MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.

Abstract

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

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Published Version (Please cite this version)

10.1016/j.ccell.2015.12.005

Publication Info

Hu, Jing, Tao Sun, Hui Wang, Zhengxin Chen, Shuai Wang, Lifeng Yuan, Tingyu Liu, Hai-Ri Li, et al. (2016). MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B. Cancer Cell, 29(1). pp. 49–60. 10.1016/j.ccell.2015.12.005 Retrieved from https://hdl.handle.net/10161/11667.

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Scholars@Duke

McLendon

Roger Edwin McLendon

Professor of Pathology

Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum.  My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understand the processes involved in the etiology, pathogenesis, and treatment of brain tumors.  Using the resources of the Preston Robert Brain Tumor Biorepository at Duke, our team, consisting of Henry Friedman, Allan Friedman, and Hai Yan and lead by Darell Bigner, have helped to identify mutations in Isocitrate Dehydrogenase (IDH1 and IDH2) as a marker of good prognosis in gliomas of adults.  This test is now offered at Duke as a clinical test.  Working with the Molecular Pathology Laboratory at Duke, we have also brought testing for TERT promoter region mutations as another major test for classifying gliomas in adults.  Our collaboration with the Toronto Sick Kids Hospital has resulted in prognostic testing for childhood medulloblastomas, primitive neuroectodermal tumors, and ependymomas at Duke.

Friedman

Allan Howard Friedman

Guy L. Odom Distinguished Professor of Neurosurgery, in the School of Medicine

At the present time, I am participating in collaborative research in the areas of primary malignant brain tumors, epilepsy and subarachnoid hemorrhage.

Primary malignant brain tumors are increasing in frequency. Patients harboring glioblastoma, the most malignant primary brain tumor, have a life expectancy of less than one year. In collaboration with the Division of Neurology and the Department of Pathology, clinical and laboratory trials have been initiated to identify better treatment for this condition. At present, trials of monoclonal antibodies and novel chemotherapeutic agents are being carried out.

Although physicians have been interested in seizures since the time of Hippocrates, the origin of seizures remains obscure. At Duke University we have treated approximately thirty seizure patients a year by removing abnormal portions of brain. Tissue from these resections is being analyzed for genetics and receptor abnormalities. Positron emission tomography and magnetic resonance imaging are being used to ferret out the origin of the patient's seizures.

Approximately 28,000 patients each year suffer a ruptured intracranial aneurysm. Approximately ten percent of these patients have a genetic predisposition to forming intracranial aneurysms. In conjunction with the Division of Neurology, we are screening candidate genes searching for the cause of intracranial aneurysms.

Bigner

Darell Doty Bigner

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine

The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.

For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.

As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.

My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor and with anti-CD40, a fully human monoclonal antibody which converts tumor stimulant macrophages into tumor suppressive macrophages. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I was Principal Investigator, was funded for 30 years at which time the type of grant was discontinued. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. My last NCI Award was an Outstanding Investigator Award from 2014 to 2022.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Li

Qi-Jing Li

Adjunct Associate Professor in the Department of Immunology

Recent clinical success in cancer immunotherapy, including immune checkpoint blockades and chimeric antigen receptor T cells, have settled a long-debated question in the field: whether tumors can be recognized and eliminated by our own immune system, specifically, the T lymphocyte. Meanwhile, current limitations of these advanced treatments pinpoint fundamental knowledge deficits in basic T cell biology, especially in the context of tumor-carrying patients. Aiming to develop new immunotherapies against cancers, and interconnected with clinical trials executed by clinician collaborators and immunogenomic tools developed in house, my research program rests on three pillars – the T cell, the Tumor Microenvironment, and Immunotherapy.

We regard the tumor as an acquired immunosuppressive organ. By this scientific precept, we study how tumors inhibit T cell-mediated immunity both locally and systemically. Our early TCR repertoire profiling of gastric tumors and tumor-free patient mucosa revealed the correlation between tissue resident T cell diversity and patient survival. Our recent single cell RNA sequencing study depicted complex pathways to develop T cell memory intratumorally. Currently, aided by bioinformatics and animal models, we are actively dissecting signaling pathways, transcription regulatory networks, and epigenetic programs governing T cell differentiation in the tumor microenvironment. Moving beyond the local microenvironment, our previous studies also demonstrated that tumors remotely modulate T cell antigen-priming events in the spleen. This ongoing in-depth investigation has gradually unveiled the profound impact of this “tele-education”: established tumors hijack hematopoiesis to protect themselves against T cell surveillance. The next step is to identify those evil envoys sent out by tumors carrying signals for systemic immune suppression.

The expanding boundary of T cell biology is the frontier of cancer immunotherapy. The contrast between the unprecedented success of T cell-based therapies for blood malignancies and their repeated failures against solid tumors vividly highlights our prevalent challenges: to understand how T cells can infiltrate tumors; how infiltrated T cells can resist microenvironmental suppression; and how activated T cells can form persistent memory to restrict tumor development and metastasis. During the last decade, my laboratory invested heavily in the microRNA (miRNA) field, deeming miRNAs a unique tool for T cell biology discovery. Identifying miRNA functions and targets is our path to discovering novel proteins, or novel functions of known proteins, in T cell regulation. Expression profiling and functional screening in the lab have produced many candidates to make T cells smarter and stronger. Due to their size, these miRNA candidates can be easily combined with targeting moieties to armor T cells, and we have incorporated these small weaponries, and introduced genomic manipulations on their downstream targets, into CAR-T cells for pre-clinical studies. Indeed, some of them greatly enhance CAR-T’s anti-tumor function. As a general principle, we believe that it is necessary to empower transferred CAR T or TCR-T cells with enhanced functionality against solid tumors. We also believe the T cell is a perfect platform to integrate genomic engineering for combinatory cancer therapy. Currently, we are actively involved in three such armored CAR-T or TCR-T trials for various solid tumor treatments.  

Accompanying these trials, and other immunotherapies carried out by colleagues on campus and world-wide, we design and execute comprehensive immune monitoring procedures to rationalize successes and failures. Clinical observations are smoothly deconstructed into basic but intriguing T cell questions for us to answer, and answers generated on the bench directly inform T cell designs in future trials. This is our closed circle of research and day-to-day operation.

Wang

Xiao-Fan Wang

Donald and Elizabeth Cooke Distinguished Professor of Cancer Research, in the School of Medicine

The current research in the Wang laboratory mainly focuses on the elucidation of molecular nature and signaling mechanisms associated with the initiation of cellular senescence. In addition, we continue to study changes in tumor microenvironment that promotes tumor progression and metastasis, particularly how tumor cells interact with the immune system. Ultimately, we hope that our studies in these areas to lead to the development of novel therapeutics for the treatment of various types of human cancer.


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