Study calls out the genes that make cancer cells so hard to kill
Researchers from the University of Toronto published a new map of cancer cells' genetic defenses against treatment.
There's a great diversity among cancer cells, though many of them share one unfortunate trait: They're often quite adept at resisting the body's immune system. The immune system's T killer cells can theoretically take out cancer cells, and immunotherapies enhance existing T cells' potency. Still, cancer cells are often impervious to them, can mutate to evade them, and worst of all, can acquire "cancer resistance mutations" that cause the disease to worsen in response to T cells. This is especially true of the cells in solid tumors.
A study from researchers at University of Toronto catalogs the genes in cancer tumors that allow the disease to so effectively resist immunotherapy. Its authors hope that their findings will eventually lead to the development of more successful cancer treatments.
The study is published in the journal Nature.
A moving target
Credit: Marcelo Leal/Unsplash
Speaking to U of T News, lead author of the study molecular geneticist Jason Moffat of the university's Donnelly Centre for Cellular and Biomolecular Research says, "Over the last decade, different forms of immunotherapy have emerged as really potent cancer treatments, but the reality is that they only generate durable responses in a fraction of patients and not for all tumor types."
There can be a significant degree of heterogeneity between cancer cells from human to human, and even within the same person, making the development of therapies maddeningly difficult. Attempting to address potential cancer-cell vulnerabilities across these variations is a life-or-death game of whack-a-mole.
"It's an ongoing battle between the immune system and cancer, where the immune system is trying to find and kill the cancer whereas the cancer's job is to evade that killing," says Moffat.
Mapping the mechanisms
Illustration: genes (red, green, and blue spots within the nuclei of HeLa cells) artificially superimposed on images of multi-well plates.
Credit: National Cancer Institute/Unsplash
Moffat and his colleagues decided to investigate and identify genes within cancer cells that help them defeat treatment. Co-lead author Keith Lawson of Moffat's lab explains that "it's important to not just find genes that can regulate immune evasion in one model of cancer, but what you really want are to find those genes that you can manipulate in cancer cells across many models because those are going to make the best therapeutic targets."
To accomplish this, the researchers, working with scientists at Agios Pharmaceuticals in Cambridge, Massachusetts, first exposed cells from breast, colon, kidney and skin cancer tumors to T cells in lab dishes. This established a baseline of their responses to treatment. Next, using CRISPR, the scientists went through the cells, exhaustively turning off one gene at a time to determine its role in immunotherapy resistance by comparing the cells' response to the T cells compared to their original baseline response.
The team identified 182 "core cancer intrinsic immune evasion genes" that affected the cells' response to T cells. The fact that some of the identified genes were already known to be involved in resistance provided the researchers with some confidence that they were on the right track.
Still, many of the genes they ID'ed had not been previously implicated. "That was really exciting to see because it means that our dataset was very rich in new biological information," says Lawson.
Unfortunately, Moffat's research also makes clear that defeating cancer-cell resistance is not as simple as removing certain genes. It's true that when the team switched off some of the genes they'd identified, the cancer cells became more vulnerable to T cells, but on the other hand, removal of some other genes made the cancer cells more resistant.
There also appear to be relationships between multiple genes that complicate matters.
The team explored the manipulation of the genes that allow cancer cells to engage in autophagy, the process by which cells clear out no-longer useful materials to facilitate speedy recovery from damage. Surprisingly, when the researchers deleted certain genes responsible for cancer cells' autophagy, they found the cells' resistance to T cells increased. Apparently, removing one autophagy gene strengthened another mutated autophagy gene.
"We found this complete inversion of gene dependency," said Moffat. "We did not anticipate this at all. What it shows us is that genetic context — what mutations are present — very much dictates whether the introduction of the second mutation will cause no effect, resistance or sensitivity to therapy."
There remains a long road ahead when it comes to unraveling cancer cells' resistance to immunotherapy. However, this new study presents a new map that can help scientists navigate what comes next.
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Northwell Health CEO Michael Dowling has an important favor to ask of the American people.
- Michael Dowling is president and CEO of Northwell Health, the largest health care system in New York state. In this PSA, speaking as someone whose company has seen more COVID-19 patients than any other in the country, Dowling implores Americans to wear masks—not only for their own health, but for the health of those around them.
- The CDC reports that there have been close to 7.9 million cases of coronavirus reported in the United States since January. Around 216,000 people have died from the virus so far with hundreds more added to the tally every day. Several labs around the world are working on solutions, but there is currently no vaccine for COVID-19.
- The most basic thing that everyone can do to help slow the spread is to practice social distancing, wash your hands, and to wear a mask. The CDC recommends that everyone ages two and up wear a mask that is two or more layers of material and that covers the nose, mouth, and chin. Gaiters and face shields have been shown to be less effective at blocking droplets. Homemade face coverings are acceptable, but wearers should make sure they are constructed out of the proper materials and that they are washed between uses. Wearing a mask is the most important thing you can do to save lives in your community.
Two massive clouds of dust in orbit around the Earth have been discussed for years and finally proven to exist.
- Hungarian astronomers have proven the existence of two "pseudo-satellites" in orbit around the earth.
- These dust clouds were first discovered in the sixties, but are so difficult to spot that scientists have debated their existence since then.
- The findings may be used to decide where to put satellites in the future and will have to be considered when interplanetary space missions are undertaken.
What are they?<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xODgyMDA0NC9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYzNTM1ODc0Mn0.NH33LuauIo__sUBi4tvhwxDcsvhflDFD-Nhx9FjlSNk/img.jpg?width=1245&coordinates=148%2C0%2C149%2C0&height=700" id="cec96" class="rm-shortcode" data-rm-shortcode-id="acb78abe2ab46a17e419ad30906751d6" data-rm-shortcode-name="rebelmouse-image" />
Artist's impression of the Kordylewski cloud in the night sky (with its brightness greatly enhanced) at the time of the observations.
