Regaining control of cancer at biological borders

Introduction

During dissemination, cancer cells must face and overcome several physiological borders, including the immediate stroma for local invasion and the endothelium for long-distance metastasis. At these critical junctures, cell plasticity between epithelial (E) and mesenchymal (M) states could determine metastasis potential. Based on our preliminary data, ideally-positioned cues emanating from the normal stroma contain the tumour in situ.

Border Breaching

Once this first border is breached, rare cancer cell-endothelial interactions trigger further dissemination through the vascular border. Moreover, cancer cell plasticity is vital throughout this process, enabling optimal response to distinct border microenvironments.

Project Overview

In BorderControl, we will build on our cutting-edge cell biology expertise and close collaboration with clinicians to define the molecular signals underlying these border “crossings” and gain unprecedented information on how cancer cells overwhelm these natural defences.

Methodology

1. Spatial Profiling: Starting with patient tissues, we will spatially profile the tumour-stroma border to identify receptor-ligand pairs that regulate invasion.

2. Microfluidics: We will use microfluidics to image, catch, and profile cancer cell crossings at endothelial hotspots and determine key molecular regulators of the process in endothelial and cancer cells.

3. E-M Transitions: Building on our novel discovery of endosomally regulated E-M cell states, we will test how E-M transitions impact border-breaching potential.

Interdisciplinary Approaches

These novel concepts will be investigated with interdisciplinary methods including:

• scRNAseq
• Synthetic biology
• Colour barcoded HTS

Additionally, we will utilize our new technologies, such as dynamically tuneable multicell-type migration and invasion imaging platforms, to determine the specific interactions and mechanisms regulating border crossings.

Clinical Relevance

Finally, we will take the molecular level discoveries from the cancer-limiting borders back to the patients, assessing clinical relevance using designer TMAs. We expect to uncover novel biomarkers and therapeutically actionable targets.