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Phosphoproteomic analysis reveals Smarcb1 dependent EGFR signaling in Malignant Rhabdoid tumor cells

Jonatan Darr1, Agnes Klochendler2, Sara Isaac3

  • 1Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. Jonatan.darr@mail.huji.ac.il.

Molecular Cancer
|September 16, 2015
PubMed
Abstract

Insights

SMARCB1 inactivation drives aggressive pediatric cancers. Restoring SMARCB1 impacts cell signaling, and inhibiting EGFR hinders tumor growth, offering a potential therapeutic strategy for Malignant Rhabdoid Tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • The SWI/SNF complex is crucial for chromatin remodeling and is implicated in cancer.
  • SMARCB1, a core SWI/SNF subunit, acts as a tumor suppressor.
  • SMARCB1 inactivation causes Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT).

Purpose of the Study:

  • To investigate Smarcb1-dependent signaling network alterations.
  • To identify phosphoproteomic changes in Smarcb1-deficient cells upon Smarcb1 re-expression.
  • To explore the therapeutic potential of targeting identified pathways.

Main Methods:

  • Utilized Stable Isotopic Labeling of Amino Acids in Cell Culture (SILAC) for quantitative phosphoproteomics.
  • Analyzed Smarcb1-deficient murine rhabdoid tumor cell lines.
  • Assessed Smarcb1 re-expression effects under varying serum conditions.

Main Results:

  • Identified broad changes in cell cycle, chromatin remodeling, cytoskeletal regulation, and focal adhesion networks.
  • Demonstrated Smarcb1-dependent alterations in EGF receptor (EGFR) phosphorylation and expression.
  • Showed that EGFR signaling inhibition restricts Smarcb1-deficient cell proliferation.

Conclusions:

  • EGFR signaling activation in Rhabdoid tumors is dependent on SMARCB1.
  • EGFR inhibitors show efficacy in reducing human MRT cell proliferation.
  • These findings support SMARCB1's role in regulating EGFR signaling and suggest therapeutic avenues.

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