Award Title: Development of a novel lung-on-a-chip platform to investigate breast cancer metastasis
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Most cancer patients do not die from the primary tumour but from its metastasis. Understanding and treating cancer metastasis is an ongoing challenge for the field. Current in vitro and in vivo cancer models are incapable of satisfactorily predicting the outcome of various clinical treatments on patients. This is seen as a serious limitation and efforts are underway to develop a new generation of highly predictive cancer models with advanced capabilities. Another major limitation is the accuracy and relevance of biological data that can be gleaned from the current animal and cell-based models. How mouse models are manipulated to develop secondary tumours is not reflective of the human situation and current in vitro cell-based metastasis models do not yet reflect the complex issues of cells under shear forces escaping the vasculature to establish a secondary tumour. Such studies use cross- species comparison (mouse vs human), whereas this proposed study will be a human vs. human comparison, which is more applicable and relevant for patients and can thus be beneficial to the NHS and population in Wales. Improving available models is important as understanding how and why particular primary tumours home to specific secondary sites could open new avenues for treatment.
In this regard, organ-on-chip models of cancer metastasis emerge as powerful predictors of disease progression. They offer physiological-like conditions where the (hypothesised) mechanistic determinants of the disease can be assessed with ease. Combined with high-throughput characteristics, the employment of organ-on-chip technology would allow pharmaceutical companies and clinicians to test new therapeutic compounds and adjust patient treatments. Microfluidic -based technologies have gained popularity in the biological field and have advantages over traditional cell culture models due to their time and reagent efficiency, and their suitability for high throughput screening. Importantly, microfluidic systems more faithfully reproduce the in vivo tumour microenvironment in terms of gene expression profiles, cell-cell interactions, and nutrient and oxygen gradients. Furthermore, microfluidic systems could assist in understanding metastasis biology and help predict the impact of potentially harmful drugs on human systems, thereby replacing the need for animal models in the early stages of drug development in a fast and economic manner, to accelerate the diagnosis of cancer and to test personalised treatments using cells from patients.
This study will create a novel bioengineered  breast cancer metastasis into the lung model, based on an established organ-chip technology (i.e., Human Emulation System), which better simulates microenvironmental complexity such as the inclusion of fluidic shear forces and mechanical stretching which are not available in current in vitro models. By combining a model lung that incorporates an air- liquid interface and mechanical stretching mimicking breathing, with breast cancer cells under shear force as if in blood circulation, our proposed model will help explore the biology of breast cancer metastasis to the lung. This system will reproduce the complexity of each patient to stand for the genetic heterogeneity of tumours and at the same time maintain this complexity low to keep the model clinically relevant. Cells from patients will be used to develop personalised models of cancer metastasis and help progress drug therapies for the NHS.

Lay Abstract: Breast cancer occurs due to changes in the breast tissue which allow cells to grow out of control.
Though breast cancer is one disease, it comes in different types and forms depending on where in the breast it starts and whether it is non-invasive or invasive. Cancer metastasis is the subsequent spread and invasion of the cancerous cells into other parts of the body beyond the breast tissue. The bones, lungs, brain, and liver are the most common places for breast cancer to spread to. Cancer spread is a leading cause of death in breast cancer patients.

Although our knowledge and treatment of breast cancer are improving, how breast cancer cells gain the ability to spread around the body is still not fully understood. To understand this better and identify
the critical steps associated with breast cancer spread, we plan to develop a new laboratory model of breast cancer spread to the lung which will better imitate what occurs in the body when breast cancer
spreads into healthy lung tissue. This will allow us to study the disease in detail and identify what factors help it spread.

At present, models that study the spread of breast cancer include animals that don’t faithfully represent the human disease or cells grown in petri-dishes in 2D which doesn’t reflect cells in the
body in a 3D environment. As a result, these models are either too complex to unravel the step-bystep changes or limited by their lack of complexity. This project proposes to take advantage of recent advances made by organ-on-chip technology, which are devices that better mimic the working of the body (i.e., any organ in the body, for instance, the lungs including the mechanism of breathing and 3D environmental conditions).

We propose using this organ-on-a-chip platform to create a lung-on-a-chip that will help us better understand the cause of breast cancer spread into the lung tissue. Lung-on-a-chips are translucent
devices that provide a window into the inner workings (i.e., the lung tissue composition, mechanical stretching imitating breathing, and flow rate imitating blood flow speeds) of the human lung without
having to invade a living body. It has the potential to be a valuable tool for testing the effects of environmental toxins, absorption of inhaled therapeutics, and the safety and efficacy of new drugs.
Such a tool may help accelerate drug development by reducing the reliance on current models.

The ability to recreate realistically both the mechanical and biological sides of the in vivo coin is an exciting innovation. Adopting this platform for modelling cancer metastasis will lead us a step closer to
a greater insight into how this disease works. This is important because patients experiencing breast cancer spread have few treatment options. Therefore, by developing a more realistic cancer model we will learn more about why breast cancer spreads to the lung in addition to other sites, and potential new ways to treat it. These models are a promising tool for drug screening in both drug development and personal drug administration for NHS patients.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS