Final Report Summary - SKINCAAGE (Longevity assurance genes in tumor suppression)
The European Re-integration Grant (ERG) has laid the foundation for a successful integration into the German academic field. In 2009, I was appointed as Junior Research Group Leader on a tenure track in the Cluster of Excellence 'Cellular stress responses in ageing-associated diseases' (CECAD) at the University of Cologne. CECAD became a focal point of ageing research in Europe. I was able to integrate my research into the heart of the CECAD research endeavour. As part of the ERG proposal, I transferred the nucleotide excision repair (NER) model from my previous host laboratory at the Erasmus Medical School, Rotterdam, to the University of Cologne.
NER is a highly complex DNA repair pathway that removes helix-distorting lesions such as typically induced by ultraviolet (UV) irradiation. Two distinct branches of NER carry out the initial damage recognition and then activate the downstream NER reaction. Global-genome (GG-) NER surveys the entire genome, while transcription-coupled (TC-) NER initiates repair when RNA polymerase (RNAP) II stalls at a UV lesion (Schumacher et al., 2008a). Most patients with NER mutations develop Xeroderma pigmentosum (XP), while patients that carry mutations that specifically affect TC-NER develop Cockayne syndrome (CS). XP is characterised by photosensitivity, skin atrophy, pigmentation abnormalities and roughly 2000-fold elevated skin cancer susceptibility. Some XP patients also develop neurodegenerative symptoms. CS patients, in contrast, exhibit developmental growth failures and degenerative symptoms, initially evident as retinal degeneration, neurological abnormalities, cachexia, and impaired sexual development. Strikingly, despite their photosensitivity, CS patients do not develop skin cancer.
Employing mouse models for CS and the related XFE progeria, we have shown that already early in life, the mice strikingly resemble natural ageing (Schumacher et al., 2008b). Intriguingly, we found that CS and XFE animals downregulate the somatotropic axis, which might account for the developmental growth failure of the associated disorder. The somatotropic axis is regulated through growth hormone receptor (GHR) and insulin-like growth factor I receptor (IGF-1R) signalling. Attenuation of somatoropic signalling leads to reduced body growth and elevated stress resistance and extended lifespan in species ranging from C. elegans to mammals. Mechanistically, we demonstrated that cells respond to transcription-blocking lesions, the culprit of TC-NER deficiencies, by attenuating the expression and activity of GHR and IGF-1R resulting in elevated cellular stress resistance (Garinis et al., 2009). We thus hypothesised that organisms respond to increasing DNA damage accumulation by reducing growth and enhancing somatic maintenance by attenuated somatotropic signalling (Garinis and Schumacher, 2009; Schumacher, 2009; Schumacher et al., 2009).
The attenuation of somatotropic signalling in response to transcription-blocking lesions offered a new concept of how organisms orchestrate the shift to a growth deprived endocrine environment in the ageing body (Schumacher, 2009). IGF-1 signalling plays an important role in mitogenic signalling and most tumour cells are critically dependent on IGF-1R mediated signal transduction to fuel their proliferative activity. We showed that specific ablation of IGF-1R in the mouse epidermis was sufficient to antagonise TPA-induced hyperplasia, an early step in tumourigenesis (Garinis et al., 2009). We thus hypothesised that attenuation of IGF-1R activity in the epidermis might antagonise carcinogenesis.
The University of Cologne has a long-standing track record of dermatological research. As part of the ERG I thus implement the NER model of skin cancer development into the dermatological focus at Cologne. I joined the successful application of the collabourative research centre (CRC) 829 on skin homeostasis in 2009. In 2012, the DNA damage responses in skin homeostasis became one of the three research areas within the successful renewal application of the CRC. In particular, I ignited a close collabouration with the skin biology group of Carien Niessen within the CRC 829 and the Center for Molecular Medicine at the University Hospital of Cologne. Together with the Niessen group, we established the UV response in epidermal mutants of IGF-1R. Epidermal IGF-1R mutants show epidermal thinning consistent with reduced mitogenic signalling. In line with reduced apoptotic signalling, we observed enhanced programmed cell death following UV irradiation. We suggest that targeting of IGF-1R signalling in the epidermis might comprise a new strategy to antagonise skin cancer development.
Implementing DNA damage responses at the new host institution has created numerous synergies within CECAD as well as with clinical groups at the Cologne campus. In the successful renewal application of the CECAD excellence cluster, I headed the newly created research area on DNA damage responses in ageing-associated diseases. This became one of six research areas of the excellence cluster. The implementation of DNA damage responses within CECAD has proven a great success of my integration at the University of Cologne. I have started numerous fruitful collabourations, including on the regulation of the p53 mediated DNA damage response together with the nephrology department (Höpker et al., 2012). Moreover, I recently participated in the successful application of the clinical research group (CRG) 286 on targeting DNA damage responses in CLL therapy. Here, we investigate the new hypothesis to specifically target TC-NER to sensitise resistant CLL cases to chemotherapy. Moreover, together with the oncology department and in close collabouration with Christian Reinhardt, we are investigating NER and DNA damage responses in tumour models (Reinhardt and Schumacher, 2012).
During my integration at the University of Cologne, I also maintained important links to my former host institution. For example, we together investigated the role of NER the metazoan C. elegans (Lans et al., 2010). I also ignited research activities on the European level. I was awarded the ERC independent starting researcher grant on exploring DNA damage responses in ageing (GENSTAGE). Importantly, I also ignited European research networks. I am currently coordinating the initial training network (ITN) on chronic DNA damage responses in ageing (CODEAGE). I am also participating in additional ITNs that also include my former host organisation (MARRIAGE and ADDRESS).
