Janusz Rak

Janusz Rak
McGill University | McGill · Department of Pediatrics

About

283
Publications
28,406
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22,824
Citations
Additional affiliations
September 1981 - September 1988
Polish Academy of Sciences
Position
  • Reasercher

Publications

Publications (283)
Article
Full-text available
Glioblastoma (GBM) is an incurable form of primary astrocytic brain tumor driven by glioma stem cell (GSC) compartment closely associated with the vascular niche. GSC phenotypes are heterogeneous and range from proneural to mesenchymal-like, the latter characterised by greater invasiveness. Here we document the secretory (angiocrine) role of endoth...
Article
Full-text available
Background Despite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has yet to be described. Methods We combined GBM patient and...
Article
Cancer associated thrombosis (CAT) including venous and arterial thromboembolism (VTE and ATE respectively), as well as subclinical hypercoagulable states pose a risk of serious morbidity and mortality and poor outcomes in cancer patients. It is increasingly clear that rather than being unspecific aftermaths of tumour growth, CAT is causally linked...
Article
Full-text available
Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opport...
Article
Full-text available
Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA (ctDNA) for such informative somatic mutat...
Article
BACKGROUND Vascular anomalies, including thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of dysregulated cancer cell genome and epigenome. Up-regulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk of venous thromboembolism in glioblastoma patients. Thus, regulation of this platelet activating...
Article
Glioblastoma multiforme (GBM) represents the most frequent and lethal form of brain tumors originating from glioma stem cells (GSCs). GBM remains lethal because the rate limiting patho-mechanisms remain poorly understood. In this regard, few limitations involve the diversity 'between' cellular states and the molecular/cellular complexity 'within' t...
Article
Full-text available
Extracellular vesicles (EVs) are membranous structures containing bioactive molecules, secreted by most cells into the extracellular environment. EVs are classified by their biogenesis mechanisms into two major subtypes: ectosomes (enriched in large EVs; lEVs), budding directly from the plasma membrane, which is common in both prokaryotes and eukar...
Article
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Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy...
Article
Full-text available
Vascular anomalies, including thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of dysregulated cancer cell genome and epigenome. Upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk of venous thromboembolism in glioblastoma patients. Thus, regulation of this platelet activating transmembra...
Article
Full-text available
Oncogenic RAS impacts communication between cancer cells and their microenvironment, but it is unclear how this process influences cellular interactions with extracellular vesicles (EVs). This is important as intercellular EV trafficking plays a key role in cancer invasion and metastasis. Here we report that overexpression of mutant RAS drives the...
Chapter
Glioblastoma (GBM) is an incurable, infiltrative high-grade brain tumour associated with dramatic vascular responses observed both locally (angiogenesis, vascular cooption, angiocrine effects, microthrombosis) and systemically (venous thromboembolism). GBM-associated vascular pathology is diagnostically relevant and constitutes a source of morbidit...
Article
Full-text available
Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for...
Article
Cancer cells shed into biofluids extracellular vesicles (EVs) — nanoscale membrane particles carrying diagnostic information. EVs shed by heterogeneous populations of tumor cells offer a unique opportunity to access biologically...
Article
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The ability to track extracellular vesicles (EVs) in vivo without influencing their biodistribution is a key requirement for their successful development as drug delivery vehicles and therapeutic agents. Here, we evaluated the effect of five different optical and nuclear tracers on the in vivo biodistribution of EVs. Expi293F EVs were labeled using...
Chapter
Extracellular vesicles (EVs) are nano-sized lipid bilayer surrounded by structures released from most cells, including archaea, bacteria, and eukaryotic cells. EVs play multiple roles in cell-to-cell communication, including immune modulation, angiogenesis, and phenotypic transformation of cells by transferring genetic material and functional prote...
Article
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Background The paracrine effects of multipotent mesenchymal stromal cells (MSCs) are mediated by their secretome composed by soluble factors (i.e., cytokines, growth factors, hormones) and extracellular vesicles (EVs). EVs promote intercellular communication, and the EV cargoes [e.g., proteins, soluble factors, microRNAs (miRNAs), messenger RNA (mR...
Article
Glioblastoma (GBM) is invariably fatal due to failure of current chemoradiation (Stupp) regimes. Biomarkers such as MGMT have proven to predict response to Temozolomide (TMZ). An equivalent biomarker for radiation (RT) has not yet been identified. Transglutaminase-2 (TGM2) has been implicated in driving radiation resistance; but the mechanism is po...
Article
Cancer-associated thrombosis (CAT) is a morbid, potentially life threatening and biologically impactful paraneoplastic state. At least in part, CAT is likely driven by cancer-specific mechanisms the nature of which is still poorly understood, hampering diagnostic, prophylactic and therapeutic efforts. It is increasingly appreciated that cancer-spec...
Article
Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to rhabdoid tumor family usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodeling complexes. Previous studies proposed that SMARCB1 loss drives rhabdo...
Article
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We studied whether cytosine phosphate–guanine (CpG) recoding in a viral genome may provide oncolytic candidates with reduced infection kinetics in nonmalignant brain cells, but with high virulence in glioblastoma stem cells (GSCs). As a model, we used well-characterized CpG-recoded Zika virus vaccine candidates that previously showed genetic stabil...
Data
Supplementary data for "Zika Virus with Increased CpG Dinucleotide Frequencies Shows Oncolytic Activity in Glioblastoma Stem Cells"
Article
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Oncogenic transformation impacts cancer cell interactions with their stroma, including through formation of abnormal blood vessels. This influence is often attributed to angiogenic growth factors, either soluble, or associated with tumor cell-derived extracellular vesicles (EVs). Here we examine some of the cancer-specific components of EV-mediated...
Article
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Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype–phenotype relationships1,2. Here we present a human ‘all-by-all’ reference interactome map of human binary protein interactions, or ‘HuRI’. With approximately 53,000 protein–protein interactions, HuRI...
Article
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Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the...
Article
A mechanism of secretory autophagy explains aspects of the packaging of proteins and RNA into extracellular vesicles and paves the way to a better understanding of their biological roles and medical applications.
Article
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Detection of unique oncogenic alterations encoded by the sequence or biochemical modification in cancer-associated transforming macromolecules has revolutionized diagnosis, classification and management of human cancers. While these signatures were traditionally regarded as largely intracellular and confined to the tumor mass, oncogenic mutations a...
Article
Glioblastoma (GBM) is the most common and deadly type of malignant brain cancer in adults. While current standard of care which combines resection, radiation therapy (RT) and Temozolomide (TMZ) effectively eliminates primary disease, recurrence is inevitable, occurs rapidly following treatment and is ultimately lethal due to limited therapeutic opp...
Article
Purpose: Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSCs) contribute to resistance to the DNA-damaging chemotherapy, temozolomide (TMZ). The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM....
Article
The elusive complexity of membranous extracellular vesicle (EVs) and membrane-less extracellular particle (EPs) populations released from various cellular sources contains clues as to their biological functions and diagnostic utility. In this study, we employed optimized multicolor nano-flow cytometry, structured illumination (SIM) and atomic force...
Article
There are emerging linkages between biological and genetic aspects of cancer progression and the mechanisms of cancer-associated thrombosis. It is argued that reciprocal influences between cancer cells, their associated vascular stroma, and the hemostatic system may shape the mechanism of coagulopathy. In this regard, glioblastoma multiforme offers...
Preprint
Full-text available
Global insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence recently revolutionized human genetics, a reference map of the human interactome network is critical to fully understand genotype-phenotype relationships. Here, we present the first human "a...
Article
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Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small...
Article
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Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase...
Article
Full-text available
Glioma are the most common type of malignant brain tumor, with glioblastoma (GBM) representing the most common and most lethal type of glioma. Surgical resection followed by radiotherapy and chemotherapy using the alkylating agent Temozolomide (TMZ) remain the mainstay of treatment for glioma. While this multimodal regimen is sufficient to temporar...
Article
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Non-coding RNA (ncRNA) species have emerged in as molecular fingerprints and regulators of brain tumor pathogenesis and progression. While changes in ncRNA levels have been traditionally regarded as cell intrinsic there is mounting evidence for their extracellular and paracrine function. One of the key mechanisms that enables ncRNA to exit from cel...
Article
Mutational and epigenetic driver events profoundly alter intercellular communication pathways in cancer. This effect includes deregulated release, molecular composition, and biological activity of extracellular vesicles (EVs), membranous cellular fragments ranging from a few microns to less than 100 nanometers in diameter and filled with bioactive...
Article
Background Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved. Methods Using The Cancer Genome Atlas (n = 436) and Cancer Ge...
Article
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We have previously uncovered the impact of oncogenic and differentiation processes on extracellular vesicles (EVs) in cancer. This is of interested in the context of glioma stem cells (GSC) that are responsible for recurrent nature of glioblastoma multiforme (GBM), while retaining the potential to undergo differentiation and self renewal. GSCs resi...
Article
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Glioblastoma multiforme (GBM) is a highly aggressive and heterogeneous form of primary brain tumors, driven by a complex repertoire of oncogenic alterations, including the constitutively active epidermal growth factor receptor (EGFRvIII). EGFRvIII impacts both cell-intrinsic and non-cell autonomous aspects of GBM progression, including cell invasio...
Article
Background Tumor‐derived extracellular vesicles (EVs) and free nucleosomes (NSs) carry into the circulation a wealth of cancer‐specific, bioactive and poorly understood molecular cargo, including genomic DNA (gDNA). Objective. Here we investigated the distribution of extracellular oncogenic gDNA sequences (HRAS and HER2) in the circulation of tumor...
Article
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease associated with a 5-year survival rate of ~9%. The most notable clinical features of PDAC are its propensity for aggressive invasion, metastasis (mainly to the liver) and an inherent resistance to conventional therapies. A better understanding of the biology of PDAC metastasis...
Article
Background: ablative radiation therapy (ABR) serves as the treatment of choice for early stage non-small cell lung cancer (NSCLC) patients who are not surgical candidates. NSCLC patients with mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) had a significant response to tyrosine kinase inhibitors (TYIs)....
Article
Molecular profiling of human cancers revealed a startling diversity in disease-causing mechanisms superseding histological and anatomical commonalities. The emerging molecular subtypes and disease entities are often driven by distinct oncogenic pathways and their effectors, including those acting extracellularly on the vascular and coagulation syst...
Article
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The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many...
Article
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Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fracti...
Article
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Tumor cells display on their surface several molecular chaperones that normally reside in the endoplasmic reticulum (ER). Because this display is unique to cancer cells, these chaperones are attractive targets for drug development. Previous epitope-mapping of autoantibodies (AutoAbs) from prostate cancer patients identified glucose-regulated-78 (GR...
Article
Tissue factor (TF) is a transmembrane receptor for coagulation factor VII/VIIa that is frequently overexpressed by cancer cells. The TF/VIIa complex acts as the main initiator of the clotting cascade in blood and a trigger of intracellular signaling that changes gene expression and the cellular phenotype. However, pathways mediating these changes a...