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Updated: May 22, 2025

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
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Deep learning prioritizes cancer mutations that alter protein nucleocytoplasmic shuttling to drive tumorigenesis

Yongqiang Zheng1, Kai Yu1,2, Jin-Fei Lin1,3

  • 1State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.

Nature Communications
|March 15, 2025
PubMed

Insights

Genetic variants called shuttling-attacking mutations (SAMs) disrupt nuclear protein import, driving cancer progression. This study identifies SAMs, revealing their role in tumor suppression loss and offering insights into cancer genetics.

Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Genetic variants can alter protein function through aberrant subcellular localization.
  • The impact of mutations on nuclear localization and cancer progression remains incompletely understood.

Purpose of the Study:

  • To systematically characterize potential shuttling-attacking mutations (SAMs) across various cancer types.
  • To develop a deep learning model (pSAM) for predicting sequence determinants of nucleocytoplasmic shuttling.
  • To investigate the functional consequences of SAMs on tumor suppressor genes.

Main Methods:

  • Development of the deep learning model pSAM for ab initio decoding of nucleocytoplasmic shuttling determinants.
  • Systematic analysis of cancer mutations across 11 cancer types to identify SAMs.
  • Experimental validation of identified SAMs, including disruption of nuclear localization signals and importin interactions.

Main Results:

  • SAMs were found to be enriched in functional genetic variations and critical cancer genes.
  • Several SAMs, including R14M in PTEN and P255L in CHFR, were experimentally validated to disrupt nuclear localization signals by interfering with importin interactions.
  • Altered nucleocytoplasmic shuttling in PTEN and CHFR due to SAMs was shown to rewire downstream signaling and abolish tumor suppressor functions.

Conclusions:

  • This study provides a comprehensive characterization of SAMs and their role in cancer.
  • The findings highlight the importance of nucleocytoplasmic shuttling in maintaining tumor suppression.
  • Understanding SAMs offers new insights into the molecular mechanisms of genetic variants in cancer progression.

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