Taken together, the ERG has enabled my successful reintegration into the German research area at the University of Cologne.
NER is a highly complex DNA repair pathway that removes helix-distorting lesions such as typically induced by ultraviolet (UV) irradiation. Two distinct branches of NER carry out the initial damage recognition and then activate the downstream NER reaction. Global-genome (GG-) NER surveys the entire genome, while transcription-coupled (TC-) NER initiates repair when RNA polymerase (RNAP) II stalls at a UV lesion (Schumacher et al., 2008a). Most patients with NER mutations develop Xeroderma pigmentosum (XP), while patients that carry mutations that specifically affect TC-NER develop Cockayne syndrome (CS). XP is characterised by photosensitivity, skin atrophy, pigmentation abnormalities and roughly 2000-fold elevated skin cancer susceptibility. Some XP patients also develop neurodegenerative symptoms. CS patients, in contrast, exhibit developmental growth failures and degenerative symptoms, initially evident as retinal degeneration, neurological abnormalities, cachexia, and impaired sexual development. Strikingly, despite their photosensitivity, CS patients do not develop skin cancer.
Employing mouse models for CS and the related XFE progeria, we have shown that already early in life, the mice strikingly resemble natural ageing (Schumacher et al., 2008b). Intriguingly, we found that CS and XFE animals downregulate the somatotropic axis, which might account for the developmental growth failure of the associated disorder. The somatotropic axis is regulated through growth hormone receptor (GHR) and insulin-like growth factor I receptor (IGF-1R) signalling. Attenuation of somatoropic signalling leads to reduced body growth and elevated stress resistance and extended lifespan in species ranging from C. elegans to mammals. Mechanistically, we demonstrated that cells respond to transcription-blocking lesions, the culprit of TC-NER deficiencies, by attenuating the expression and activity of GHR and IGF-1R resulting in elevated cellular stress resistance (Garinis et al., 2009). We thus hypothesised that organisms respond to increasing DNA damage accumulation by reducing growth and enhancing somatic maintenance by attenuated somatotropic signalling (Garinis and Schumacher, 2009; Schumacher, 2009; Schumacher et al., 2009).
The attenuation of somatotropic signalling in response to transcription-blocking lesions offered a new concept of how organisms orchestrate the shift to a growth deprived endocrine environment in the ageing body (Schumacher, 2009). IGF-1 signalling plays an important role in mitogenic signalling and most tumour cells are critically dependent on IGF-1R mediated signal transduction to fuel their proliferative activity. We showed that specific ablation of IGF-1R in the mouse epidermis was sufficient to antagonise TPA-induced hyperplasia, an early step in tumourigenesis (Garinis et al., 2009). We thus hypothesised that attenuation of IGF-1R activity in the epidermis might antagonise carcinogenesis.
The University of Cologne has a long-standing track record of dermatological research. As part of the ERG I thus implement the NER model of skin cancer development into the dermatological focus at Cologne. I joined the successful application of the collabourative research centre (CRC) 829 on skin homeostasis in 2009. In 2012, the DNA damage responses in skin homeostasis became one of the three research areas within the successful renewal application of the CRC. In particular, I ignited a close collabouration with the skin biology group of Carien Niessen within the CRC 829 and the Center for Molecular Medicine at the University Hospital of Cologne. Together with the Niessen group, we established the UV response in epidermal mutants of IGF-1R. Epidermal IGF-1R mutants show epidermal thinning consistent with reduced mitogenic signalling. In line with reduced apoptotic signalling, we observed enhanced programmed cell death following UV irradiation. We suggest that targeting of IGF-1R signalling in the epidermis might comprise a new strategy to antagonise skin cancer development.
Implementing DNA damage responses at the new host institution has created numerous synergies within CECAD as well as with clinical groups at the Cologne campus. In the successful renewal application of the CECAD excellence cluster, I headed the newly created research area on DNA damage responses in ageing-associated diseases. This became one of six research areas of the excellence cluster. The implementation of DNA damage responses within CECAD has proven a great success of my integration at the University of Cologne. I have started numerous fruitful collabourations, including on the regulation of the p53 mediated DNA damage response together with the nephrology department (Höpker et al., 2012). Moreover, I recently participated in the successful application of the clinical research group (CRG) 286 on targeting DNA damage responses in CLL therapy. Here, we investigate the new hypothesis to specifically target TC-NER to sensitise resistant CLL cases to chemotherapy. Moreover, together with the oncology department and in close collabouration with Christian Reinhardt, we are investigating NER and DNA damage responses in tumour models (Reinhardt and Schumacher, 2012).
During my integration at the University of Cologne, I also maintained important links to my former host institution. For example, we together investigated the role of NER the metazoan C. elegans (Lans et al., 2010). I also ignited research activities on the European level. I was awarded the ERC independent starting researcher grant on exploring DNA damage responses in ageing (GENSTAGE). Importantly, I also ignited European research networks. I am currently coordinating the initial training network (ITN) on chronic DNA damage responses in ageing (CODEAGE). I am also participating in additional ITNs that also include my former host organisation (MARRIAGE and ADDRESS).
Taken together, the ERG has enabled my successful reintegration into the German research area at the University of Cologne.