Lumican delays melanoma growth in mice and drives tumor molecular assembly as well as response to matrix-targeted TAX2 therapeutic peptide

Abstract

Lumican is a small leucine-rich proteoglycan (SLRP) being known as a key regulator of collagen fibrillogenesis. However, little attention has been given so far in studying its influence on tumor-associated matrix architecture. Here, we investigate the role of host lumican on tumor matrix organization as well as on disease progression considering an immunocompetent model of melanoma implanted in Lum −/− vs. wild type syngeneic mice. Conjointly, lumican impact on tumor response to matrix-targeted therapy was evaluated considering a previously validated peptide, namely TAX2, that targets matricellular thrombospondin-1. Analysis of available genomics and proteomics databases for melanoma first established a correlation between lumican expression and patient outcome. In the B16 melanoma allograft model, endogenous lumican inhibits tumor growth and modulates response to TAX2 peptide. Indeed, IHC analyses revealed that lumican deficiency impacts intratumoral distribution of matricellular proteins, growth factor and stromal cells. Besides, innovative imaging approaches helped demonstrating that lumican host expression drives biochemical heterogeneity of s.c. tumors, while modulating intratumoral collagen deposition as well as organization. Altogether, the results obtained present lumican as a strong endogenous inhibitor of tumor growth, while identifying for the first time this proteoglycan as a major driver of tumor matrix coherent assembly.

Roles of Proteoglycans and Glycosaminoglycans in Cancer Development and Progression

“…Biglycan knock-out led tumor cell apoptosis by decreasing cyclin A and cyclin D1 expression in colon cancer [207]. As mentioned above, lumican, an antiproliferative PG, inhibited cell growth potential in melanoma cells [208,209] and inhibited cell proliferation in animal models of melanoma [210] and pancreatic cancer [104]. Additional supplementation with lumican suppressed cell growth by binding to EGFR and, subsequently, blocked downstream pathways in pancreatic cancer [50].…”

Biomarkers of tumor invasiveness in proteomics (Review)

“…The role of lumican in cancer appears to vary according to the type of tumor, with a restrictive role in prostate cancer invasion (121) and a role in colorectal adenoma-to-carcinoma progression (122). Its complex role has been investigated in detail in several studies, revealing in particular that glioblastoma and neuroblastoma cancer stem-like cells promote the activation of large quantities of lumican and decorin in the context of temozolomide resistance (123), while lumican deficiency promotes a pro-angiogenic tumor phenotype in melanoma (124).…”

Catabolism of Fibromodulin in Developmental Rudiment and Pathologic Articular Cartilage Demonstrate Novel Roles for MMP-13 and ADAMTS-4 in C-Terminal Processing of SLRPs

“…However, with the appreciation of OA as a multifactorial global disorder and that degenerative changes in cartilage are affected by degeneration in the synovium, subchondral bone, infra-patellar fat pad, meniscus, ligaments and tendons [43][44][45][46][47][48][49][50][51][52][53] there is now a greater appreciation of contributions from all these joint tissues in the achievement of optimal knee functional properties [54][55][56][57]. inhibiting the migration of melanoma cells and cell-matrix interactions required to promote tumor progression [30,67]. This inhibitory activity resides in a peptide named lumcorin located in LRR-9 of LUM [68].…”