Functional Distinction in Oncogenic Ras Variant Activity in Caenorhabditis Elegans

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2024 Jul 1

PMID 38946472

Authors

Haimeng Lyu

Helen M Chamberlin

Affiliations

Soon will be listed here.

Abstract

Ras genes are important oncogenes that are frequently mutated in cancer. Human oncogenic variants exhibit functional distinctions in terms of their representation in different cancer types, impact on cellular targets and sensitivity to pharmacological treatments. However, how these distinct variants influence and respond to the cellular networks in which they are embedded is poorly understood. To identify novel participants in the complex interplay between Ras genotype and cell interaction networks in vivo, we have developed and tested an experimental framework using a simple vulva-development assay in the nematode C. elegans. Using this system, we evaluated a set of Ras oncogenic substitution changes at G12, G13 and Q61. We found that these variants fall into distinct groups based on phenotypic differences, sensitivity to gene dosage and inhibition of the downstream kinase MEK and their response to genetic modulators that influence Ras activity in a non-autonomous manner. Together, our results demonstrated that oncogenic C. elegans Ras variants exhibit clear distinctions in how they interface with the vulva-development network and showed that extracellular modulators yield variant-restricted effects in vivo.

References

Le Roux O, Pershing N, Kaltenbrun E, Newman N, Everitt J, Baldelli E . Genetically manipulating endogenous Kras levels and oncogenic mutations in vivo influences tissue patterning of murine tumorigenesis. Elife. 2022; 11. PMC: 9451540. DOI: 10.7554/eLife.75715. View

Hunter J, Manandhar A, Carrasco M, Gurbani D, Gondi S, Westover K . Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res. 2015; 13(9):1325-35. DOI: 10.1158/1541-7786.MCR-15-0203. View

Church D, Guan K, Lambie E . Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans. Development. 1995; 121(8):2525-35. DOI: 10.1242/dev.121.8.2525. View

Bruinsma J, Jirakulaporn T, Muslin A, Kornfeld K . Zinc ions and cation diffusion facilitator proteins regulate Ras-mediated signaling. Dev Cell. 2002; 2(5):567-78. DOI: 10.1016/s1534-5807(02)00151-x. View

Prior I, Lewis P, Mattos C . A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012; 72(10):2457-67. PMC: 3354961. DOI: 10.1158/0008-5472.CAN-11-2612. View

Han M, Sternberg P . let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a ras protein. Cell. 1990; 63(5):921-31. DOI: 10.1016/0092-8674(90)90495-z. View

Reiner D, Gonzalez-Perez V, Der C, Cox A . Use of Caenorhabditis elegans to evaluate inhibitors of Ras function in vivo. Methods Enzymol. 2008; 439:425-49. DOI: 10.1016/S0076-6879(07)00430-2. View

Sternberg P, Han M . Genetics of RAS signaling in C. elegans. Trends Genet. 1998; 14(11):466-72. DOI: 10.1016/s0168-9525(98)01592-3. View

Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D . RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011; 11(11):761-74. PMC: 3632399. DOI: 10.1038/nrc3106. View

10.

van der Hoeven D, Truong T, Naji A, Thapa S, Hancock J, van der Hoeven R . Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans. J Vis Exp. 2020; (164). DOI: 10.3791/61788. View

11.

Zand T, Reiner D, Der C . Ras effector switching promotes divergent cell fates in C. elegans vulval patterning. Dev Cell. 2011; 20(1):84-96. PMC: 3028984. DOI: 10.1016/j.devcel.2010.12.004. View

12.

Liu H, Dowdle J, Khurshid S, Sullivan N, Bertos N, Rambani K . Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation. Dev Cell. 2017; 41(4):392-407.e6. PMC: 5508591. DOI: 10.1016/j.devcel.2017.04.024. View

13.

Wu Y, Han M . Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Genes Dev. 1994; 8(2):147-59. DOI: 10.1101/gad.8.2.147. View

14.

Grossman R, Heath A, Ferretti V, Varmus H, Lowy D, Kibbe W . Toward a Shared Vision for Cancer Genomic Data. N Engl J Med. 2016; 375(12):1109-12. PMC: 6309165. DOI: 10.1056/NEJMp1607591. View

15.

Stetak A, Gutierrez P, Hajnal A . Tissue-specific functions of the Caenorhabditis elegans p120 Ras GTPase activating protein GAP-3. Dev Biol. 2008; 323(2):166-76. DOI: 10.1016/j.ydbio.2008.08.026. View

16.

Chamberlin H, Jain I, Corchado-Sonera M, Kelley L, Sharanya D, Jama A . Evolution of Transcriptional Repressors Impacts Caenorhabditis Vulval Development. Mol Biol Evol. 2020; 37(5):1350-1361. PMC: 7182219. DOI: 10.1093/molbev/msaa009. View

17.

Dickinson D, Pani A, Heppert J, Higgins C, Goldstein B . Streamlined Genome Engineering with a Self-Excising Drug Selection Cassette. Genetics. 2015; 200(4):1035-49. PMC: 4574250. DOI: 10.1534/genetics.115.178335. View

18.

Han M, Golden A, Han Y, Sternberg P . C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature. 1993; 363(6425):133-40. DOI: 10.1038/363133a0. View

19.

Buhrman G, Holzapfel G, Fetics S, Mattos C . Allosteric modulation of Ras positions Q61 for a direct role in catalysis. Proc Natl Acad Sci U S A. 2010; 107(11):4931-6. PMC: 2841912. DOI: 10.1073/pnas.0912226107. View

20.

Burdine R, Branda C, Stern M . EGL-17(FGF) expression coordinates the attraction of the migrating sex myoblasts with vulval induction in C. elegans. Development. 1998; 125(6):1083-93. DOI: 10.1242/dev.125.6.1083. View