Targeting JAK/STAT signalling for sensitization of colorectal cancer cells to chemoradiotherapy

by Kristin Kördel
Doctoral thesis
Date of Examination:2021-07-06
Date of issue:2021-07-08
Advisor:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Thomas Meyer
Referee:PD Dr. Marian Grade
Referee:Prof. Dr. Dieter Kube
Persistent Address: http://dx.doi.org/10.53846/goediss-8719

 

 

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Abstract

English

Despite ever-evolving treatment and screening procedures, Colorectal cancer (CRC) remains a major cause of cancer-related deaths worldwide. Preoperative chemoradiotherapy (CRT), followed by standardized surgical resection of the tumor, represents the standard treatment for locally advanced rectal cancers. However, tumor cells can possess or acquire resistance to CRT, so that affected patients do not benefit from treatment but are afflicted with potential negative side-effects of anti-cancer treatment without any clinical benefit. Therefore, the resistance of tumor cells to CRT represents a fundamental problem in oncology and requires the elucidation of the molecular mechanisms underlying this issue. It is already known that the dysregulation of signalling pathways can cause serious diseases such as cancer and this dysregulation is significantly involved in the development of therapy resistance. Inflammatory cytokines have a key role in cancer progression by regulating many pathways in both, tumor cells and tumor microenvironment. Hence, it is important to understand the tumor intrinsic mechanisms by which CRT resistance is controlled. In this thesis the importance of active STAT3 signalling in mediating CRT resistance in CRC cell lines was evaluated. The requirement of active STAT3 signalling was demonstrated by mutational analysis of STAT3 and subsequent reconstitution studies in the presence and in the absence of cytokine receptor activation. Nevertheless, when combined with chemoradiotherapy, inhibition of STAT3 signalling using Napabucasin completely abolished tumor growth in a xenograft mouse model. Using a RNA-Seq-based screening approach, several STAT3 target genes were identified, such as the RBPJ, that are dually influenced by inflammation induced STAT3 activation and STAT3 knockdown. Strikingly, genetic inhibition of RBPJ, a key transcriptional regulator of the NOTCH cascade, re-sensitized colorectal cancer cells to chemoradiotherapy. Additionally, genetic and pharmaceutical inhibition of the entire NOTCH signalling also re-sensitized chemoradiotherapy resistant cells. Interestingly, inhibition of NOTCH signalling phenocopied the effect of blocking STAT3 signalling. Genetic profiling of rectal cancer patients revealed the importance of the NOTCH signalling axis by correlating NOTCH expression with clinical outcome. This thesis uncovered, that treatment resistance is orchestrated by a poorly understood signal axis that combines two classical intracellular pathways, inflammatory cell signalling mediated by STAT3, and cell fate decision NOTCH axis controlled by RBPJ. The identification of this crosstalk serves the molecular basis for chemoradiotherapy resistance and paves the way for a personalized, multimodal treatment of patients with rectal cancers that are positive for STAT3/NOTCH-related markers.
Keywords: Colorectal cancer; JAK/STAT Signalling; NOTCH Signalling; Chemoradiotherapy resistance
 
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