Matrix Metalloproteinase-11 Promotes Early Mouse Mammary Gland Tumor Growth through Metabolic Reprogramming and Increased IGF1/AKT/FoxO1 Signaling Pathway, Enhanced ER Stress and Alteration in Mitochondrial UPR

Abstract

Matrix metalloproteinase 11 (MMP11) is an extracellular proteolytic enzyme belonging to the matrix metalloproteinase (MMP11) family. These proteases are involved in extracellular matrix (ECM) remodeling and activation of latent factors. MMP11 is a negative regulator of adipose tissue development and controls energy metabolism in vivo. In cancer, MMP11 expression is associated with poorer survival, and preclinical studies in mice showed that MMP11 accelerates tumor growth. How the metabolic role of MMP11 contributes to cancer development is poorly understood. To address this issue, we developed a series of preclinical mouse mammary gland tumor models by genetic engineering. Tumor growth was studied in mice either deficient (Loss of Function-LOF) or overexpressing MMP11 (Gain of Function-GOF) crossed with a transgenic model of breast cancer induced by the polyoma middle T antigen (PyMT) driven by the murine mammary tumor virus promoter (MMTV) (MMTV-PyMT). Both GOF and LOF models support roles for MMP11, favoring early tumor growth by increasing proliferation and reducing apoptosis. Of interest, MMP11 promotes Insulin-like Growth Factor-1 (IGF1)/protein kinase B (AKT)/Forkhead box protein O1 (FoxO1) signaling and is associated with a metabolic switch in the tumor, activation of the endoplasmic reticulum stress response, and an alteration in the mitochondrial unfolded protein response with decreased proteasome activity. In addition, high resonance magic angle spinning (HRMAS) metabolomics analysis of tumors from both models established a metabolic signature that favors tumorigenesis when MMP11 is overexpressed. These data support the idea that MMP11 contributes to an adaptive metabolic response, named metabolic flexibility, promoting cancer growth.

Glycine‐Serine‐Threonine Metabolic Axis Delays Intervertebral Disc Degeneration through Antioxidant Effects: An Imaging and Metabonomics Study

“…Therefore, human metabolic pathway subgroups were retrieved from the NCBI GEO database and used for induction. A heat map on the correlation between core genes and metabolic pathways showed that main changes are changes in the metalloproteinase families [40,41] and their tissue-specific inhibitory enzyme familyrelated factors. Moreover, Gene Ontology functional enrichment analysis showed that decomposition of collagen and ECM is the main source of disc degeneration differences [19,42,43].…”

Analysis of Metabolic Pathways by 13C-Labeled Molecular Probes and HRMAS Nuclear Magnetic Resonance Spectroscopy: Isotopologue Identification and Quantification Methods for Medical Applications

“…Mice were subjected to the intraperitoneal injection of [U- 13 C]-glucose for 48 h before being sacrificed. This work was done as part of a study on the impact of MMP11 on tumor progression in the PyMT-MMTV mouse model of mammary tumors . The final insert used for the experiment contained 14 mg of biopsy specimen and 5 μL of D 2 O.…”

“…This work was done as part of a study on the impact of MMP11 on tumor progression in the PyMT-MMTV mouse model of mammary tumors. 15 The final insert used for the experiment contained 14 mg of biopsy specimen and 5 μL of D 2 O.…”

Obesity-Associated ECM Remodeling in Cancer Progression

“…An alteration to the MMP expression or in the balance between MMPs and their tissue-specific inhibitors is crucial for ECM remodeling during normal tissue development and disease progression. During obese development, an increased expression of MMP3, MMP11, MMP12, MMP13, and MMP14 has been detected and a reduction in MMP7, MMP9, MMP16, and MMP24 has been detected [ 55 , 56 , 57 ]. MMP13 cleaves interstitial collagens such as type I and III.…”

“…MMP13 cleaves interstitial collagens such as type I and III. MMP3 and MMP7 are mainly involved in fibronectin degradation [ 55 , 56 , 57 ]. Among these MMPs, MMP14 (MT1-MMP1) is the predominant pericellular collagenase in adipose tissue [ 55 ].…”