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Papers by Andrea Loipetzberger

Research paper thumbnail of Cooperative Hedgehog-EGFR signaling

Frontiers in Bioscience, 2012

It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, ... more It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, BCL2) can fuel cancer growth (1-5), but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy. The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy. Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/GLI and Epidermal Growth Factor Receptor (EGFR) signaling, two clinically relevant oncogenic pathways involved in the development of many human malignancies. We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways.

Research paper thumbnail of Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation

Oncogene, 2013

Imiquimod (IMQ), a nucleoside analogue of the imidazoquinoline family, is used in the topical tre... more Imiquimod (IMQ), a nucleoside analogue of the imidazoquinoline family, is used in the topical treatment of basal cell carcinoma (BCC) and other skin diseases. It is reported to be a TLR7 and TLR8 agonist and, as such, initiates a Th1 immune response by activating sentinel cells in the vicinity of the tumour. BCC is a hedgehog (HH)-driven malignancy with oncogenic glioma-associated oncogene (GLI) signalling activated in a ligand-independent manner. Here we show that IMQ can also directly repress HH signalling by negatively modulating GLI activity in BCC and medulloblastoma cells. Further, we provide evidence that the repressive effect of IMQ on HH signalling is not dependent on TLR/MYD88 signalling. Our results suggest a mechanism for IMQ engaging adenosine receptors (ADORAs) to control GLI signalling. Pharmacological activation of ADORA with either an ADORA agonist or IMQ resulted in a protein kinase A (PKA)-mediated GLI phosphorylation and reduction in GLI activator levels. The activation of PKA and HH pathway target gene downregulation in response to IMQ were abrogated by ADORA inhibition. Furthermore, activated Smoothened signalling, which positively signals to GLI transcription factors, could be effectively counteracted by IMQ. These results reveal a previously unknown mode of action of IMQ in the treatment of BCC and also suggest a role for ADORAs in the regulation of oncogenic HH signalling.

Research paper thumbnail of Cooperative Hedgehog-EGFR signaling

Frontiers in Bioscience, 2012

It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, ... more It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, BCL2) can fuel cancer growth (1-5), but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy. The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy. Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/GLI and Epidermal Growth Factor Receptor (EGFR) signaling, two clinically relevant oncogenic pathways involved in the development of many human malignancies. We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways.

Research paper thumbnail of Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells

EMBO Molecular Medicine, 2012

Research paper thumbnail of Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat

Cell, 2012

Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all ... more Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca 2+ -Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of ''selective partial agonists,'' capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.

Research paper thumbnail of Cooperative Hedgehog-EGFR signaling

Frontiers in Bioscience, 2012

It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, ... more It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, BCL2) can fuel cancer growth (1-5), but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy. The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy. Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/GLI and Epidermal Growth Factor Receptor (EGFR) signaling, two clinically relevant oncogenic pathways involved in the development of many human malignancies. We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways.

Research paper thumbnail of Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation

Oncogene, 2013

Imiquimod (IMQ), a nucleoside analogue of the imidazoquinoline family, is used in the topical tre... more Imiquimod (IMQ), a nucleoside analogue of the imidazoquinoline family, is used in the topical treatment of basal cell carcinoma (BCC) and other skin diseases. It is reported to be a TLR7 and TLR8 agonist and, as such, initiates a Th1 immune response by activating sentinel cells in the vicinity of the tumour. BCC is a hedgehog (HH)-driven malignancy with oncogenic glioma-associated oncogene (GLI) signalling activated in a ligand-independent manner. Here we show that IMQ can also directly repress HH signalling by negatively modulating GLI activity in BCC and medulloblastoma cells. Further, we provide evidence that the repressive effect of IMQ on HH signalling is not dependent on TLR/MYD88 signalling. Our results suggest a mechanism for IMQ engaging adenosine receptors (ADORAs) to control GLI signalling. Pharmacological activation of ADORA with either an ADORA agonist or IMQ resulted in a protein kinase A (PKA)-mediated GLI phosphorylation and reduction in GLI activator levels. The activation of PKA and HH pathway target gene downregulation in response to IMQ were abrogated by ADORA inhibition. Furthermore, activated Smoothened signalling, which positively signals to GLI transcription factors, could be effectively counteracted by IMQ. These results reveal a previously unknown mode of action of IMQ in the treatment of BCC and also suggest a role for ADORAs in the regulation of oncogenic HH signalling.

Research paper thumbnail of Cooperative Hedgehog-EGFR signaling

Frontiers in Bioscience, 2012

It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, ... more It has been known for many years that cooperative interactions between oncogenes (e.g. RAS, MYC, BCL2) can fuel cancer growth (1-5), but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy. The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy. Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/GLI and Epidermal Growth Factor Receptor (EGFR) signaling, two clinically relevant oncogenic pathways involved in the development of many human malignancies. We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways.

Research paper thumbnail of Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells

EMBO Molecular Medicine, 2012

Research paper thumbnail of Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat

Cell, 2012

Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all ... more Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca 2+ -Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of ''selective partial agonists,'' capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.