Developmental Origin of Cancer Risks

  • Functional and Structural Genomics
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Dr. Pei-Chi Wei

Principal Investigator

Cancer risk may begin before birth. We investigate how normal processes of embryonic development create DNA breakage, and how maternal and environmental factors can reinforce these vulnerabilities. Our mission is to understand how these early-life risks persist and manifest as disease later in life, and to identify actionable targets for prevention. Our primary research focus is on brain development, with the aim of extending these insights to other organs and biological systems.

Our Mission: Unraveling the Role of DNA Diversity in Brain Health

Illustration depicting a brain with colorful bar-like structures representing gene expression in different regions. To the right, additional graphs display varying gene activity levels indicated by contrasting colors, highlighting the relationship between genetic patterns and brain function.

Brain Development is a Dynamic Process  
The human brain is built from billions of neurons and astrocytes, generated through hundreds of divisions by neural progenitor cells. Remarkably, most of these cells form within just 24 weeks during fetal development. This process is carefully orchestrated in both time and space, shaping the ~400g newborn brain.

My lab explores fundamental questions: How do neural progenitor cells know when to stop dividing? Why and how do they extend their cell cycles? Does rapid cell division increase DNA damage in these cells? Understanding these mechanisms is key to uncovering how brain cancer begins, progresses, and evolves.

Methods and technologies 
We have developed experimental and analytical tools to uncover the interactions between the cellular machinery responsible for copying and reading DNA sequences. Using high-throughput sequencing technologies, we measure the timing and speed of DNA replication and examine the transcriptional "traffic" created by the machinery decoding DNA. 

Additionally, we create mouse models to investigate how neural stem cells compete for space and resources during early brain development. Our work also includes designing experimental systems that allow us to "travel back in time," tracing early developmental neural stem cell behaviors at later stages of life.

Goals and societal relevance 
Brain cancer prevention faces significant challenges due to our limited understanding of how early cellular processes contribute to tumor formation. Our mission is to bridge this gap by uncovering how neural stem and progenitor cells drive brain development while maintaining DNA integrity. By studying the mechanisms of clonal expansion, cellular competition, and genomic stability, we aim to identify key risk factors and develop strategies for preventing brain cancers. Through this work, we strive to advance brain health and reduce the societal impact of neurological diseases.

Research Projects

DNA damage

Building a brain takes countless rounds of cell division, and every division has to faithfully copy three billion letters of our genetic code. Sometimes the copying machinery stalls, and the long string of DNA snaps. When the cell glues the broken ends back together in the wrong way, whole chunks of the genetic instructions go missing or get duplicated by accident — unplanned losses and gains the cell never scheduled. These changes are among the strongest known risk factors for autism and brain cancer. Yet why they keep happening at the same spots has remained a puzzle.

We identified a fundamental source. Working with the stem cells that build the brain, we found a handful of "weak spots" in the genetic code. These sit inside the longest genes used by brain cells — the very genes that help neurons connect and talk to each other — and they snap especially easily when DNA copying runs into trouble.

We showed that these weak spots are the starting point for the unplanned losses. The breaking itself is predictable — it happens at the same spots every time DNA copying is stressed — but the repair is not: some cells heal cleanly, some lose the same chunk again and again, forming the recurrent changes seen in disease, and others patch the damage into large, one-of-a-kind rearrangements, leaving each neuronal cell with a slightly different set of genetic building blocks. The same scheduled event is "bad luck" for cells whose repair goes wrong, and a source of natural diversity for the rest — a cell-to-cell variation now recognized as a normal feature of healthy brains, and a contributor to diseased ones. Strikingly, silencing the long genes shut down the breaks and the unplanned changes altogether.

The findings recast these weak spots as a central source of genetic diversity in the developing brain, opening new avenues for understanding how brain disorders and brain tumors begin.

Sources:
Corazzi and Ing et al., (2026) Nature Communications
Corazzi and Ionasz et al., (2024) Nature Communuications

Current team

  • A woman with long black hair smiles softly at the camera. She is wearing a light gray sleeveless top with lace detailing on one shoulder. The background is plain and white, highlighting her facial features and expression.

    Dr. Pei-Chi Wei

    Principal Investigator

  • A smiling laboratory technician wearing a lab coat and gloves is seated at a workbench filled with various laboratory equipment and containers. The environment appears organized, with shelves lined with chemical reagents and tools used for scientific research.

