
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.11.612492
preprint
1
Article
U2AF1 S34F enhances tumorigenic potential of lung cells by exhibiting synergy with KRAS mutation and altering response to environmental stress
Liang Cindy E
Hrabeta-Robinson Eva
Behera Amit
Arevalo Carlos
Fetter Isobel J.
Soulette Cameron M. http://orcid.org/0000-0001-8274-1838

Thornton Alexis M.
Sikandar Shaheen S.
Brooks Angela N. http://orcid.org/0000-0002-7898-3073

15 9 2024
2024.09.11.612492https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.09.11.612492
nihpp-2024.09.11.612492.pdf
SUMMARY

Although U2AF1 S34F is a recurrent splicing factor mutation in lung adenocarcinoma (ADC), U2AF1 S34F alone is insufficient for producing tumors in previous models. Because lung ADCs with U2AF1 S34F frequently have co-occurring KRAS mutations and smoking histories, we hypothesized that tumor-forming potential arises from U2AF1 S34F interacting with oncogenic KRAS and environmental stress. To elucidate the effect of U2AF1 S34F co-occurring with a second mutation, we generated human bronchial epithelial cells (HBEC3kt) with co-occurring U2AF1 S34F and KRAS G12V . Transcriptome analysis revealed that co-occurring U2AF1 S34F and KRAS G12V differentially impacts inflammatory, cell cycle, and KRAS pathways. Subsequent phenotyping found associated suppressed cytokine production, increased proliferation, anchorage-independent growth, and tumors in mouse xenografts. Interestingly, HBEC3kts harboring only U2AF1 S34F display increased splicing in stress granule protein genes and viability in cigarette smoke concentrate. Our results suggest that U2AF1 S34F may potentiate transformation by granting precancerous cells survival advantage in environmental stress, permitting accumulation of additional mutations like KRAS G12V , which synergize with U2AF1 S34F to transform the cell.
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pmc
