Thomas R. Cox, May 2019
LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity
Our lab has contributed to a recent paper by Zeltz and colleagues looking at the interplay between Lysyl Oxidase Like 1 (LOXL1) and Integrin α11 in Non-Small Cell Lung Cancer (NSCLC). The work was published in the Open-Access journal Cancers.
In this study we found that Non-Small Cell Lung Cancer (NSCLC) cells secrete TGF-β that promotes the expression of integrin α11 on nearby cancer-associated fibroblasts (CAFs) via the Smad signaling pathway. Integrin α11, in turn, induces LOXL1 expression in the CAFs. Once secreted by the CAFs, LOXL1 cross-links collagen fibers to further enhance integrin-mediated collagen matrix remodeling. As part of this remodeling, alignment of collagen fibers leads to the enhancement of tumour growth and tumour progression.
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.
Zeltz C et al. LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity
Cancers (2019) | doi: 10.3390/cancers11050705
Lysyl Oxidase, Integrin α11, Lung Adenocarcinoma, Matrix Cross-linking, Tumour Progression
This work was supported by grants from the Canadian Cancer Society (#019293 and #020527), Canadian Institutes of Health Research grant MOP-115174, Terry Fox Foundation STIHR, CIHR grant TGT-53912 (BB), and the Ontario Ministry of Health and Long-Term Care. M.-S.T. is the M. Qasim Choksi chair in Lung Cancer Translational research. T.R.C. is supported by the NHMRC, Cancer Institute NSW, Cancer Council NSW and a grant from Susan G. Komen.