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Aghi Lab Newsletter
Volume 3 - January 2019
“Cancer is a noun but in the body it acts like a verb...”
Manish Aghi, MD PhD, directs a research lab and operates on brain tumor patients at UCSF. His surgical practice and lab emphasize (1) glioblastoma, an aggressive primary brain tumor resistant to current treatments; (2) metastases of malignant cancers that spread to the brain from other organs; and (3) pituitary adenomas, benign tumors that dramatically impact a patient’s quality of life upon reaching critical size. The primary focus of the lab is the microenvironment of these tumors, recognizing that many cancer treatments fail because they do not recognize cancer for what it is, a dynamic organ with complex interplay between tumor cells and their microenvironment. Integrating Dr. Aghi's lab and clinical practice maximizes the impact of both by studying human tissues in the lab and implementing concepts developed in the lab into clinical trials to help patients. The 8 to 12-person research team consists of postdoctoral fellows, students, and volunteers, several of whom have their research highlighted below.
Current Research
Using CRISPR libraries and 3D bioengineered models of glioblastoma to define novel druggable mediators of invasion
The poor prognosis of glioblastoma is largely due to glioblastoma cell invasion, which enables escape from surgical resection and drives inevitable recurrence, typically 2 cm from the location at diagnosis.  This invasion ultimately proves fatal as tumor cells invade the brain’s essential real estate and sever its intricate synapses, with reoperation exerting equally devastating effects on quality of life. In a sense, GBM is a grenade that has exploded, piercing the brain with its shrapnel of tumor cells. Through a grant recently awarded to the Aghi lab, we are collaborating with the Kumar lab in the UC Berkeley bioengineering department to use 3D engineered culture models of invasion and CRISPR libraries targeting the draggable human genome to identify novel draggable mediators of invasion in glioblastoma.
3D bioengineered models of parenchymal and perivascular invasion in which tumor cells are loaded into a cell reservoir and are then watched under a microscope for their migration towards an open channel that models a blood vessel (perivascular invasion).
CD97: a novel therapeutic target in glioblastoma
The poor prognosis of glioblastoma (GBM) reflects the capacity of GBM cells to supplement proliferative programs with pro-tumoral interactions with the microenvironment, including invasion, angiogenesis, and immunosuppression. There is a need to simultaneously target these processes, as, at the microscopic level, these processes can be temporally, mutually exclusive phenotypes that toggle back and forth. A single molecule with the ability to impact all of these processes therefore has the potential for a far greater anticancer effect than conventional agents limited to one mechanism of action. Towards that end, UCSF neurosurgery resident Michael Safaee has developed intriguing data revealing the previously underappreciated importance of CD97 in driving these processes in GBM. Mike then established a collaboration between the Aghi lab and Planet Biotechnology, a company that developed DAF-Fc, a small molecule targeting CD97 in GBM. Through an NIH Small Business Innovation Research (SBIR) grant awarded to the Aghi lab and Planet Biotechnology and an F32 postdoctoral fellowship awarded to Dr. Safaee, preclinical evaluation of this treatment is underway in the hopes of eventually going to a clinical trial.
Three mechanisms of pro-tumoral effects of CD97 and five anti-tumoral effects of DAF-Fc
Using CRISPR libraries and novel models of intravasation and extravasation to define draggable mediators of brain metastases
Current Aghi lab manager Harsh Wadhwa has built cell culture models for studying the process by which cancers intravasate into the circulation and extravasate out of the circulation, crucial steps in the metastatic cascade. Using these models with CRISPR libraries will enable Harsh to define mediators of brain metastases.
Shown are cell culture models using human endothelial cells and tumor cells to model tumor intravasation into the circulation and extravasation out of the circulation.
Bevacizumab-resistance in glioblastoma: regulators and targetable mediators
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 follow up to the Aghi lab's 2017 publication in Proceedings of the National Academy of Sciences produced by Arman Jahangiri, a recent MD/PhD graduate from the Aghi lab, in which Arman found that a protein complex between two cell receptors, c-Met and β1 integrin, drives bevacizumab resistance, the lab has been awarded an NIH grant to screen for small molecules that prevent the formation of this complex and could therefore prolong the duration of bevacizumab responsiveness in glioblastoma.
