Aghi Lab Newsletter January 2018

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Aghi Lab Newsletter
January 2018

“Cancer is a noun but in the body it acts like a verb...”

Overview

Manish Aghi, MD PhD, directs a research lab and operates on brain tumor patients at UCSF. His surgical practice and lab emphasize glioblastoma, an aggressive tumor resistant to current treatments, and pituitary adenomas, benign tumors that dramatically impact a patient’s quality of life upon reaching critical size. Integrating the lab and clinical practice maximizes the impact of both by studying human tissues in the lab, defining variables that maximize the impact of surgery for patients, and implementing concepts developed in the lab into clinical trials to help patients. The eight-person research team consists of postdoctoral fellows, students, and volunteers, several of whom have their research highlighted below.

Current Research

Macrophages in Pituitary Adenomas and Glioblastomas: Friends or Foe?

Representation of pituitary adenomas forcing the pituitary gland out away from the sphenoid bone.

While the role for the tumor microenvironment in malignant tumors has been well described by the Aghi lab and numerous other groups, to date, little is known about the role of the tumor microenviornment in driving the biology of benign tumors like pituitary adenomas. Ongoing work by UCSF neurosurgery resident Martin Rutkowski and Aghi lab postdoc Garima Yagnik has shown that macrophages represent a significant portion of the cells in pituitary adenomas and many adenoma macrophages can be pro-tumoral, enabling them to drive adenoma proliferation and invasion in the way that we have shown to occur in glioblastoma.

Macrophages (white) surrounding tumor site in glioblastoma

Neutrophils in Glioblastoma: Passive Bystander or Driver of Tumor Biology?

Neutrophil migration and chemical signaling

Neutrophils, the most common circulating white blood cells, have long been known to be detectable in cancers but were historically regarded as passive bystanders in cancer. However, work from Aghi lab postdoctoral fellow Garima Yagnik has shown that they actually contribute to the aggressive tumor biology of glioblastoma. Using flow cytometry and single cell sequencing, Garima showed that neutrophils represent 1-10% of the cells in glioblastomas and that a predominant pro-tumoral subset of neutrophils express osteopontin, enabling them to drive tumor cell proliferation in a manner inhibited by an osteopontin blocking antibody.

Neutrophil (red) migration at tumor edge (green) visualized by
Dr. Garima Yagnik, PhD.

Quality of Life Issues in Glioblastoma Patients: Post-op Seizures and Delirium, Outcomes for Elderly

In 2017, Patrick Flanigan of the clinical group in the Aghi lab published three studies on functional outcomes after glioblastoma surgery, looking at the impact of timely surgery in patients who present with seizures, the effect that postoperative delirium has on glioblastoma patients, and defining an algorithm that predicts outcomes of elderly patients with glioblastoma. The goal of this work is to integrate quality of life considerations into surgical decision making for glioblastoma patients.

A Protein Complex in Glioblastoma and Metastases

(R) Representation of regional biopsies taken from a glioblastoma tumor for protein analysis of cMET/B1 integrin complex. (L) Western blot protein analysis of regional biopsies.

Bevacizumab (avastin), a VEGF blocking antibody, cuts off the tumor blood supply and can be effective for glioblastoma but with limited response duration shown in two phase III trials. In work published in the October 2017 issue of Proceedings of the National Academy of Sciences, Arman Jahangiri, an MD/PhD student in the Aghi lab, has found that a protein complex between two cell receptors, c-Met and β1 integrin, forms throughout bevacizumab-resistant glioblastomas and that glioblastomas with this complex have a worse prognosis than those without. In this complex, the two receptors bind and cross-activate each other, driving the invasive resistance that limits bevacizumab treatment. Arman also found the complex to be present in brain metastases, work that is currently being carried on by UCSF neurosurgery resident Darryl Lau.

Fluorescently labeled imaging of cMET/B1 complex (red) on the surface of breast cancer cells.

Cancer-associated Fibroblasts in Glioblastoma

Fibroblasts have been shown to promote the growth of a variety of cancers through deposition of extracellular proteins, but their presence or role in glioblastoma is not well studied. Our laboratory has identified cancer-associated fibroblasts in glioblastoma and shown that they specifically produce EDA-expressing fibronectin, a splice variant that is associated with other cancers. Work to date by Jonathan Rick, a UCSF medical student funded by a Howard Hughes Medical Institute (HHMI) fellowship, has shown that EDA-expressing fibronectin promotes aggressive biology in glioblastoma, including invasiveness and pro-tumoral macrophage polarization. We have also shown that cancer-associated fibroblasts and EDA-Fibronectin preferentially accumulate in the periventricular regions of glioblastoma, an area that harbors more aggressive tumors. A better understanding of cancer-associated fibroblasts and EDA-Fibronectin may better elucidate how glioblastoma progresses and open new approaches to therapy.

EDA-Fibronectin (red) is found in regions surrounding cancer-associated fibroblasts (green). Stained and imaged by Jonathan Rick, 3rd-year medical student at the University of California, San Francisco School of Medicine and HHMI Fellow.

GLUT3 Inhibitors in bevacizumab-resistant GBM and Glioma Stem Cell Maintenance

Glucose transporter 3 (GLUT3) is upregulated in tumors continuously treated with bevacizumab and in glioma stem cells. Thus, GLUT3 may serve as an Achilles Heel in treating glioblastoma. By using novel GLUT3 inhibitors, we hope to overcome bevacizumab resistance in glioblastoma while inhibiting the spread of tumor-initiating cells.

In the January 2017 issue of JCI Insight, the Aghi lab published a study showing that glucose transporter 3 (GLUT3) is upregulated in tumors continuously treated with bevacizumab and in glioma stem cells. Thus, GLUT3 may serve as an Achilles Heel in treating glioblastoma. Ankush Chandra, a medical student working in the Aghi lab under funding from an HHMI fellowship, is studying novel small molecule GLUT3 inhibitors to treat bevacizumab-resistant glioblastoma. Because GLUT3 is also expressed by tumor-initiating cells, these inhibitors may be able to target these cells that are a key source of therapeutic resistance in glioblastoma.

Glioma stem cell culture by Ankush Chandra,2nd year medical student at Wayne State University School of Medicine and HHMI Fellow.

3D Microfluidics System for the Study of Tumor Cell Invasion

In collaboration with the Kumar Lab at the University of California, Berekely, we are utilizing a 3D model of invasion to study the mechanisms and rate at which tumor cells invade through their microenvironment.

Advantages of 3D vs 2D systems

For More Information

For more information about research in the Aghi Lab or how to support our efforts, visit our website at http://www.aghilab.com. To schedule a tour, please contact Joseph Neisen in the UCSF Development Office at 415-502-8309. If you do not wish to receive further fundraising communications from UCSF, please contact: Record Manager, UCSF Box 0248, San Francisco, CA 94143-0248 or email HIPAAOPTOut@support.ucsf.edu or call 1-888-804-4722.

Copyright © 2018 Aghi Lab, All rights reserved.

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aghilab@ucsf.edu

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