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Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a

Manale El Kharbili1,2, Muriel Cario3,4, Nicolas Béchetoille5

  • 1Centre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR5534, Université de Lyon, F-69003 Lyon, France.

Cancers
|May 28, 2020
PubMed

Insights

Tetraspanin 8 (Tspan8) promotes melanoma spread by enabling cancer cells to invade the dermis. Targeting Tspan8 with antibodies may block this early stage of skin cancer metastasis.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • Melanoma is an aggressive skin cancer with challenging treatments.
  • Early melanoma dissemination involves dermal-epidermal junction (DEJ) degradation and dermal invasion, with underlying mechanisms poorly understood.
  • Tetraspanin 8 (Tspan8) was previously identified as a key factor in melanoma invasiveness.

Purpose of the Study:

  • To elucidate the mechanisms by which Tspan8 drives melanoma dermal invasion.
  • To investigate the role of Tspan8 in melanoma cell interaction with surrounding keratinocytes.
  • To evaluate the therapeutic potential of Tspan8-blocking antibodies against melanoma spread.

Main Methods:

  • Utilized a validated skin-reconstruct model mimicking melanoma dermal penetration through an authentic DEJ.
  • Analyzed Tspan8 expression in melanoma cells and its effect on keratinocyte activation.
  • Assessed levels of matrix metalloproteinase-9 (MMP-9), MMP-3, and tissue inhibitor of metalloproteinase-1 (TIMP-1).
  • Tested the efficacy of a specific Tspan8-blocking antibody in reducing proMMP-9 activation and dermal invasion.

Main Results:

  • Tspan8 expression was sufficient to induce melanoma cell translocation into the dermis.
  • Tspan8-positive melanoma cells promoted keratinocyte-derived proMMP-9 activation, leading to collagen IV degradation and dermal colonization.
  • Elevated active MMP-3 and reduced TIMP-1 levels were observed, favoring MMP-9 activity.
  • A Tspan8-specific antibody significantly reduced proMMP-9 activation and melanoma dermal invasion.

Conclusions:

  • Melanoma cells utilize Tspan8 to cooperatively engage keratinocytes, facilitating invasion via MMP-9 activation and collagen degradation.
  • This study reveals a novel, cell non-autonomous mechanism of melanoma invasion mediated by Tspan8 and keratinocytes.
  • Tspan8-blocking antibodies show promise for impeding early melanoma spread and preventing metastasis.
Keywords:
MMP-9Tetraspanin 8dermal-epidermal junctiondermismelanoma invasionmelanoma-keratinocytes crosstalktumor microenvironment

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