    Lorenzo Corazzi

    PhD student

  • A smiling woman wearing a lab coat and gloves stands in a laboratory. She has glasses and is near a workbench with various lab equipment and containers in the background. The atmosphere suggests a scientific research environment.

    Giulia Di Muzio

    Ph.D. student

  • A smiling laboratory technician wearing a white lab coat and gloves measures a sample with a pipette. He stands at a lab bench with various scientific equipment and containers visible around him, emphasizing a professional and diligent work environment.

    Boyu Ding

    MD student

  • Matilde Foschi, MS intern (October 2026)

    Matilde Foschi

    Master student

  • A smiling man wearing glasses and a lab coat sits at a laboratory bench, surrounded by scientific equipment and instruments. He appears friendly and approachable, likely engaged in research or experimentation.

    Marco Giaisi

    Lab Manager

  • Alex Ing, Senior data scientist (since year 2025)

    Dr. Alex Ing

    Senior Scientist

  • Hsin-Jui Lu, Ph.D. student (year 2025)

    Hsin-Jui Lu

    Ph.D. student

Entire Team

Associated members

Michael Allers
M.D. student with Prof. Dr. Dr. Peter Huber (E055)
E-mail: m.allers(at)dkfz-heidelberg.de
Phone: +49 6221 42 3249

 

Selected Publications

2026 - bioRxiv

Boyu Ding, Alex Ing, Li-Chin Wang, Lorenzo Corazzi, Marco Giaisi, Victoria Marini, Lumír Krejčí, Diala Shatleh, Rami Aqeilan, Pei-Chi Wei

2026 - The Journal of Neuroscience

Maya Thomas, Pei-Chi Wei

2026 - Nature Communications

Lorenzo Corazzi, Alex Ing,  Eva Benito, Marco Raffaele Cosenza, Patrick Hasenfeld, Thomas Weber, Anna J. M. Marx, Vivien S. Ionasz, Nathan Trausch, Sarah Benedetto, Giulia Di Muzio, Boyu Ding, Jana Berlanda, Marco Giaisi, Nina Claudino, Thomas Höfer, Jan O. Korbel & Pei-Chi Wei

2025 - bioRxiv

Giulia Di Muzio, Sarah Benedetto, Li-Chin Wang, Lea Weber, Franciscus van der Hoeven, Brittney Armstrong, Hsin-Jui Lu, Jana Berlanda, Verena Körber, Nina Claudino, Michelle Krogemann, Thomas Höfer, Pei-Chi Wei

2024 - Nature Communications

Lorenzo Corazzi, Vivien S Ionasz, Sergej Andrejev, Li-Chin Wang, Athanasios Vouzas, Marco Giaisi, Giulia Di Muzio, Boyu Ding, Anna J M Marx, Jonas Henkenjohann, Michael M Allers, David M Gilbert, Pei-Chi Wei 

2024 - Nature

Anderson CJ, Talmane L, Luft J, Connelly J, Nicholson MD, Verburg JC, Pich O, Campbell S, Giaisi M, Wei PC, Sundaram V, Connor F, Ginno PA, Sasaki T, Gilbert DM, López-Bigas N, Semple CA, Odom DT, Aitken SJ, Taylor MS

2016 - Cell

Wei PC, Chang AN, Kao J, Du Z, Meyers RM, Alt FW, Schwer B

Open positions

Replication stress is a hallmark of cancer. Oncogene overexpression, loss of tumor suppressors, and other yet-unknown factors naturally promote the formation of DNA breaks through replication stress. It has been speculated that this endogenous replication stress not only drives cancer progression but also fuels its evolution. Paradoxically, however, increasing replication stress—by targeting the DNA replication machinery—has also emerged as an effective strategy to selectively kill cancer cells.

Our laboratory is currently seeking a Ph.D. student to investigate the mechanisms underlying this Achilles’ heel of cancer: replication stress. We have developed both computational and experimental tools to dissect, at single-nucleotide resolution, the molecular processes leading to DNA breaks in the genomes of cancer cells.

Apply the Ph.D. position here:
https://jobs.dkfz.de/en/jobs/168906/phd-student-dna-break-signature-in-cancers?mtm_campaign=dkfz-en&mtm_kwd=168906 

Team Building

Get in touch with us

A woman with long black hair smiles softly at the camera. She is wearing a light gray sleeveless top with lace detailing on one shoulder. The background is plain and white, highlighting her facial features and expression.

Dr. Pei-Chi Wei

Principal Investigator
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