Sabine Mai and Aline Rangel-Pozzo, CancerCare Manitoba Research Institute and University of Manitoba, Winnipeg, Canada, discuss genomic instability in relation to the 3D spatial organization of telomeres
Genomic instability and cancer
Genomic instability is a hallmark of cancer. It drives the evolution of cancer cells with a different genome than normal cells. It allows for the development of cell clones and cell-to-cell heterogeneity within the tumor and between the tumor and its metastatic site(s).
The presence of genomic instability in cancer was first reported by David von Hanseman (1858-1920). His work as a pathologist in Virchow’s group in Berlin concluded that cells with genomic instability were not found in normal tissues but only in tumor tissues. His illustrations showed chromosomal instability, which included aberrant chromosome numbers (aneuploidy: gain or loss of chromosomes); and poor chromosomal segregation between daughter cells.
The first mechanistic studies of genomic instability were performed by Theodor Boveri (1862-1915), whose work proposed that genomic instability led to the development of cancer and was not compatible with normal cell life. Although he did not use the term “genomic instability”, his data clearly implicated him in this malignant process.
Genomic instability is a dynamic process and continues to evolve with each cell division. Therefore, if samples are taken at an early stage of tumor development and at later stages, genetic changes will have occurred.
The three-dimensional (3D) space of the nucleus: spatial disorder of the genome in cancer
The nucleus houses the genetic information. This information is not just randomly arranged but has a clear organization. In normal cells, chromosomes occupy specific places in the 3D space of the nucleus. The spaces occupied by the chromosomes are called “chromosomal territories”. They have been conserved during evolution and are specific to cell type and differentiation. This organization has a functional importance; for example, animals with night vision have a chromosomal organization in their rod cells that is distinct from that found in animals with day vision. Similarly, hepatocytes have a different arrangement of chromosomal territories and chromosomal neighborhoods than lymphocytes.
The organization of chromosomes and the genes they house is the key to transcriptional regulation. Genes located near the periphery of the 3D nucleus are usually repressed, while genes found in the center of the nucleus are expressed.
Cancer cells have rearranged genetic information in the nuclear space and often alter the position and orientation of chromosomes, allowing new transcription patterns. Cancer cells also change the way their DNA is packaged and increase the presence of interchromatin space. Moreover, when using telomeres, the ends of chromosomes, as structural markers of genome (in)stability, cancer cells, compared to normal cells, show very significant changes in their 3D organization. .
3D profiling of telomeres in cancer
3D imaging of telomeres, developed and performed at the Genomic Center for Cancer Research and Diagnosis (GCCRD) at the University of Manitoba and at CancerCare Manitoba (Winnipeg, Canada) has enabled the fine mapping of the nuclear organization of the genome of cells cancerous. At nanoscale resolution, Dr. Mai’s team and collaborators visualized and measured the structural organization of the cancer genome; telomeres have been used as surrogate markers of genome organization and shown to play a role as structural biomarkers of genomic instability.
Several cancers were examined. 3D telomere profiling allowed the team to quantify the level of genomic instability, risk of progression and/or response to treatment. Examples include lymphoid (such as Hodgkin’s lymphoma, multiple myeloma, chronic myeloid leukemia, myelodysplastic syndromes, and acute myeloid leukemia) and solid tumors (such as neuroblastoma, glioblastoma, thyroid cancer, and prostate cancer). The software developed by the team (TeloView® – currently owned by Telo Genomics Corp. Toronto, Canada) enabled single cell profiling and informed each patient’s cancer.
Following these early clinical studies, a biotechnology company, Telo Genomics Corp., was founded. Telo Genomics Corp. is located in the MaRS Discovery District in Toronto, ON, Canada (telodx.com). The company is dedicated to personalized cancer medicine solutions, with a particular focus on multiple myeloma.
An example of nuclear remodeling: nuclear remodeling and risk assessment in prostate cancer
Prostate cancer is the 2nd most common cancer in men worldwide, with 1.4 million new cases in 2020. Intermediate-risk prostate cancer in men is often stable, but sometimes aggressive . There is no clear test that can predict which patient has either type of prostate cancer. Research carried out by the Mai team, in collaboration with urologists Drs. Drachenberg and Saranchuk of CancerCare Manitoba (Winnipeg, Canada) focused on circulating tumor cells (CTCs) isolated from the blood of prostate cancer patients. These isolates are called “liquid biopsies” and these blood samples contain (CTCs) that come from the tumor. Our analyzes of 3D telomere profiling indicate that the genomic profile of CTCs in intermediate-risk prostate cancer better predicts disease stability or aggressiveness than the commonly used prostate-specific antigen (PSA) or score. by Gleason (Drachenberg et al., Cancers, 2019, Jun 20;11(6):855. doi: 10.3390/cancers11060855.PMID: 31226731). This study was funded by the Prostate Cancer Fight Foundation/Manitoba Ride for Dad.
Assessment of nuclear architecture allows analysis of genomic instability in cancer. Structural biomarkers, such as the spatial arrangement of cancer genomes, are poised to become future tools for assessing personal risk for patients.
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© 2019. This work is under license CC-BY-NC-ND.