(A) Normal humoral levels of VEGF bind tumor cell VEGFR2 and sequester c-met and β1 integrin, preventing them from binding, but bevacizumab-induced VEGF depletion frees c-Met and β1 integrin to bind each other and form a complex that drives invasive resistance. (B) c-Met displaces a5 integrin from β1 integrin and keeps β1 integral in its high affinity form, leading to greater affinity for fibronectin than what a5β1 integrin normally exhibits.
Ankush Chandra, a recent Howard Hughes Medical Institute (HHMI) research fellow in the Aghi lab investigated bevacizumab resistance earlier during its evolution and found that transcription factor Zeb1 mediated the phenotypic changes found in these resistant tumors. Ankush is currently evaluating the naturally occurring honokiol as a means of prolonging responsiveness to bevacizumab in glioblastoma.
Single cell sequencing of a bevacizumab-resistant glioblastoma revealed transcriptional factor ZEB1 to be unregulated in late clones emerging during prolonged treatment, consistent with it being a treatment-induced regulator of resistance.
Defining the cellular makeup of the perivascular niche of glioblastoma
Glioblastoma (GBM) originates from stem cells that are difficult to treat due to their heterogeneity. Our lab has recently identified two unique cell types that reside near GBM stem cells and support the stem cells: cancer-associated fibroblasts (CAFs) and tumor-associated neutrophils (TANs). Jonathan Rick, a UCSF medical student funded by a Howard Hughes Medical Institute (HHMI) fellowship, showed that stem cells recruit CAFs from the circulation into GBM via platelet-derived growth factor (PDGF) secretion. Garima Yagnik, Aghi lab postdoctoral fellow, and Sumedh Shah, a medical student in the Aghi lab funded by an HHMI fellowship, showed that TANs support GBM stem cells via osteopontin secretion. Defining these pathways may enable disruption of the stem cell niche in GBM.
The cellular makeup of the stem cell niche of glioblastoma
Developing tunable immunomodulatory gene circuits for glioblastoma
Glioblastomas create a tumor microenvironment that is very T-cell depleted. Jordan Spatz, PhD, a postdoctoral fellow and current UCSF medical student in the Aghi lab, is developing a novel gene therapy approach to address this issue by delivering four immunomodulatory genes to glioblastoma.
A four-pronged gene tunable immunomodulatory gene circuit approach for glioblastoma.
Defining role of macrophages in pituitary adenoma growth
Work by postdoctoral fellow Garima Yagnik and former UCSF neurosurgery resident Martin Rutkowski in the Aghi lab has shown that pituitary adenoma growth is controlled by tumor cytokines that regulate the tumor-associated macrophages (TAMs). They found that, at some point, small pituitary adenomas enter a growth phase in which tumor-secreted monocyte chemoattractant protein-1 (MCP-1) attracts monocytes out of the circulation which then differentiate into TAMs and are polarized into M2 pro-tumoral macrophages that cause pituitary adenoma cells to secrete EZH2 and S100A9, which promote adenoma proliferation and invasion, respectively. Over time, adenoma cells secrete GM-CSF which changes TAMs to an M1 anti-tumoral subtype that slows adenoma growth, causing the adenoma to enter a quiescent phase. These findings may someday enable immunomodulatory approaches to treat pituitary adenomas that are refractory to standard treatments.
The role of macrophages in pituitary adenoma growth
Clinical Studies 2018
Aside from the basic science work described above, physician-scientist members of our team published the following clinical studies in 2018:
  1. Medical student Cecilia Dalle Ore published a study in which she found that the presence of treatment effect in specimens generated from surgery for recurrent glioblastoma did not aversely impact patient prognosis.
  2. HHMI fellow Jonathan Rick published a study in which he found that 25% of the pituitary tumors in acromegalic patients stain for prolactin in addition to growth hormone and that these dual staining hormones had more aggressive clinical presentations and postoperative outcomes than acromegalics whose tumors just stained for growth hormone.
  3. HHMI fellow Ankush Chandra published a study in which he defined the worse outcomes that glioblastoma patients with limited insurance or no primary care physician are confronted with.
  4. UCSF medical student Fara Dayani and UCSF neurosurgery resident Jake Young published a study in which they found that patients with bilateral "butterfly" glioblastomas experience a prognostic benefit with surgical resection with a minimum extent of resection of 86% needed to observe survival benefits. 
For More Information
For more information about research in the Aghi Lab or how to support our efforts, visit our website at To schedule a tour, please contact Anders Yang 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 or call 1-888-804-4722.
Copyright © 2018 Aghi Lab, All rights reserved.

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