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Direct interaction of TrkA/CD44v3 is essential for NGF-promoted aggressiveness of breast cancer cells

Sarah Trouvilliez1, Julien Cicero1,2, Romain Lévêque1

  • 1University Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France.

Journal of Experimental & Clinical Cancer Research : CR
|March 29, 2022
PubMed
Abstract

Insights

Blocking the CD44v3/TrkA interaction inhibits triple-negative breast cancer growth and metastasis. This study identifies CD44v3 as a key binding partner for TrkA, offering a potential therapeutic target for aggressive breast cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • CD44 is a glycoprotein involved in growth factor signaling.
  • CD44 and Tropomyosin kinase A (TrkA) form a complex after nerve growth factor (NGF) stimulation.
  • The pro-tumoral role of NGF in breast cancer involves TrkA/CD44 interactions.

Purpose of the Study:

  • To elucidate the interaction mechanism between CD44 and TrkA.
  • To investigate the functional consequences of inhibiting the TrkA/CD44 complex.
  • To evaluate the therapeutic potential of blocking this interaction in triple-negative breast cancer.

Main Methods:

  • Proximity ligation assays identified CD44v3 as the interacting isoform.
  • Molecular modeling and site-directed mutagenesis pinpointed key amino acids in the interaction.
  • A CD44v3 mimetic peptide was synthesized to block the interaction.
  • In vitro and in vivo assays assessed the peptide's effects on cancer cell behavior and tumor growth.
  • Tumor samples were analyzed for TrkA/CD44v3 expression and correlation with prognostic parameters.

Main Results:

  • CD44v3, not CD44v6, binds TrkA upon NGF stimulation.
  • The interaction requires the C-terminal amino acids of CD44v3 and TrkA residue H112.
  • Inhibition of TrkA/CD44v3 interaction by a peptide reduced cancer cell migration, invasion, and in vivo tumor growth and metastasis.
  • TrkA/CD44v3 complex was exclusively found in tumor tissues, not normal adjacent tissues.

Conclusions:

  • The CD44v3/TrkA interaction is crucial for NGF-driven pro-tumoral effects in triple-negative breast cancer.
  • Blocking the CD44v3/TrkA interaction represents a promising therapeutic strategy.
  • Targeting CD44v3/TrkA may offer a novel treatment option for triple-negative breast cancers.
Keywords:
Breast cancerCD44v3MetastasisNGFTrkA

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