Lysyl oxidase‐like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression

Abstract

Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain-and loss-offunction mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy.

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

“…Conditional Loxl2 deletion ( L2 fl/fl ) or overexpression ( R26 STOPL2 ) mouse lines were recently described (22); presenting a mixed genetic background (50% FVB and 50% mix from C57BL/6, CD1 and 129v strains). PyMT mice harboring conditional Loxl2 deletion ( PyMT;L2 Δ/- ) or overexpression ( PyMT;R26 L2 ) in the mammary gland were generated by intercrossing L2 fl/fl or R26 STOPL2 females with their corresponding MMTV-PyMT +/T ;MMTV-Cre +/T ;Loxl2 fl/- and MMTV-PyMT +/T ;MMTV-Cre +/T ;R26 STOPL2 males.…”

“…Total RNA extraction from breast tumors, lungs and cells, cDNA synthesis and quantitative real-time PCR and semi-quantitative RT-PCR were performed as previously described (22). Each PCR reaction was carried out in triplicates from each tissue sample.…”

“…Initial studies suggested that LOXL2 action on tumorigenesis and metastasis could be similar to that of LOX, thus related to its potential ECM crosslinking activity (8, 18, 19). Nevertheless, subsequent studies demonstrated an unconventional action of intracellular LOXL2 in invasion and metastasis (12, 17, 20–22), including induction of epithelial to mesenchymal transition (EMT), Snail1 stabilization (a key EMT transcription factor), and activation of the UPR pathway (23, 24). LOXL2/Snail1-mediated repression of E-cadherin and other epithelial genes contributes to the dedifferentiated and metastatic phenotype of squamous cell carcinomas and basal breast carcinoma cells, respectively (12, 20).…”

“…However, the function of endogenous LOXL2 in in vivo tumor contexts and its relation/cooperation with other LOX/LOXL proteins has not been explored previously. We have recently reported the generation of constitutive Loxl2 gain- and loss-of function genetic mouse models, characterized in the context of epidermal squamous cell carcinomas (22). In the present study we address the function of endogenous Loxl2 in breast cancer metastasis through the generation of two complementary mouse models that conditionally delete or overexpress Loxl2 in the mammary gland of PyMT transgenic mouse model of breast cancer.…”

Lysyl Oxidase Isoforms and Potential Therapeutic Opportunities for Fibrosis and Cancer

“…It is widely over-expressed in cancers, including metastatic cancers. For example, high levels of LOXL2 occur in colon cancer associated fibroblasts 128 , skin cancer 129 , oral cancer 130 , skin and head and neck squamous cell carcinoma 101 , liver metastasis 103 , cholangiocarcinoma 131 , breast cancer 76, 92, 132, 133 , and gastric cancer metastasis 102 . Attenuation of LOXL2 expression was shown to inhibit metastasis or the invasive cell phenotypes in most of these studies.…”