LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Abstract

Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…This mechanosignaling then directs their transition to a myofibroblast-like phenotype that secretes high levels of matrisomal proteins as well as ECM remodeling enzymes (153). This mechanoresponsive signaling creates a selfreinforcing amplification loop that further increases the ECM stiffness in the tumor microenvironment to promote the growth of primary NSCLC tumors (154)(155)(156) (Figure 1E). In in vitro models, this mechanoresponsive fibroblast activation can persist for several weeks once the matrix stiffness is reduced, suggesting that transient stiffening of lung tissue in response to injury may also induce long lasting effects on cellular behavior that can potentiate tumorigenic processes (157).…”

Development and Validation of a Novel DNA Methylation-Driven Gene Based Molecular Classification and Predictive Model for Overall Survival and Immunotherapy Response in Patients With Glioblastoma: A Multiomic Analysis

“…Persano et al (2012) reported that BMP2 can increase GBM responsiveness to temozolomide by downregulating the HIF-1α/MGMT axis and can serve as a favorable predictor of survival, which is consistent with our study. LOXL1, which encodes a matrix cross-linking enzyme, has been identified as closely associated with the tumorigenesis of multiple cancers, including non-small cell lung cancer, breast cancer, and urological cancer (Jeong et al, 2018;Zeltz et al, 2019). Wu et al (2007) demonstrated that LOXL1 is epigenetically silenced by promoter hypermethylation and can inhibit the Ras/ ERK signaling pathway in bladder cancers.…”

Potential association of LOXL1 with peritoneal dissemination in gastric cancer possibly via promotion of EMT

“…LOXL1 is an extracellular copper-dependent amine oxidase [ 11 ]. It is known that LOXL1 is expressed in stromal cells and promotes non-small cell lung cancer tumorigenesis by extracellular matrix remodeling [ 29 ]. Interestingly, a recent study reported that LOXL1 is overexpressed in GC cells, and that high LOXL1 expression is a poor prognostic factor in GC patients [ 30 ].…”