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Neurofibromatosis 

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Brosseau et al. Neurology2018 

The NF1 Microenvironment: Friend or Foe?

Funded by the US Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP) Neurofibromatosis Early Investigator Research Award

Patients with NF1 are associated with mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposed them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients (e. g. melanoma, glioblastoma, lung cancer, squamous cell carcinoma, and ovarian cancer). It suggests that NF1 heterozygosity is refractory to at least some cancer types but this idea contrasts with the fact that NF1 is considered a cancer predisposition syndrome as NF1 patients have an increased risk of developing multiple malignancies. In two orthogonal mouse models representing NF1 and nonNF1-related tumors, we discovered that an Nf1+/- microenvironment accelerates the formation of a benign tumor but impairs further progression to malignancy. A careful and extensive inspection of the clinical literature indicated that the characteristic lesions in NF1 patients developed earlier and have a more benign course than their sporadic counterparts. Therefore, we propose a unifying model that reconciles these apparent discrepancies: NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.

Alternative Splicing

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Brosseau AppliedCancerResearch2018 

Deciphering the alternative splicing regulatory program driving the myofibroblast state

Funded by the Natural Sciences and Engineering Research Council of Canada (NSERC)

Alternative splicing is a powerful mechanism that expands the proteome diversity by allowing the transcription of multiple messenger RNAs from a single gene. Numerous examples have illustrated the functional impact of alternative splicing in the literature. There is also a high level of understanding of the major factors influencing a splicing decision (e.g. RNA sequence in cis and RNA binding factors acting in trans), recently culminating into a "splicing code". However, there is not much known about the upstream mechanisms controlling the expression/activity of splicing factors and even less linking extracellular factors to alternative splicing regulation. Our laboratory is interested in deciphering the regulatory mechanisms upstream of an alternative splicing network orchestrating key developmental programs in humans.

Mouse Model

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Brosseau et al. NatureCommunications2018

Development of NF1 Gene Therapy

Funded jointly by the Cancer Research Society (CRS) and the Institute of Musculoskeletal Health and Arthritis from the Canadian Institute of Health Research (CIHR-IMHA)

The goal of this research program is to de-risk the long-term goal of providing safe and efficient gene therapy to Neurofibromatosis Type I patients. Neurofibroma is a tumor type that manifested in Neurofibromatosis Type I patients with 99% penetrance. In addition to the important psychosocial consequence, these disfiguring tumors can severely affect mobility and day-to-day life. Surgery is the only treatment option but is not practical when facing hundreds of tumors or innervating a vital organ in a deep location. Gene therapy (i.e. to restore the function of a defective gene) is an attractive way to cure Neurofibromatosis Type I manifestations such as neurofibromas. Sequencing Schwann cells from neurofibroma reveal that NF1, a tumor suppressor gene, is the only gene mutated in multiple samples, and hence a monogenic disease highly suitable for gene therapy. Most NF1 mutations lead to truncated NF1 proteins with reduced GTPase activity, ultimately culminating in high RAS signaling. Still, it is unknown if restoring NF1 GTPase activity would actually impair neurofibroma maintenance and act as a definitive cure for Neurofibromatosis Type I patients. Here, we propose to proof-of-principle NF1 gene therapy in a mouse model and test NF1 gene therapy in human Schwann cells from NF1 patients.

Tumor-Associated Fibroblasts Impairing Malignant Progression

Funded by the Canadian Institute of Health Research (CIHR)

 

How to stop cancer progression is an elusive question in cancer biology. On the one hand, it was discovered that some wild animals, such as the blind mole rat Spalax do not get cancer. Understanding the underlying protective mechanisms that prevent cancer in that specie, and then translating the concepts learned, would hold the promise of a giant step forward into the rational design of a new generation of anti-cancer therapies. It turns out that the main reason why Spalaxes are cancer-free is due to some fibroblasts hypersecreting ECM with tumor suppressor activity. This phenomenon is reminiscent of cutaneous neurofibroma, a benign tumor with zero malignant potential characteristics of Neurofibromatosis type I patients. In a pilot screen on cutaneous neurofibromas by single-cell RNA sequencing and mass spectrometry, we discovered multiple subpopulations of fibroblasts secreting distinct ECM proteins with tumor suppressor activity such as Col14a1+ fibroblasts. In contrast to Spalaxes, which is not practical to breed and genetically manipulate in the laboratories, we developed a cancer-resistant mice model recapitulating the zero malignant potential of cutaneous neurofibroma. To demonstrate a novel anti-cancer mechanism where tumor-associated fibroblasts impair malignant progression in vivo. Leveraging from our cancer-resistant mice, we will test our working model where overexpression of ECM proteins with tumor-suppressing activity impairs malignant progression of benign tumors.

Molecular and Cellular Mechanism Promoting the Benign State of a Tumor

Funded by the Fond de recherche du Québec- Health (FRQS)

Nearly 1 in 2 Canadians will receive a cancer diagnostic during their lifetime (www.cancer.ca). Recently, I discovered that a large sub-group of hereditary cancer syndromes are actually characterized by benign tumors that rarely progress to malignant tumors, syndromes that I reclassified as “hereditary benign tumor syndromes”. The archetype is a rare genetic disorder named Neurofibromatosis type I (NF1). Ninety-nine percent of NF1 patients develop characteristic benign lesions by the age of 20. The reason why they rarely if ever progress to a malignant state is an elusive question. I propose to study and learn from benign tumors that are naturally refractory to malignant progression to get novel mechanistic insights with regards to the benign-malignant progression that could be conceptually transposed to any cancer type.

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