TGFβ mediated chromosomal instability in human colorectal cancer cells
by Simranjeet Kaur
Date of Examination:2023-06-15
Date of issue:2023-06-28
Advisor:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Holger Bastians
Referee:Prof. Dr. Peter Burfeind
Persistent Address:
http://dx.doi.org/10.53846/goediss-9958
Files in this item
Name:PhD_thesis_SimranKaur.pdf
Size:13.4Mb
Format:PDF
The following license files are associated with this item:
Abstract
English
Chromosomal instability (CIN) is a major hallmark of human cancer and is defined as persistently high rate of the generation of chromosomal aberrations leading to genetic variability, tumour heterogeneity and tumour evolution. CIN can be divided into structural chromosomal instability (S-CIN), which leads to structural aberrations and whole chromosomal instability (W-CIN), which is directly related to errors during mitosis resulting in chromosome mis-segregation and aneuploidy. Previous work from our lab discovered that increased microtubule polymerisation rates in mitotic spindles serves as a key trigger for whole chromosome mis-segregation and thus, for W-CIN in cancer cells. Another type of genetic instability, microsatellite instability (MSI) is a condition of genetic hypermutability in cancer cells that results from impaired DNA mis-match repair system. One significant target gene for mutational inactivation in MSI+ cells is TGFBR2, encoding for the TGFβ receptor 2. As a consequence, MSI+ cells suffer from a weak TGFβ signalling. In contrast, CIN+ cancer cells retain a wild-type TGFBR2 but often show a loss of tumour suppressor SMAD4, which is a well-known downstream mediator of TGFβ signalling. While the molecular mechanisms leading to MSI are well understood, the mechanisms causing CIN are unclear. Therefore, this study aimed to address the molecular mechanisms of CIN in colorectal cancer cells. Since TGFβ signalling is impaired selectively in MSI+ cells, I focussed on the role of functional TGFβ signalling as a potential trigger for CIN. In fact, I demonstrate that TGFβ is a key mediator for W-CIN, and causes aberrant microtubule dynamics and chromosome mis-segregation in mitosis. TGFβ-mediated mitotic errors are independent of the canonical SMAD-dependent signalling, but require the non-SMAD MEK-ERK pathway. Importantly, inhibition of TGFBR1/2 or MEK-ERK is sufficient to suppress mitotic errors and chromosome mis-segregation in CIN+ colorectal cancer cells. In addition, chromosomal instability induction in CIN+ cells might involve secreted TGFβ ligands that can also act in a paracrine manner to induce CIN in otherwise chromosomally stable cells. Due to the mutational inactivation of TGFBR2, MSI+ cells are resistant to paracrine induction of chromosomal instability, which might help explaining the mutual exclusivity of MSI and CIN in human cancer. Furthermore, this study presents first evidence that loss of SMAD4 leads to replication stress, which causes mitotic errors. In this setting, TGFβ signalling might act downstream of replication stress to mediate chromosomal instability by activating a DNA damage response. With this, my study provides significant new insights into the role of SMAD4 and TGFβ signalling in cancer chromosomal instability.
Keywords: Chromosomal instability; TGFβ signalling; Mitosis
Schlagwörter: Chromosomal instability; TGFβ signalling; Mitosis
