Nazanin Tatari

McMaster University | McMaster · Brain Tumor Stem Cell Research Program, Stem Cell and Cancer Research Institute (SCC-RI), Department of Biochemistry and Biomedical Sciences

A major challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is the immunosuppressive microenvironment (iTME), which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Blockade of CD47, a “don’t-eat-me” signal overexpressed by GBM cells, disrupts the CD47-SIRPα axis, and regulat...

Glioblastoma (GBM), the most common malignant primary adult brain tumor, is characterized by extensive cellular and genetic heterogeneity. The standard of care therapy and clinical trials have not been successful in improving patients’ survival which underscores an urgent need for developing new effective therapies. In silico and in vitro analysis...

A major challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting of CD47, a “don’t-eat-me” signal overexpressed by tumor cells, disrupts the CD47-S...

INTRODUCTION Glycoprotein nonmetastatic melanoma protein B (GPNMB) is active in the extracellular matrix of glioblastoma and presents a promising immunotherapy target for both tumor cells and immunosuppressive macrophages. METHODS Immunohistochemistry was performed on patient derived xenograft (PDX) brains and tissue samples of 16 patient-matched...

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia- and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high expression of sialic acid-binding immunoglobulin-like lect...

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is known to be active in the extracellular matrix of glioblastoma and has been identified as a promising immunotherapy target for both tumor cells and immunosuppressive macrophages. Methods: Immunohistochemistry was performed on patient derived xenograft (PDX) brains and tissue samples of 16 pat...

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastat...

Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as microglia (MG) or monocyte-derived cells (MdCs). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in innate-centered immunotherapy against GBM. T...

Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Due to GBM displaying extreme heterogeneity and immune suppression, prognosis remains dismal. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has previously been identified as a clinically relevant target in GBM while being absent in normal brain tissues...

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high level of Siglec-9 expression correlates with reduced surviv...

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent...

Recurrence of solid tumors renders patients vulnerable to advanced, treatment-refractory disease state with mutational and oncogenic landscape distinctive from initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We pr...

Glioblastomas (GBM), the most common malignant primary adult brain tumors, are uniformly lethal and are in need of improved therapeutic modalities. GBM contain extensive regions of hypoxia and are enriched in therapy resistant brain tumor-initiating cells (BTICs). Carbonic anhydrase 9 (CA9) is a hypoxia-induced cell surface enzyme that plays an imp...

Brain metastases (BM) are the most common brain tumours in adults and a prominent cause of cancer-related mortality globally. Leading sources of BM are cancers of the lung, breast and melanoma, which together account for approximately 80% of all BM. Unfortunately, current clinical modalities for BM including surgery, radiation therapy and chemother...

Many protein immunotherapeutics are hindered by transport barriers that prevent the obtainment of minimum effective concentrations (MECs) in solid tumors. Local delivery vehicles with tunable release (infusion) rates for immunotherapeutics are being developed to achieve local and sustained release. To expedite their discovery and translation, in vi...

Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the pos...

Purpose Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of cancer stem cells (CSCs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here, w...

Medulloblastoma (MB) remains a leading cause of cancer-related mortality among children. The paucity of MB samples collected at relapse has hindered the functional understanding of molecular mechanisms driving therapy failure. New models capable of accurately recapitulating tumor progression in response to conventional therapeutic interventions are...

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absen...

Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to...

Purpose: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of brain tumor initiating cells (BTICs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving c...

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. A wealth of literature describes the biology of primary GBM (p-GBM), but we currently lack an understanding of how GBM evolves through therapy to become a very different tumor at recurrence, which may explain why therapies against p-GBM fail to work in recurrent GB...

Glioblastoma (GBM) is the most common malignant adult brain tumor that is resistant to the standard care therapy. Advances in chimeric antigen receptor (CAR) T cell therapies have spurred renewed interest in developing CAR T cell therapies to target chemoradiotherapy-resistant brain tumor-initiating cells. This protocol shows how to isolate periphe...

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derive...

Brain metastases (BM) are the most common brain tumour in adults and are ten times more likely to develop than primary brain tumours. More than 20% of patients with cancer will develop BM with the three most common sources being primary cancers of the lung, breast, and melanoma. Unfortunately, current treatment options for BM do not effectively era...

CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 a...

