In our group, we try to understand how cancer spreads through the body (a process called metastasis) as this is responsible for over 90% of cancer patient deaths. Metastasis is strongly influenced by the tumor microenvironment. We study how cells sense and respond to the tumor microenvironment in such a way as to become more aggressive, with a particular focus on cell-cell and cell-matrix interactions.
All solid tumors contain regions of hypoxia (low oxygen) due to insufficient blood supply and chaotic tumor vasculature. Hypoxic tumor cells are resistant to radiation and many forms of chemotherapy. In addition, hypoxic tumor cells have increased invasive and metastatic potential. Hypoxia is clinically correlated with metastasis and poor patient survival. We are investigating the underlying molecular mechanism responsible for these events.
Lysyl oxidase (LOX) is an extracellular matrix protein that initiates the covalent crosslinking of collagens and elastin. We have shown that LOX expression is regulated by hypoxia-inducible factor (HIF), and is correlated with hypoxia in human cancer patient tumors. Patients with high LOX expressing tumors have increased metastasis and decreased survival. Inhibition of LOX significantly reduces tumor growth and metastasis in various cancer models, through effects on invasion and metastatic growth. Thus, LOX represents a novel therapeutic target for the treatment and prevention of metastases.
Lysyl oxidase-like 2 (LOXL2) is a LOX family member that has similar collagen and elastin cross-linking function. We have shown that LOXL2 expression is clinically correlated with metastasis and decreased patient survival. Inhibition of LOXL2 function prevents metastasis through effects on extracellular matrix remodeling and invasion. Our pre-clinical data shows that LOXL2 is also an excellent therapeutic target.
New data suggests a critical role for LOX-mediated matrix modifications in malignant progression. These include matrix remodeling and an increase in tissue stiffness, which are characteristics of solid tumors. Emerging clinical data supports that stiffness is associated with more aggressive cancers. Our research has shown that both LOX and LOXL2 increase matrix stiffness, and we are very keen on understanding how cells sense these changes and respond in such a way that they behave more aggressively.
Our aim is to better understand how the tumor microenvironment drives metastatic progression and how LOX family proteins act as mediators. We are characterizing the signaling networks associated with metastatic progression. Through the integration of multiple types of data, we aim to build predictive models of cell behavior, and to identify network drugs, biomarkers and effective treatment strategies.
Selected recent publications
The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Thomas R. Cox, Robin M.H. Rumney, Erwin M. Schoof, Lara Perryman, Anette M. Høye, Ankita Agrawal, Demelza Bird, Norain Ab Latif, Hamish Forrest, Holly R. Evans, Iain D Huggins, Georgina Lang, Rune Linding, Alison Gartland, Janine T. Erler
Read the paper here (not possible to download or print)
Identification of hypoxia-regulated proteins using MALDI mass spectrometry tissue imaging and quantitative analysis. Djidja MC, Chang J, Hadjiprocopis A, Schmich F, Sinclair J, Mrsnik M, Schoof EM, Barker HE, Linding R, Jørgensen C and Erler JT. Journal of Proteome Research, epub ahead of print.
Brain cancer spreads. Perryman L and Erler JT. Science Translational Medicine 6 (2014), pp. 247 (Focus).
Molecular Pathways: Connecting fibrosis and solid tumour metastasis. Cox TR and Erler JT. Clinical Cancer Research 20 (2014), pp. 3637-43.
Disabling defences in the brain. Erler JT. Nature 508 (2014), pp. 46-7. (News&Views)
Lysyl oxidase in cancer research. Perryman, L and Erler JT. Future Oncology, in press.
LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling. Chang J, Nicolau M, Cox TR, Wetterskog D, Martens JW, Barker HE and Erler JT. Breast Cancer Research 5 (2013), pp. R67.
Tumor-secreted LOXL2 activates fibroblasts through FAK signaling. Barker HE, Bird D, Lang G and Erler JT. Molecular Cancer Research 11 (2013), pp. 1425-36.
LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G and Erler JT. Cancer Research 73 (2013), pp. 1723-32.
Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis. Baker AM, Bird D, Welti J, Gourlaouen M, Lang G, Murray GI, Reynolds AR, Cox TR and Erler JT. Cancer Research 73 (2013), pp. 583-94.
Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Baker AM, Bird D, Lang G, Cox TR and Erler JT. Oncogene 32 (2013), pp.1863-8.
The potential for targeting extracellular LOX proteins in human malignancy. Mayorca-Guiliani A and Erler JT. OncoTargets & Therapy 6 (2013), pp.1729-1735.
The importance of LOX family members on modulating cell-ECM interactions in carcinogenesis. Cox TR and Erler JT. Journal of Carcinogenesis and Mutagenesis (Special Issue) (2013) S13.
Lysyl oxidase in colorectal cancer. Cox TR and Erler JT. American Journal of Pathology Gastrointest Liver Physiol. 305 (2013), pp. G659-66.