Dissecting the cancer epigenome – fundamental lessons from developmental biology

Introduction

DNA methylation is a tightly controlled mechanism that is essential for normal development and genome regulation. Although maintained in a highly static pattern across healthy tissues, DNA methylation is globally reprogrammed in nearly all malignant cancers, including gains at thousands of gene promoters and global loss across large domains.

Research Background

Substantial work from our group to characterize multiple primary tumor cohorts, transgenic animal models, and cancer cell lines finds that current experimental systems rarely, if ever, capture key features of the cancer epigenome. In contrast, our parallel efforts to understand epigenetic dynamics in development suggest an alternative, highly innovative hypothesis with a clear path for investigation.

Key Findings

We find that the epigenetic alterations in cancer very closely mirror patterns that emerge in the early placenta, a tissue that naturally acquires invasive, immune suppressive, angiogenic, metabolically plastic, and mutationally tolerant properties. Notably, this cancer-like epigenome depends on dynamic, previously undiscovered configurations of regulators that can be triggered without genetic mutation.

Methodology

With these insights, we have innovated tractable in vitro and in vivo platforms to dissect the biochemical, genetic, and physiological properties of this unique form of genome regulation as it supports developmental processes.

Objectives

We believe these efforts will demonstrate that the placenta and, by extrapolation, the cancer epigenome reflect a switch-like reprogramming event that can be studied at high resolution. In line with the ERC-ADG program’s goals, we will:

1. Pursue ambitious and critical questions.
2. Resolve long-standing paradoxes.
3. Provide a complete model of epigenetic transformation in development with direct disease implications.

Team and Impact

Our world-class interdisciplinary team, extensive preliminary data, experimental design, and proven track record will enable us to turn this grant into high-impact and translationally relevant discoveries.