Spontaneous Tumor Regression in Tasmanian Devils Associated with RASL11A Activation

Mark J Margres; Manuel Ruiz-Aravena; Rodrigo Hamede; Kusum Chawla; Austin H Patton; Matthew F Lawrance; Alexandra K Fraik; Amanda R Stahlke; Brian W Davis; Elaine A Ostrander; Menna E Jones; Hamish McCallum; Patrick J Paddison; Paul A Hohenlohe; David Hockenbery; Andrew Storfer

doi:10.1534/genetics.120.303428

Spontaneous Tumor Regression in Tasmanian Devils Associated with RASL11A Activation

Genetics. 2020 Aug;215(4):1143-1152. doi: 10.1534/genetics.120.303428. Epub 2020 Jun 18.

Authors

Mark J Margres^{1

2}, Manuel Ruiz-Aravena³, Rodrigo Hamede^{3

4}, Kusum Chawla^{5

6}, Austin H Patton⁷, Matthew F Lawrance⁷, Alexandra K Fraik⁷, Amanda R Stahlke⁸, Brian W Davis^{9

10}, Elaine A Ostrander¹⁰, Menna E Jones³, Hamish McCallum¹¹, Patrick J Paddison⁵, Paul A Hohenlohe⁸, David Hockenbery^{5

6}, Andrew Storfer⁷

Affiliations

¹ School of Biological Sciences, Washington State University, Pullman, Washington 99164 [email protected].
² Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138.
³ School of Natural Sciences, University of Tasmania, Hobart, Tasmania 7001, Australia.
⁴ Centre for Integrative Ecology, Deakin University, Waurn Ponds, Victoria 3216, Australia.
⁵ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
⁶ Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
⁷ School of Biological Sciences, Washington State University, Pullman, Washington 99164.
⁸ Department of Biological Sciences, Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, Idaho 83844.
⁹ Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843.
¹⁰ Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
¹¹ School of Environment, Griffith University, Nathan, Queensland 4111, Australia.

Abstract

Spontaneous tumor regression has been documented in a small proportion of human cancer patients, but the specific mechanisms underlying tumor regression without treatment are not well understood. Tasmanian devils are threatened with extinction from a transmissible cancer due to universal susceptibility and a near 100% case fatality rate. In over 10,000 cases, <20 instances of natural tumor regression have been detected. Previous work in this system has focused on Tasmanian devil genetic variation associated with the regression phenotype. Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5' untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression. RASL11A was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with RASL11A downregulation in human cancers. Induced RASL11A expression significantly reduced tumor cell proliferation in vitro The RAS pathway is frequently altered in human cancers, and RASL11A activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.

Keywords: cancer; gene expression; tumor regression; tumor suppressor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Proliferation*
Female
Gene Expression Regulation, Neoplastic*
Marsupialia / physiology*
Monomeric GTP-Binding Proteins / genetics
Monomeric GTP-Binding Proteins / metabolism*
Neoplasm Regression, Spontaneous*
Neoplasms / genetics
Neoplasms / pathology
Neoplasms / veterinary*
Tumor Cells, Cultured

Substances

Monomeric GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding