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Author Spotlight: Assessing the Potential of Circulating Tumor Cells in Leptomeningeal Disease Research
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LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance

Ola Billing1, Ylva Holmgren2,3, Daniel Nosek4

  • 1Department of Surgical and Perioperative Sciences/Surgery, Umeå University, Umeå, Sweden. ola.billing@umu.se.

Oncogene
|May 5, 2021
PubMed

Insights

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) suppresses melanoma growth by regulating receptor tyrosine kinase signaling. Recombinant LRIG1 shows potential as a therapy for BRAF inhibitor-resistant melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a known tumor suppressor and negative regulator of receptor tyrosine kinase (RTK) signaling.
  • Its specific role in melanoma, particularly concerning RTK signaling and therapeutic resistance, remains largely uninvestigated.

Purpose of the Study:

  • To elucidate the function of LRIG1 in melanoma tumorigenesis.
  • To investigate LRIG1's impact on RTK signaling, specifically the epidermal growth factor receptor (EGFR) pathway.
  • To determine LRIG1's role in the development of resistance to BRAF inhibitors.

Main Methods:

  • Analysis of LRIG1 expression during melanoma tumorigenesis.
  • Functional studies on LRIG1's effect on EGFR activation in melanoma cells.
  • Investigation of conserved LRIG1-EGFR signaling in *C. elegans*.
  • Correlation of LRIG1 expression with patient survival in metastatic melanoma.
  • In vitro modeling of BRAF inhibitor resistance and assessment of LRIG1's role.
  • Treatment of resistant melanoma cells with recombinant LRIG1.

Main Results:

  • LRIG1 is downregulated in early melanoma tumorigenesis.
  • LRIG1 negatively regulates EGFR activation in melanoma cells, a conserved mechanism observed in *C. elegans*.
  • LRIG1 expression correlates with improved survival in a subset of metastatic melanoma patients (triple wild-type, high EGFR).
  • BRAF inhibitor resistance is associated with decreased LRIG1 expression and increased EGFR signaling, mimicking LRIG1 knockout.
  • Recombinant LRIG1 treatment reduces AKT activation and proliferation in resistant melanoma cells.

Conclusions:

  • LRIG1 acts as a conserved negative regulator of RTK signaling, including in melanoma.
  • LRIG1 downregulation contributes to melanoma progression and BRAF inhibitor resistance.
  • Recombinant LRIG1 presents a promising therapeutic strategy for BRAF inhibitor-resistant melanoma.

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