HMGB2 programming and structural variations as tumor supportive mechanisms in cancer

by Adi Mackay née Danieli
Doctoral thesis
Date of Examination:2025-05-19
Date of issue:2025-06-17
Advisor:Prof. Dr. Argyris Papantonis
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Elisabeth Hessmann
Persistent Address: http://dx.doi.org/10.53846/goediss-11335

 

 

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Abstract

English

Cancer is a widespread disease that affects many. In order to escape into malignancy, a cell has to undergo a multistep process during which it acquires a set of traits. These traits allow it to replicate indefinitely and evade elimination by the immune system or therapy. This multistep process involves major reorganization of the genome on the both DNA and 3D architecture levels. The conformation of the genome, known as 3D genome topology, reflects the way our chromosomes are folded in the nucleus to ensure proper gene expression programs. It represents an, until recently, underappreciated mechanism for driving tumor gene expression programs. 3D genome organization is dynamic, allowing cells to respond and adapt to new conditions and is modulated by the binding of different proteins to chromatin. One such protein is HMGB2, a DNA-binding and modulating factor that partakes in shaping the chromosomal structure. In addition, HMGB2 levels correlate with cells’ replicative potential and is strongly overexpressed in multiple cancer types. In my thesis, I investigate two major facets of cancer biology: the deregulation of gene expression through 3D epigenomic alterations and the acquired ability for unrestricted proliferation. In Chapter 1, I dissect 3D genome organization as a mean for unveiling genome reorganization as regards structural and copy number variants and chromatin looping. Using persistent, patient-derived glioblastoma stem cells population, a direct interplay between genomic rearrangements and glioblastoma-favoring transcription is revealed. In Chapter 2, I focus on the detrimental pancreatic ductal adenocarcinoma (PDAC) to investigate the involvement of the DNA-binding protein HMGB2 on their enhanced replicative capacity. Using multiple models, including patient tissues, cell lines, patient-derived organoid, and orthotopically transplanted mice, I decipher how it functions to promote persistent replication via control of chromatin accessibility at the promoters of various cell cycle-related genes. On the basis of this analysis, I suggest that HMGB2 is a promising target, inhibition of which constrains tumor growth to increase survival. Collectively, I explore the effects of 3D genome organization on cancer-supportive transcriptional programs, define HMGB2 as a vital protein supporting proliferation through adjustment of chromatin accessibility, and propose it as a novel target in the fight against cancer.
Keywords: PDAC; GBM; HMGB2; Single-cell genomics; Patient-derived organoids; 3D-genome organization