Nav: Home

Study finds macrophages' pathway to nurture PTEN-deficient glioblastoma

June 10, 2019

HOUSTON -- A common genetic deficiency empowers glioblastoma to broadcast a molecular message to the wrong type of immune cell, summoning macrophages that protect and nurture the brain tumor instead of attacking it, researchers at The University of Texas MD Anderson Cancer Center report in Cancer Cell.

The team's work in mouse models of glioblastoma that lack functional cancer-suppressor gene PTEN points to new potential targets for treating the most common and lethal brain tumor, said senior author Ronald DePinho, M.D., professor of Cancer Biology and past president of MD Anderson.

About a third of all glioblastomas are PTEN-deficient. Median survival for glioblastoma is about 12 to 15 months, and only 5 percent of patients survive for five years.

"We've identified a symbiotic circuit that is activated in PTEN-deficient glioblastoma which creates a mutually supportive relationship between the cancer cell and macrophages that come into the tumor microenvironment and provide growth factor support for the tumor," DePinho said.

Macrophages engulf and digest microbes, cellular debris and tumor cells as part of an immune response, and they secrete cytokines that affect other cells. They are bipolar. In their M1 form, they actively assist immune response and inhibit tumor growth. In M2, they are in repair mode, helping post-immune recovery, which can also promote cancer growth and progression.

Up to half the live cells found in glioblastoma are macrophages. They are major components forming the tumor microenvironment, the researchers note.

First author Peiwen Chen, Ph.D., postdoctoral fellow in Cancer Biology, DePinho and colleagues set out to find common mutations in glioblastoma associated with immune changes in the tumor microenvironment.

They not only defined the pathway that brings macrophages into glioblastoma, but also pinpointed a growth factor secreted by the macrophages that in turn protects cancer cells from programmed cell death and fuels the growth of new blood vessels.

"We first found that only PTEN-deficiency, but not other common genetic alterations, is associated with macrophage infiltration in glioblastoma," Chen said.

In a series of experiments, in PTEN knockout cell lines and later in mouse models of glioblastoma, they showed:
  • With PTEN down, a gene called YAP1 is activated, a transcription factor that increases expression of LOX, a novel potent attractor of macrophages;
  • LOX connects to the β1 integrin-PYK2 pathway on macrophages, spurring their migration into the tumor microenvironment;
  • Macrophages directly aid glioma cells by secreting the growth factor SPP1, which the team showed increases cancer cell survival and blood vessel formation to protect the tumors.
Thwarting LOX shrinks tumors, blocks macrophage infiltration

The team developed human xenograft mouse models of glioblastoma that had high expression of LOX, YAP1, and macrophage markers. Depleting LOX in these models using either shRNA, the small-molecule LOX inhibitor BAPN or an anti-LOX antibody impaired tumor growth and significantly reduced macrophage infiltration.

LOX inhibition in four PTEN-deficient glioblastoma mouse models extended survival in all models.

Blocking LOX had no impact on glioma cell proliferation but did increase cancer cell programmed cell death and decrease the formation of tumor-supporting blood vessels.

As a first check on the possible impact of their findings on humans, the team performed unsupervised clustering of an established macrophage signature in 489 human glioblastoma samples from The Cancer Genome Atlas.

By clustering cases by macrophage-high (201), macrophage-medium (153) and macrophage-low (135) groups, as well as analyzing tumor-associated macrophages compared to blood-derived monocytes from glioblastoma mouse models and patients, they identified eight genes correlated with macrophage infiltration in patients. Among the eight, SPP1 was the gene with the greatest increase in expression.

The macrophage-high group had more frequent PTEN mutations or deletions, higher YAP1 and LOX expression and poorer survival than patients in the macrophage-low cluster.

LOX, SPP1 are new targets for PTEN-deficient glioblastoma

The most targetable components in the pathway are LOX and SPP1, DePinho said, with drugs under development to hit both genes.

