Paul Kong
3Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
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Jean S. Campbell
5Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
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Robert H. Pierce
5Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
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James R. Goldenring
6Vanderbilt University Medical Center, Department of Surgery and the Epithelial Biology Center, and the Nashville VA Medical Center, Nashville, TN, USA
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Eunyoung Choi
6Vanderbilt University Medical Center, Department of Surgery and the Epithelial Biology Center, and the Nashville VA Medical Center, Nashville, TN, USA
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Nina R. Salama
1Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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  • ORCID record for Nina R. Salama
  • For correspondence: nsalama@fredhutch.org
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Abstract

More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp), even though the bacterium is not always present at time of diagnosis. Infection is thought to lead to cancer by promoting the accumulation of oncogenic mutations downstream of inflammation; once oncogenic pathways become activated, infection may become dispensable for cancer development. Gastric preneoplastic progression involves sequential changes to the tissue, including loss of parietal cells, spasmolytic polypeptide-expressing metaplasia (SPEM), intestinal metaplasia (IM) and dysplasia. In mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate whether Hp infection has additional roles in preneoplastic progression, beyond initiating inflammation. Mice were assessed by evaluating tissue histology, gene expression changes, the immune cell repertoire, and expression of metaplasia and dysplasia markers. Compared to Hp-/KRAS+ mice, Hp+/KRAS+ mice had i) severe T cell infiltration and altered macrophage polarization; ii) altered expression of metaplasia markers, including increased expression of CD44v9 (SPEM) and decreased expression of TFF3 (IM); iii) more dysplastic (TROP2+) glands; and iv) greater proliferation of metaplastic and dysplastic glands. Hp was able to persistently colonize the stomach during the onset of these tissue changes, and eradication of Hp with antibiotics prevented metaplastic, dysplastic and proliferation marker changes. Collectively, these results suggest that gastric preneoplastic progression differs between Hp+ and Hp-cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression, in addition to its established role in initiating chronic inflammation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Disclosures: the authors declare that no conflict of interest exists.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 06, 2020.
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Helicobacter pylori accelerates KRAS-dependent gastric dysplasia
Valerie P. O’Brien, Amanda Koehne, Julien Dubrulle, Armando E. Rodriguez, Christina K. Leverich, Paul Kong, Jean S. Campbell, Robert H. Pierce, James R. Goldenring, Eunyoung Choi, Nina R. Salama
bioRxiv 2020.10.06.328518; doi: https://doi.org/10.1101/2020.10.06.328518
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Helicobacter pylori accelerates KRAS-dependent gastric dysplasia
Valerie P. O’Brien, Amanda Koehne, Julien Dubrulle, Armando E. Rodriguez, Christina K. Leverich, Paul Kong, Jean S. Campbell, Robert H. Pierce, James R. Goldenring, Eunyoung Choi, Nina R. Salama
bioRxiv 2020.10.06.328518; doi: https://doi.org/10.1101/2020.10.06.328518

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