Dr. Jahani-Asl’s research program is centered on developing novel therapeutic strategies for devastating brain diseases, presently with no cure. The aim is to employ state-of-art technologies to unravel the key signalling pathways that are altered in a rare population of stem cells in the diseased brain. Specifically, the research program is focused on 1) Developing new treatments to combat malignant and resistant brain tumor stem cells in glioblastoma (the most aggressive brain cancer); 2) Identifying key signaling pathways involved in the malignant transformation of neural stem cells (NSC); and 3) Defining the key molecular events involved in the reprogramming of NSC that leads to the impairment of neurodevelopmental programs and intellectual disability (ID).
Glioblastoma (GB) is the most malignant primary brain tumor in adults. The present standard of care includes maximal surgical removal of the tumors followed by radiation and chemotherapy. The discovery of brain tumor stem cells (BTSCs), more than a decade ago, has transformed our understanding of GB pathogenesis. BTSCs are a rare population of self-renewing stem cells that have the capacity to give rise to all the cellular subpopulations within a tumor and as such are thought to recapitulate the functional heterogeneity of the tumor. BTSCs are highly proliferative but at the same time show resistance to DNA damaging chemotherapy and ionizing radiation (IR). This raises the possibility that during treatment of GB tumors, a BTSC may exit the cell cycle/maintain a dormant state and re-enter cell cycle at a later time point to generate a cellular hierarchy that contributes to the acquisition of drug resistance. A better understanding of BTSC regulation is at the forefront of efforts to combat deadly GB.
Jahani-Asl and colleagues have employed next generation sequencing platforms, proteomics, imaging, bioinformatics, and patient derived tumor models to map oncogenic signalling network in BTSCs. This work led to the groundbreaking discovery that the cytokine receptor for Oncostatin M (OSMR) plays a key role brain tumour (Jahani-Asl et al, 2016 Nature Neuroscience). At the plasma membrane, OSMR forms a co-receptor with EGFRvIII and orchestrates a feed forward mechanism to amplify STAT3 signalling. Deletion of OSMR impairs the ability of BTSC to form brain tumors in preclinical models. These striking preclinical and mechanistic data have led Dr. Jahani-Asl’s laboratory to investigate the full spectrum of OSMR function in BTSC biology and its potential as a viable drug target for GB therapy. The aim of this project is to map the interacting domains of OSMR with its partner using mammalian membrane two hybrid (MaMTH) technology and employ drug screening including FDA approved compounds and Fluorescence Resonance Energy Transfer (FRET) imaging to identify small molecules that inhibit this pathway. These promising studies, presently funded by a 5-year CIHR project grant in the Jahani-Asl laboratory, are expected to yield novel agents for the treatment of GB.
Metabolic reprogramming is a hallmark of glioma and contributes to drug resistance. A classic metabolic shift that provides the brain tumor cells with a survival advantage is their adaptation to aerobic glycolysis, characterized by high glucose uptake, low oxygen consumption and high lactate production. However, BTSCs possess a unique metabolic phenotype, with a distinct upregulation of oxidative phosphorylation (OXPHOS) and a low glycolytic rate. This metabolic profile of BTSCs resembles that of neurons, as opposed to many of the cells in the bulk of the tumour that rely on aerobic glycolysis. Thus, the inhibitors of glycolysis do not work for BTSCs. Identification of metabolic vulnerabilities and their targeting in BTSCs provides a promising approach to overcome GB resistance to therapy. A major research program in Dr. Jahani-Asl’s laboratory has been screening for signaling pathways that regulate BTSC metabolism and resistance to stress. In particular, they are focused on the role of cytokines and carbohydrate binding proteins (CHB). A recent discovery in the Jahani-Asl laboratory has revealed that inhibition of cytokine signalling, converging on the mitochondria, alters the metabolic reprogramming that is typically the characteristics of BTSC. Importantly, they discovered a mitochondrial OSMR that interacts with complex 1 of respiratory chain complex and upregulates mitochondrial oxidative phosphorylation, oxygen consumption rate, and resistance to DNA damaging stress, independently of its role in proliferation. By suppressing this signalling pathway, they were able to halt energy production machineries of BTSCs and succumb them to death. Jahani-Asl’s laboratory will employ mass spectrometry techniques and proteomics to unravel signalling pathways that regulate the co-localization of OSMR to the mitochondria including an investigation of post-translational modifications. In particular, OSMR harbors multiple phosphorylation sites. The team will design reagents to inhibit specific sites within OSMR and assess its impact on OSMR recruitment to the mitochondria and regulation of energy production for cancer cells. These studies will yield important insights to develop new strategies that help starve BTSCs and sensitize glioblastoma response to therapy.