"The results in mice are compelling enough and the correlative studies in human glioblastoma provide additional confidence to motivate the testing of this approach in a clinical setting of recurrent glioblastoma patients," DePinho said.

It would be important to enlist only those with PTEN-deficient tumors, he said, because their research shows LOX inhibition does not work in tumors with wild-type PTEN.
Co-authors with Chen and DePinho are Di Zhao, Ph.D., Xin Liang, M.D., Jiexi Li, Andrew Chang, M.D., Zhengdao Lan, M.D., Ph.D., Denise Spring, Ph.D., and Alan Wang, Ph.D., of Cancer Biology; Jun Li, Ph.D., of Genomic Medicine; and Verlene Henry and Ganesh Rao, M.D., of Neurosurgery. Jiexi Li is a graduate student in the MD Anderson/UTHealth Graduate School of Biomedical Sciences.

DePinho holds the Harry Graves Burkhart III Distinguished University Chair in Cancer Biology.

This research was supported by the Cancer Research Institute Irvington Postdoctoral Fellowship, the Caroline Ross Endowed Fellowship, The Harold C. and Mary L. Daily Endowment Fellowship, the Burkhart III Distinguished University Chair in Cancer Research Endowment, Clayton & Modesta Williams Cancer Research Fund, the Emerson Collective Award, and grants from the National Cancer Institute of the National Institutes of Health, (P01 CA117969 14, R01 CA084628, R01 CA231349, K99 CA226360, R01 NS094615) including MD Anderson's Cancer Center Support Grant from the NCI (P30CA16672).

University of Texas M. D. Anderson Cancer Center

Related Immune Response Articles:

How to boost immune response to vaccines in older people
Identifying interventions that improve vaccine efficacy in older persons is vital to deliver healthy ageing for an ageing population.
Unveiling how lymph nodes regulate immune response
The Hippo pathway keeps lymph nodes' development healthy. If impaired, lymph nodes become full of fat cells or fibrosis develops.
Early immune response may improve cancer immunotherapies
Researchers report a new mechanism for detecting foreign material during early immune responses.
Researchers decode the immune response to Ebola vaccine
The vaccine rVSV-EBOV is currently used in the fight against Ebola virus.
Immune response depends on mathematics of narrow escapes
The way immune cells pick friends from foes can be described by a classic maths puzzle known as the 'narrow escape problem'.
Signature of an ineffective immune response to cancer revealed
Our immune system is programmed to destroy cancer cells. Sometimes it has trouble slowing disease progression because it doesn't act quickly or strongly enough.
Putting the break on our immune system's response
Researchers have discovered how a tiny molecule known as miR-132 acts as a 'handbrake' on our immune system -- helping us fight infection.
Having stressed out ancestors improves immune response to stress
Having ancestors who were frequently exposed to stressors can improve one's own immune response to stressors, according to Penn State researchers.
Researchers discovered new immune response regulators
The research groups of Academy Professor Riitta Lahesmaa and Research Director Laura Elo from Turku Centre for Biotechnology have discovered new proteins that regulate T cells in the human immune system.
Blueprint for plant immune response found
Washington State University researchers have discovered the way plants respond to disease-causing organisms, and how they protect themselves, leading the way to potential breakthroughs in breeding resistance to diseases or pests.
More Immune Response News and Immune Response Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

One of the most consistent questions we get at the show is from parents who want to know which episodes are kid-friendly and which aren't. So today, we're releasing a separate feed, Radiolab for Kids. To kick it off, we're rerunning an all-time favorite episode: Space. In the 60's, space exploration was an American obsession. This hour, we chart the path from romance to increasing cynicism. We begin with Ann Druyan, widow of Carl Sagan, with a story about the Voyager expedition, true love, and a golden record that travels through space. And astrophysicist Neil de Grasse Tyson explains the Coepernican Principle, and just how insignificant we are. Support Radiolab today at