Final Report Summary - ATOH1MEDULLO (Atoh1/Math1 regulation and function during cerebellar normal development and medulloblastoma)
Organ-specific mechanisms governing organ development and tumor formation are closely linked. During cerebellar development, several signaling pathways play key roles in cell fate determination, axis formation, and patterning. However, deregulation in those developmental processes contribute to medulloblastoma (MB), the most common malignant pediatric brain tumor. To date, one third of patients die from MB and existing therapies for MB have severe side effects, which make finding new drugs a priority. MB is divided into four subgroups in which distinct pathways are affected. Group 1 is associated with mutations in the WNT pathway (15% of cases), whereas group 2 shows a constitutive activation of Sonic Hedgehog (SHH) signaling (25% of cases). Group 3 and 4 are less characterized.
Our general team goal is to decipher fundamental mechanisms related to the complex biology of MB. Because signaling pathways that are dysregulated in brain cancer are also at the basis of normal cerebellar development, we perform our studies back and forth in the normal development and cancer contexts. To elucidate mechanisms involved in MB, we are using adapted and innovative tools in the area of biochemistry, cell biology and mouse models.
Recently, we and others uncovered that the bHLH transcription factor Atoh1 plays a crucial role in SHH MB. Because Atoh1 acts as a “lineage addiction transcription factor” in SHH MBs and its down regulation inhibits tumor progression, deciphering molecular pathways that regulate Atoh1 might help to identify potential new targets for therapeutic intervention. However, up to date how Atoh1 is regulated at the protein level remains poorly understood.
In this context our recent finding shows that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1 (Forget*, Bihannic*, et al., Dev. Cell, 2014). Strikingly, we found that lower HUWE1 expression level defined a subset of patients with poor prognosis within the SHH subgroup in which Atoh1 is upregulated. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in SHH MB.
In conclusion, we anticipate that characterization of Atoh1 regulation and function will provide novel insights into Atoh1 as a potential therapeutic target in the treatment of SHH MB.
Our general team goal is to decipher fundamental mechanisms related to the complex biology of MB. Because signaling pathways that are dysregulated in brain cancer are also at the basis of normal cerebellar development, we perform our studies back and forth in the normal development and cancer contexts. To elucidate mechanisms involved in MB, we are using adapted and innovative tools in the area of biochemistry, cell biology and mouse models.
Recently, we and others uncovered that the bHLH transcription factor Atoh1 plays a crucial role in SHH MB. Because Atoh1 acts as a “lineage addiction transcription factor” in SHH MBs and its down regulation inhibits tumor progression, deciphering molecular pathways that regulate Atoh1 might help to identify potential new targets for therapeutic intervention. However, up to date how Atoh1 is regulated at the protein level remains poorly understood.
In this context our recent finding shows that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1 (Forget*, Bihannic*, et al., Dev. Cell, 2014). Strikingly, we found that lower HUWE1 expression level defined a subset of patients with poor prognosis within the SHH subgroup in which Atoh1 is upregulated. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in SHH MB.
In conclusion, we anticipate that characterization of Atoh1 regulation and function will provide novel insights into Atoh1 as a potential therapeutic target in the treatment of SHH MB.