A collection of oncogenic mutations in the healthy NSC population has the potential to transform them into malignant cancerous stem cells (i.e., BTSC) and lead to the pathogenesis of brain cancer. A major interest in Dr. Jahani-Asl's laboratory is to unravel the signalling pathways that are involved in the malignant transformation of neural stem cells (NSC) via reprogramming of transcriptional machineries. In the past few years, Jahani-Asl’s laboratory has discovered that a carbohydrate binding protein, termed galectin1, regulates mesenchymal subtype of glioblastoma. Strikingly, they found that genetic and pharmacological inhibition of galectin1 impairs BTSC self-renewal and brain tumor formation. Subsequent analysis revealed that galectin1 interacts with a transcription factor called HOXA5. This interaction results in the activation of transcriptional programs that promote oncogenesis. Dr Jahani-Asl proposes to determine the functional consequences and the nature of this interaction in stem cell fate regulation using genetically engineered mouse models (GEMM) and patient derived tumours. In addition, galectin-1 is shown to confer resistance to chemotherapeutic modalities in different human cancer including chronic myeloid leukemia and cervical cancer, raising the question of whether suppressing of the galectin1/HOXA5 signalling is beneficial for chemo-resistant GB tumours. Dr. Jahani-Asl's group will investigate the therapeutic targeting of Gal1/HOXA5 in chemo-resistant BTSCs. This work which is supported by a Cancer Research Society (CRS) operating grant, will shed light on the therapeutic potential of targeting CHB proteins in GB.
The healthcare costs of intellectual disability (ID) are enormous. No effective treatments are available for ID, and thus there is an urgent need for improved understanding of these disorders. Brain development is an intricate process that entails multiple stages from the commitment of NSC and generation of newly born neurons to their migration and positioning and establishment of neuronal circuits. Neurogenesis is outlined as a process in which new neurons are generated from NSCs. This process is comprised of proliferation and fate specification of NSCs, migration of newborn neurons, and their maturation. Evidence is accumulating that a number of XLID genes play important roles in maintaining stem cell function or cell fate determination. These studies raise the possibility that loss of function of XLID genes may lead to impaired neuronal connectivity and cognitive deficits via re-programming of NSC during early phases of corticogenesis. A major research interest of Dr. Jahani-Asl is the study of the XLID syndrome, Börjeson-Forssman-Lehmann syndrome (BFLS), which is caused by mutations in the transcriptional regulator, the plant homeodomain zinc finger protein (PHF6).
Dr. Jahani-Asl’s laboratory has performed ChIP-Seq and RNA-Seq analyses to establish PHF6 genome wide targets in the developing mouse cortex. Intersection of these data led to the identification of a large panel of candidate target genes, involved in neurogenesis. This research program investigates how mutations of Phf6 in BFLS patients may impair neuronal connectivity via impairing neurogenesis and neuronal positioning. In other words, the key question is whether PHF6 mutations in BFLS patients impact neurodevelopmental programs by altering the fate specification of NSC during early corticogenesis. Dr. Jahani-Asl’s team employs PHF6 knockout mouse model as well as BFLS patient mutation models to investigate the impact of PHF6 on transcription and neurodevelopment. Expanding on these studies, Dr. Jahani-Asl’s team proposes experiments to unravel the full spectrum of PHF6 function in the developing brain and specifically in these pathologically relevant models to gain a better understanding of how different BFLS patient mutations alter neurogenesis. The experiments include scRNA seq and multiomic analyses of different BFLS mice cortices at the defined developmental timelines. In parallel, other parameters including analysis of neuronal migration, maturation, positioning, as well as the establishment of neuronal circuits will be studied.
Genome wide target analysis of PHF6 in the Jahani-Asl laboratory has led to the identification of multiple genes, as direct downstream targets of PHF6. Some of these targets are expressed during corticogenesis and play crucial roles in the proper formation of the brain. The goal of this research program is to validate these targets in preclinical animal models harboring different BFLS patient mutations. This work can lead to developing novel compound for better management of XLID.