# A Degradomic Landscape of Proteolytic Remodeling in Melanoma Lung Metastasis

## TL;DR

This study maps proteolytic changes in melanoma lung metastasis, identifying key enzymes and patterns across different compartments.

## Contribution

The work provides a multicompartment degradomic resource for melanoma lung metastasis, revealing novel proteolytic signatures and enzyme contributions.

## Key findings

- Over 8,000 semitryptic peptides were identified, with the secretome showing the highest cleavage burden.
- Distinct cleavage-site motifs were found in tissue, plasma, and secretome, implicating specific proteases like MMP2 and cathepsins.
- Proteolytic remodeling impacts extracellular matrix, inflammation, and metabolism in metastatic niches.

## Abstract

Melanoma metastasis
involves extensive remodeling of the tumor
microenvironment, yet the proteolytic processes underlying pulmonary
colonization remain poorly defined. Using the B16F10 intravenous melanoma
model in C57BL/6J mice, we performed an integrative degradomic analysis
of metastatic lung tissue, plasma, and secretome of early passaged
primary cultures derived from metastatic foci. Semispecific database
searches identified nearly 8,000 semitryptic peptides across compartments,
with the secretome exhibiting the highest burden of cleavage events,
indicating an intensely proteolytic microenvironment. Cleavage profiles
were compartment-specific, dominated by actin in metastatic lung tissue,
α2-macroglobulin in plasma, and SPARC in the secretome. Cleavage-site
motif analysis revealed conserved His/Ser (P1/P1′) preferences
in tissue and plasma, whereas the secretome showed a distinct Leu/Ser
pattern. Discriminant-feature analysis uncovered unique proteolytic
signatures for each compartment, and peptide-level mapping implicated
at least 11 proteasesincluding MMP2, cathepsin D, and cathepsin
Eas major contributors to metastatic niche remodeling. Functional
enrichment demonstrated coordinated impacts on extracellular matrix
organization, inflammation, and metabolic adaptation. This work provides
a multicompartment degradomic resource that captures proteolytic remodeling
in melanoma lung metastasis and establishes a foundation for future
functional and translational studies.