What Autism can Teach us about Brain Cancer
Glioblastoma multiforme, or GBM, is a deadly cancer with median survival of only 12-15 months. Recently, we found a gene that had been previously implicated in autism to also contribute to GBM. The gene NHE9 makes a protein that exchanges sodium ions for hydrogen ions (also called protons) across the boundaries of endosomes, hence it’s moniker “sodium-hydrogen exchanger”. But what are endosomes and why is the function of NHE9 important?
Highway Traffic: All cells contain many “cargo packages” surrounded by membranes, depicted in the expanded view as a blue compartment in the figure below. These so-called endosomes carry newly minted proteins to specific destinations throughout the cell and haul away old proteins for destruction. Key to their “shipping speed” is the level of acidity inside the endosomes. Acidity relates to the number of protons, which are controlled by balancing the activity of “pumps” that push protons into endosomes to increase their acidity with that of “leaks,” like the protein NHE9, that remove protons.
There’s a Hole in the Bucket: You can think of endosomes as leaky buckets of water. Altering either the faucet or the leak rate can dramatically change the water level in the bucket. In autism, NHE9 is mutated and non-functional. In the absence of proton leak, the endosomes become too acidic and prematurely clear away important proteins on nerve ends, leading to neurological dysfunction. Helper cells called astrocytes cannot clear away neurotransmitter signals fast enough, and this leads to hyperexcitability or seizures associated with autism.
Too Much of a Good Thing: in contrast to autism, NHE9 is overactive in brain cancer, causing endosomes to leak too many protons and become too alkaline. This slows down the “shipping rate” of cancer-promoting cargo and leaves them on the cell surface for too long where they inappropriately prolong signals of growth and migration, the two main characteristics of invasive cancer cells. Fortunately, when the leak is plugged by inhibiting NHE9 with drugs, tumor growth is blocked. Currently, the drugs are not good enough to use on patients, so an important step going forward will be to discover better drugs that target NHE9. These could be used in combination with other drugs for treatment of this deadly disease.
Paper: A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma. Kondapalli et al. (2015) Nature Communications http://goo.gl/dAa5NG
Johns Hopkins News Story: http://goo.gl/XAsGDb
A Part of the Puzzle: NHE9 and Autism https://plus.google.com/u/0/+RajiniRao/posts/fsNzo1yKsQG
Congratulations on the Nature Com pub. Coincidentally we started working on patient derived xenografts of GBMs. One of them had me stumped because it apparently created only microblood vessels around the tumor instead the usual mixture of large and small vessels.
You should talk to Marty and Ben to see if the NHE9 defect confers a difference in uptake of a radioisotope, like I-125 or Ga-67. You might be able to get an in vivo signature of the defect. (thinking out loud).
Chad Haney thanks. This was the culmination of about 3 years of work from two labs. It was awesome to work with Dr. Q, the neurosurgeon, who gave us access to patient tumor samples. The Kaplan Meier plots of patient survival are quite striking: tumors with high NHE9 are essentially resistant to radiation and chemotherapy and the prognosis is grim. What an interesting idea on the isotope uptake! It’s quite possible that endosome-mediated uptake of radio-markers will be different based on lumen acidity. Thanks for the suggestion, is it testable in murine models? (We have access to SAARP equipment if that helps).
Rajini Rao should be testable in murine models. That’s what we do. I can find out about NDA and sharing policy of the PDX based GBMs.
Chad Haney ok, great. I know Marty of course, but is it Ben Tsui you mentioned? The other Ben I know works on breast cancer.
Yes, Ben Tsui graduated from UChicago and works with Marty. They would be able to do in vivo imaging of radioisotope uptake.
Thanks, Peter Lindelauf , Not yet, but I’m going out now just so I can report back to you 😀
Thank you so much for breaking it down, making it simple. 🙂
Rashmi Pahuja some of the imagery came from a science writer at my institution. I worked with her to try to get the concepts scientifically correct, so that we were both happy with the end product. I’m glad that you found it readable 🙂
Peter Lindelauf there is not yet one flower in bloom. I’m going to have to move to Canada! By the way, I was in Seattle recently and spring was beautiful there..so not surprised that you are already in the garden.
Yeah, because Peter Lindelauf keeps sending the cold weather south and east.
I guess it’s fair, Peter Lindelauf, since the American teams keep winning the Stanley Cup.
This is amazing scientific progress.
Fantastic post Rajini Rao ~ Congratulations on the publication of your study! So nice you have time to post again 😉
Thanks so much, Mara Rose ! I see that spring is in full swing in the NW. I’m getting vicarious pleasures seeing your pix and anticipating our turn. I’m glad to be back on G+, shouldn’t have stayed away.
I hope your turn comes soon Rajini Rao ~ you deserve it! I think we are a month earlier than usual.
Great explanation, as always. Rajini Rao Re: your prior comment, More scientists should hire science writers and work in tandem, partners. There’s never been a greater time to snap up a quality journalist (and be in awe of what they can do). (Nasw.org to start )
Lorri Hopping thanks. The professional science writing team is part of the university so no additional expense to us! When they hear of a newsworthy result, they “interview” us in our offices and labs, then put together a draft that we can edit together. I really should take advantage of their service more often!
Really interesting find here. There wouldn’t happen to be a list somewhere on which call sites on this gene are associated with autism?
Eric Shaw thanks! If by call sites you mean gene variants, yes, there is a list of NHE9 variants linked to autism in the Science paper by Morrow et al. http://www.ncbi.nlm.nih.gov/pubmed/18621663
The variants are in a supplemental table.
We subsequently evaluated some of these and found that they inactivated the function of NHE9. See our Nat. Comm. paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815575/
Both are free on PubMedCentral. Let me know if you have any questions.
Rajini Rao Not that I understand that language but it sounds very factual and I am very impressed.
Gabriele Muellenberg I’m here on G+ to answer questions or explain further, please feel free to ask about any of my posts! For example, gene variants are another name for mutations. They could be harmless (and just part of the variations between people) or be causal to some function of the protein.
Some searching told me SLC9A9 is the NHE9 gene, so I searched for this on my 23andme profile. My son is a nonverbal autistic, and I’m pretty sure I have Aspergers. I noticed a lot of variation in this gene between the profiles that are shared, with my profile and the Gregor Mendel profile that is shared with everybody being the different ones very often. (We never were able to get my son to spit for his sample).
Eric Shaw you bring up the tricky part about autism, that members of the same family, even siblings, can present all across the spectrum. I think NHE9/SLC9A9 is a risk factor and the more hits a pathway gets, the stronger the neural effects. In the near future, we’re going to be able to reverse check variants in any particular gene back to the electronic medical records in databases of 100-200K patients (stripped of identity, so we don’t know who they are!) to make better correlations.
There is a closely related protein that we also study, called NHE6/SLC9A6. This one is on the X-chromosome, so mutations are just awful on boys, who don’t have a second copy. Very severe symptoms, syndromic autism.
Tagging: Lynda Lencaster
Wow that is interesting how perturbing the exo/endocytic pathway can be an intriguing clinical target.
Tau-Mu Yi thanks- and membrane proteins are quite “druggable” targets too, so we’re hoping to move this project forward.
Thanks rajni roi ji
I’m not smart to understand all words , but very interesting and knowledge too.
Thanks for sharing the valuable article Rajini Rao ji..
Hello can u tell me how to work with autism children