Loss of the laminin subunit alpha‐3 induces cell invasion and macrophage infiltration in cutaneous squamous cell carcinoma. (1st December 2020)

• Record Type: Journal Article
• Authors: Caley, M.P.; Martins, V.L.; Moore, K.; Lashari, M.; Nissinen, L.; Kähäri, V.‐M.; Alexander, S.; Jones, E.; Harwood, C.A.; Jones, J.; Donaldson, M.; Marshall, J.F.; O'Toole, E.A.
• Is Part Of: British journal of dermatology. Volume 184:Number 5(2021)
• Page Start: 923
• Page End: 934
• Publication Date: 2020-12-01
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.19471
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: Background: Cutaneous squamous cell carcinoma (cSCC) is a common cancer that invades the dermis through the basement membrane. The role of the basement membrane in poorly differentiated cSCC is not well understood. Objectives: To study the effect that loss of the laminin subunit alpha‐3 (α3) chain from the tumour microenvironment has on tumour invasion and inflammatory cell recruitment. Methods: We examined the role of the basement membrane proteins laminin subunits α3, β3 and γ2 in SCC invasion and inflammatory cell recruitment using immunohistochemistry, short hairpin RNA knockdown, RNA‐Seq, mouse xenograft models and patient tumour samples. Results: Analysis of SCC tumours and cell lines using antibodies specific to laminin chains α3, β3 and γ2 identified a link between poorly differentiated SCC and reduced expression of laminin α3 but not the other laminin subunits investigated. Knockdown of laminin α3 increased tumour invasion both in vitro and in vivo . Western blot and immunohistochemical staining identified increased phosphorylated myosin light chain with loss of laminin α3. Inhibition of ROCK (rho‐associated protein kinase) but not Rac1 significantly reduced the invasive potential of laminin α3 knockdown cells. Knockdown of laminin subunits α3 and γ2 increased monocyte recruitment to the tumour microenvironment. However, only the loss of laminin α3 correlated with increased tumour‐associated macrophages both in xenografted tumours and in patient tumour samples. Conclusions: These data provide evidence that loss of the laminin α3 chain in cSCC has an effect on both the epithelial and immune components of cSCC, resulting in an aggressive tumour microenvironment. Abstract : What is already known about this topic? The tumour microenvironment, including the extracellular matrix, plays an important role in modulating tumour behaviour and inflammatory infiltration. Data on laminin expression in poorly differentiated squamous cell carcinomas (cSCCs) are limited. What does this study add? Poorly differentiated cSCCs have significantly reduced laminin α3 expression. Loss of laminin α3 increases tumour invasion, amoeboid migration and ROCK (rho‐associated protein kinase) signalling. Expression of laminin α3 in patient tumours is inversely correlated with macrophage recruitment. Our results provide novel evidence for the role of laminin α3 in the recruitment of tumour‐associated macrophages in SCC. What is the translational message? There is a potential prognostic value of laminin α3 expression in predicting cSCC metastasis. There is potential for targeting ROCK activity in cSCCs lacking laminin α3 to block tumour invasion. The role played by the laminin α3 chain in macrophage polarization into tumour‐associated macrophages presents additional targets for immunotherapy or immunoregulation in cSCC. Linked Comment: Leb‐Reichl et al. Br J Dermatol 2021; 184 :799 .