Signaling in Development and Brain Tumours

Organ-specific mechanisms governing organ development and tumor formation are closely linked. To study the relationship between human development and the biology underlying cancer cells we have being focusing on the developing cerebellum and the solid brain tumor medulloblastoma (MB) as models. The cerebellum is a laminar structure mediating important sensorimotor and cognitive functions such as thinking, reasoning, and remembering. Deregulations in those developmental processes and genetic alterations together contribute to the establishment and progression of MB. MB is the most common aggressive embryonic tumor of the cerebellum, causing a high degree of pediatric morbidity and mortality. To date, almost one third of patients die from this terrible disease and survivors could suffer important developmental, neuroendocrine and psychosocial sequelae making a better understanding of the biology underlying MB and the development of new therapeutic strategies a priority.

MB classification:

The international consensus recognizes four distinct MB subgroups with distinct molecular characteristics, incidence and patient outcomes. Group 1 is characterized by an activation of the Wingless (WNT) pathway. The WNT subgroup has the best prognosis, with an overall survival around 95-100%. Group 2 is associated with an aberrant activation of the Sonic Hedgehog (SHH) signaling. Patients with SHH MB have an intermediate prognosis, with a 5-year overall survival of approximately 75% when treated with standard therapy. The etiology of the two remaining subgroups remains elusive, as remarked by their generic names Group 3 (G3) and Group 4 (G4). Both account for more than half of patients; G3 has the worse outcome among all MBs while G4 is the most prevalent subgroup although it is the less characterized today. Recently, the international community recognized a subdivision of the 4 subgroups into subtypes highlighting a more complex reality of the MB biology.

Objectives:

Despites major advances, the biology underlying MB genesis remains to be refined, and crucial questions in the field must be addressed:

(i)  From which cell type does each of the MB subgroups originate?

(ii) What are the key molecular and cellular events controlling each MB subtype?

(iii) Can better targeted therapies be developed?

Our general team goal is thus 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. In that regard, we have been implemented an innovative interdisciplinary approach as well as developed novel tools at the interface of developmental neurobiology and cancer biology.

Our main objectives are the following:

• Investigating key players and associated mechanisms in both cerebellar development and cancer using advanced technology.
• Undertaking a comprehensive overview of the MB biology utilizing groundbreaking multi-omics analysis.

Team highlights:

• We got new insights into how the transcription factor Atoh1, essential for cerebellar histogenesis and MB formation, was regulated in both the normal and disease contexts (Forget*, Bihannic* et al., Dev Cell, 2014 and Cigna et al., in preparation).
• We unraveled novel functions for Atoh1 using advanced and newly developed technology. Our data reveal a novel mechanism whereby Atoh1 modulates the primary cilium functions to regulate cerebellar and MB development (Chang*, Zanini*, Shirvani* et al., Dev Cell, 2019).
• We developed a multi-omics profiling of all subgroups of MB integrating phosphoproteomics data (Forget et al., Cancer Cell, 2018). From this study:

(i) Proteomics analysis highlights the activation of the Receptor Tyrosine Kinase signaling, as well as the receptor ERBB4 and phosphorylated SRC specifically in Group 4.

(ii) Integrative multi-omics analysis unveils that mRNA poorly predicted protein expression profiles in both Groups 3 and 4.