In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.

La maladie d’Alzheimer (MA) est une neurodégénérescence liée à l’âge, caractérisée par l’agrégation intracérébrale du peptide Aβ. Plusieurs études ont montré que la signalisation insulin-like growth factor (IGF), régulateur clé de la longévité, est impliquée dans la progression de la MA. Nous avons récemment démontré que la suppression de la signalisation IGF neuronale à l’âge adulte chez un modèle de souris MA freine la progression de la pathologie amyloïde par une clairance de l’Aβ facilitée. L’objectif de ma thèse est d’identifier les mécanismes cellulaires et moléculaires liant signalisation IGF et neuroprotection contre la protéotoxicité Aβ. J’ai démontré que l’ablation de l’IGF-1R neuronal au cours du vieillissement protège des déficits cognitifs et de la neuroinflammation liée aux oligomères Aβ, et réduit substantiellement la taille du soma neuronal adulte. Pour identifier les voies impliquées dans cette neuroprotection, j’ai caractérisé le profil transcriptomique de neurones KO IGF-1R microdisséqués dans la région CA1 de l’hippocampe. J’ai démontré que la MA et l’ablation de l’IGF-1R neuronal impactent les mêmes fonctions biologiques, comme la neurotransmission, la croissance, et la transduction du signal, et presque tous les changements d’expression géniques communs à la MA et au KO IGF-1R neuronal se produisent dans le même sens. En revanche, dans les cerveaux MA, une proportion significative des gènes dérégulés par la MA sont inversés par le KO IGF-1R neuronal. Mes résultats révèlent que l’inhibition de la voie IGF neuronale à l’âge adulte protège de la pathologie Aβ en régulant l’organisation du cytosquelette, la neurotransmission, et la réponse au stress. / Alzheimer's disease (AD) is an age-related neurodegenerative disease, characterized by intracerebral amyloid-β (Aβ) peptide aggregation. Several studies have shown that insulin-like growth factor (IGF) signaling, a key regulator of longevity, is involved in AD progression. We recently showed that suppression of neuronal IGF signaling during adulthood alleviates amyloid pathology and cognitive deficits in AD mice through A clearance. In this context, the aim of my thesis was to identify the cellular and molecular mechanisms linking IGF signaling to neuronal protection against Aβ proteotoxicity. I demonstrated that ablation of neuronal IGF-1R during aging reduces cognitive deficits and neuroinflammation linked to A oligomers (AO), and induces a conspicuous decrease in neuronal soma size. To identify which pathways are involved in previously observed neuroprotection, I characterized the transcriptome profiling of microdissected hippocampal CA1 neurons from mice where neuronal IGF-1R was conditionally ablated at 3 months of age. I found that AD and neuronal IGF-1R inactivation impact on similar neuronal functions, namely neurotransmission, growth and differentiation, and signal transduction, and almost all of the changes in gene expression common to AD and IGF-1R ablation occurred in the same direction. However, in AD brains, a significant proportion of genes deregulated by AD were reversed by IGF-1R knockout. My results also reveal that inhibition of IGF signaling in adult neurons protects from A pathology by regulating cytoskeleton organization, neurotransmission, and response to stress.

In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.