Mechanistic insight into signaling pathways downstream of surface receptors has been revolutionized with integrated cancer genomics. This has fostered current treatment modalities, namely immunotherapy, to capitalize on targeting key oncogenic signaling nodes downstream of a limited number of surface markers. Unfortunately, rudimentary mechanistic...

Background: Glioblastoma (GBM) is the most common malignant primary adult brain tumor, characterized by extensive cellular and genetic heterogeneity. Even with surgery, temozolomide chemotherapy and radiation, tumor re-growth and patient relapse are inevitable, with a median survivorship of just 15 months. Genomic profiling studies have shown that...

Increased angiogenesis is a characteristic feature of remodeling in asthmatic airways and stems from the imbalance between pro-angiogenic and anti-angiogenic factors. Surprisingly, the factors regulating this process in allergic asthma are poorly defined. Previously, we showed an important role of semaphorins 3E (Sema3E) in growth factor–induced ai...

Early development of human organisms relies on stem cells, a population of non-specialized cells that can divide symmetrically to give rise to two identical daughter cells, or divide asymmetrically to produce one identical daughter cell and another more specialized cell. The capacity to undergo cellular divisions while maintaining an undifferentiat...

Utilization of human embryonic stem cells (hESCs) as a model system to study highly malignant pediatric cancers has led to significant insight into the molecular mechanisms governing tumor progression and has revealed novel therapeutic targets for these devastating diseases. Here, we describe a method for generating heterogeneous populations of neu...

The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility o...

Fig. S1. Knockdown of OTX2 in Group 3 and Group 4 MB decreases tumorsphere formation and self‐renewal. Fig. S2. Semaphorin genes are negatively correlated with OTX2 expression in Group 3 and Group 4 MB cells. Fig. S3. Axon guidance gene expression is upregulated following OTX2 knockdown in Group 3 and Group 4 MB cells. Fig. S4. Recombinant semap...

Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcri...

The extensive heterogeneity within the medulloblastoma (MB) molecular variants has revealed a critical need for subtype-specific biomarkers and therapeutic strategies. Using a high throughput flow cytometry screen and gain/loss of function studies, we previously identified CD271/p75NTR as a candidate stem/progenitor cell marker specifically in SHH...

Medulloblastoma (MB) is a highly heterogeneous primary malignant pediatric brain cancer that is frequently accompanied by metastatic dissemination and poor long-term prognosis. The most aggressive tumors are refractory to conventional chemotherapy and radiation. Our goal is to identify new signaling pathways that regulate the treatment-resistant MB...

Medulloblastoma (MB) is the most common malignant primary brain tumor and is currently classified into 5 distinct molecular subtypes based on genomic alterations, gene expression profile, response to treatment and cell of origin. This extensive heterogeneity has revealed a critical need for subtype-specific, functionally validated biomarkers and th...

Neutrophil migration is an essential step in leukocyte trafficking during inflammatory responses. Semaphorins, originally discovered as axon guidance cues in neural development, have been shown to regulate cell migration beyond the nervous system. However, the potential contribution of semaphorins in the regulation of neutrophil migration is not we...

Medulloblastoma (MB) is a highly heterogeneous primary malignant pediatric brain cancer. Despite improved 5-year survival rates, MB is frequently accompanied by metastatic dissemination and poor long-term prognosis. The most aggressive tumors are refractory to conventional chemotherapy and radiation. Our goal is to identify new signaling pathways t...

Medulloblastoma (MB) is the most common malignant primary brain tumor in children. Despite improved clinical outcomes, children with MB often suffer from consequences of treatment such as surgery, chemotherapy and radiation. MB is currently classified into 4 distinct molecular subtypes based on genomic alterations, gene expression profiles, respons...

Airway smooth muscle (ASM) hyperplasia is a key feature of airway remodeling in development of lung diseases such as asthma. Anomalous proliferation of ASM cells directly contributes to ASM hyperplasia. However, the molecular mechanisms controlling ASM cell proliferation are not completely understood. Semaphorins are versatile regulators of various...

Major research efforts have focused on defining cell surface marker profiles for characterization and selection of brain tumor stem/progenitor cells. Medulloblastoma is the most common primary malignant pediatric brain cancer and consists of 4 molecular subgroups: WNT, SHH, Group 3 and Group 4. Given the heterogeneity within and between medulloblas...