Integrative profiling and engineering of clonal cancer cell behaviours: from the tissue level down to the molecular scale

Introduction

Clonal evolution in tumours, the process by which cancer cells expand, diversify and are selected, is a major determinant of tumour growth and response to therapy. How the co-existence of diverse cancer cell clones shapes tumour development is a fundamental question that remains open, in part because of limitations on existing experimental platforms and analytical frameworks.

Expertise and Advances

Our expertise inferring multicellular behaviours within tissue microenvironments, together with recent advances in imaging, assay automation, and cell engineering, timely place us in an excellent position to profile and engineer clonal interactions within tumours from the tissue level down to the molecular scale. This enables targeting this important question with unprecedented throughput and spatial resolution.

Objectives of SpaceClones

In SpaceClones, we aim to:

1. Characterize clonal interactions in genetically engineered tumours at sub-100 nm resolution.
2. Characterize clonal signatures under metabolically defined environmental conditions.
3. Examine the cell state of engineered clonal spatial patterns.

Methodological Approach

To overcome a variety of challenges to understanding molecular and cellular mechanisms of clonal behaviours in tumours, I have designed a ground-breaking approach that combines:

• Highly-multiplexed imaging
• In vitro and in vivo tumour models
• Cell engineering
• Super-resolution microscopy
• Combinatorial low-volume liquid handling
• Algorithms for deconstruction of spatial patterns

Implications

Altogether, SpaceClones will exemplify how to imply causality on the emergence of clonal spatial patterns in tumours, having far-reaching implications for the study of any other multicellular system. Ultimately, a deeper understanding of clonal evolution will contribute to the design of more effective cancer therapies and tools to predict clinical outcomes.