Understanding malignant transformation of precancerous lesions in human colon

Introduction

A crucial milestone in tumor progression is the transformation from a benign adenoma to a malignant cancer, which has a profound impact on clinical outcome and therapy design. Despite its importance, it is poorly understood why it manifests itself as a bottleneck that can restrain precancerous adenomas for years.

Challenges in Understanding Tumor Evolution

While recent sequencing efforts inform ‘static’ insights into the status of cancer genomes, these are incomplete to infer how they evolved, assess the functional consequence of mutations, nor how much malignancy is environmentally instructed.

Practical limitations hamper scientific advancement into the dynamic nature of tumor evolution. Foremost, studying human tumor evolution is challenging as sequential sampling is not feasible, and pre-malignant events that may hold the clue for understanding transformation often occur years before cancer diagnosis. Moreover, experimental models that reflect malignant transformation, let alone of human origin, are lacking.

Project Overview

TRANSFORMATION aims to resolve how human cancer genomes evolve towards malignancy, and its role in triggering malignancy.

Research Approach

To gain new insights on this matter, TRANSFORMATION takes a unique approach to produce experimental insights into evolutionary parameters that are inherently dynamic in nature and cannot be obtained from tumor sequencing alone.

1. Using paired biopsies from early-stage colon cancers, I generated unique organoid models from pre- and post-transformation regions.
2. Together with in situ analysis of matched tumors, TRANSFORMATION will reveal:
   • The elusive rate and order by which mutations and copy-number alterations are acquired.
   • The patterns by which cancer karyotypes evolve.
   • Dissecting functional from non-functional genetic heterogeneity on tumor phenotypes.
   • Investigating possible selection pressures imposed by environmental conditions.

Conclusion

TRANSFORMATION will solve how colon tumors evolve pre-malignancy, which properties promote malignancy, and why transformation is an evolutionary bottleneck.