Metastasis and the tumour microenvironment

Metastases are responsible for over 90% of cancer patient deaths. Understanding how tumours acquire the ability to invade and metastasise is critical for the identification of new targets and development of therapies against metastatic disease. Metastasis is a multistep process influenced by the immediate microenvironment, specifically cell-cell and cell-matrix interactions, and by the extended microenvironment, such as vascularity and tissue stiffness. All solid tumours contain regions of hypoxia (low oxygen) due to insufficient blood supply and chaotic tumour vasculature. Hypoxic tumour cells are resistant to radiation and many forms of chemotherapy. In addition, hypoxic tumour cells have increased invasive and metastatic potential. Hypoxia is clinically correlated with metastasis and poor patient survival.

Lysyl oxidase (LOX) is an extracellular matrix protein that initiates the covalent crosslinking of collagens and elastin. We have shown that LOX expression is correlated with hypoxia in human cancer patient tumours. Patients with high LOX expressing tumours have increased metastasis and decreased survival. Inhibition of LOX significantly reduces tumour growth and metastasis in various cancer models, through effects on invasion and metastatic growth. Lysyl oxidase-like 2 (LOXL2) is a LOX family member whose expression is clinically correlated with metastasis and decreased patient survival. Inhibition of LOXL2 function prevents metastasis through effects on extracellular matrix remodelling and invasion. Our pre-clinical data shows that LOXL2 is also an excellent therapeutic target, and we are highly supportive of current clinical trials using the Arresto/Gilead LOXL2-targeting antibody therapy.

New data suggests a critical role for LOX-mediated matrix modifications in malignant progression. These include matrix remodelling and an increase in tissue stiffness, which are characteristics of solid tumours. 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.

Network and Interdisciplinary Systems Medicine

A second major theme of our research is to take an interdisciplinary approach to investigate cancer progression. Almost all projects in the lab use systems wide approaches to help investigate questions. We believe that interdisciplinary research can advance our knowledge in ways that are not possible using single disciplinary or conventional approaches to scientific research.

In the Erler lab, we study cancer spread using a variety of approaches, and aim to investgate effects on the whole biological system rather than a few selected components. To do this, we use multiple global, unbiased methods, such as mass spectrometry-based proteomics, phosphoproteomics, kinase profiling, transcriptomics, DNA methylation and genomics in our work. We also use cross-disciplinary approaches, for example we have a project to understand the physics of cancer cells during invasion, using mechanical tweezers and advanced microscopy to measure forces.

Precision Cancer Medicine

We know that all cancers are different, and tumours of the same type don’t always respond to treatment in the same way. We also know that cancer therapy can be extremely difficult to endure, so the third big theme of our work is to develop precision (or personalised) medicine for cancer patients in Denmark. This collaborative effort combines my research group and clinical partners in a local hospital. The aim of the precision medicine project is to analyse a patient’s tumour to understand its molecular and genetic profile, then identify potentially effective therapies for each individual patient. We are developing techniques to test these therapies on cells isolated from the individual cancer patient grown in the lab. The ultimate goal is to offer the best possible therapy to patients, maximising the likelihood of a successful outcome and reducing unnecessary suffering.

You can find out more about our research at BRIC, University of Copenhagen