G. Horváth<p>The<a href="https://en.wikipedia.org/wiki/Kordylewski_cloud" target="_blank"> Kordylewski clouds</a> are two dust clouds first observed by Polish astronomer Kazimierz Kordylewski in 1961. They are situated at two of the <a href="https://www.space.com/30302-lagrange-points.html" target="_blank">Lagrange points</a> in Earth's orbit. These points are locations where the gravity of two objects, such as the Earth and the Moon or a planet and the Sun, equals the centripetal required to orbit the objects while staying in the same relative position. There are five of these spots between the Earth and Moon. The clouds rest at what are called points four and five, forming a triangle with the clouds and the Earth at the three corners.</p><p>The clouds are enormous, taking up the same space in the night sky as twenty lunar discs; covering an area of 45,000 miles. They are roughly 250,000 miles away, about the same distance from us as the Moon. They are entirely comprised of specks of dust which reflect the light of the sun so faintly most astronomers that looked for them were unable to see them at all. </p><p>The clouds themselves are probably ancient, but the model that the scientists created to learn about them suggests that the individual dust particles that comprise them can be blown away by solar wind and replaced by the dust from other cosmic sources like comet tails. This means that the clouds hardly move but are <a href="https://www.nationalgeographic.com/science/2018/11/news-earth-moon-dust-clouds-satellites-planets-space/" target="_blank">eternally changing</a>. </p>
How did they discover this?<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xODgyMDAzNi9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY1Nzc4MjQ4MX0.7uU9OqmQcWw5Ll1UXAav0PCu4nTg-GdJdAWADHanC7c/img.jpg?width=1245&coordinates=0%2C180%2C0%2C181&height=700" id="952fb" class="rm-shortcode" data-rm-shortcode-id="a778280a20f1c54cd2c14c8313224be2" data-rm-shortcode-name="rebelmouse-image" />
"In this picture the central region of the Kordylewski dust cloud is visible (bright red pixels). The straight tilted lines are traces of satellites."
J. Slíz-Balogh<p>In their study published in the <a href="https://academic.oup.com/mnras" target="_blank">Monthly Notices of the Royal Astronomical Society</a>, Hungarian astronomers Judit Slíz-Balogh, András Barta, and Gábor Horváth described how they were able to find the dust clouds using polarized lenses.</p><p>Since the clouds were expected to polarize the light that bounces off of them, by configuring the telescopes to look for this kind of light the clouds were much easier to spot. What the scientists observed, polarized light in patterns that extended outside the view of the telescope lens, was in line with the predictions of their mathematical model and ruled out other possible sources. </p>
Why are we just learning this now?<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8xODgyMDAzOS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY2MjUyNDMyMH0.Zl8GmQ_rJHiL4b7hN0r_YBmgb6_ZqIRvqOVuko2ubpw/img.jpg?width=1245&coordinates=0%2C141%2C0%2C185&height=700" id="87afe" class="rm-shortcode" data-rm-shortcode-id="dd4c0b5088e601d7279cc5eb226f8b7b" data-rm-shortcode-name="rebelmouse-image" />
"Mosaic pattern of the angle of polarization around the L5 point (white dot) of the Earth-Moon system. The five rectangular windows correspond to the imaging telescope with which the patterns of the Kordylewski cloud were measured."
J. Slíz-Balogh<p>The objects, being dust clouds, are very faint and hard to see. While Kordylewski observed them in 1961, other astronomers have looked there and given mixed reports over the following decades. This discouraged many astronomers from joining the search, as study co-author Judit Slíz-Balogh <a href="https://ras.ac.uk/news-and-press/research-highlights/earths-dust-cloud-satellites-confirmed" target="_blank">explained</a>, <em>"The Kordylewski clouds are two of the toughest objects to find, and though they are as close to Earth as the Moon are largely overlooked by researchers in astronomy. It is intriguing to confirm that our planet has dusty pseudo-satellites in orbit alongside our lunar neighbor."</em></p>
Will this have any impact on space travel?<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="c3d797fff5430c64afcb5a49bddc3616"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/Ou8N3v9SFPE?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span><p>Lagrange points have been put forward as excellent locations for a space station or satellites like the <a href="https://jwst.nasa.gov/about.html" target="_blank">James Webb Telescope</a> to be put into orbit, as they would require little fuel to stay in place. Knowing about a massive dust cloud that could damage sensitive equipment already being there could save money and lives in the future. While we only know about the clouds at Lagrange points four and five right now, the study's authors suggest there could be more at the other points.</p><p>While the discovery of a couple of dust clouds might not seem all that impressive, it is the result of a half-century of astronomical and mathematical work and reminds us that wonders are still hidden in our cosmic backyard. While you might never need to worry about these clouds again, there is nothing wrong with looking at the sky with wonder at the strange and fantastic things we can discover. </p>
New cancer-scanning technology reveals a previously unknown detail of human anatomy.
- Scientists using new scanning technology and hunting for prostate tumors get a surprise.
- Behind the nasopharynx is a set of salivary glands that no one knew about.
- Finding the glands may allow for more complication-free radiation therapies.
PSMA PET/CT technology<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="676e611b970c9b516cace0870447b325"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/RHAyoQF09X4?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span><p>PSMA PET/CT is a new combination of <a href="https://www.mayoclinic.org/tests-procedures/pet-scan/about/pac-20385078" target="_blank">PET scans</a> and <a href="https://www.mayoclinic.org/tests-procedures/ct-scan/about/pac-20393675" target="_blank">CT scans</a> that is believed to offer a more reliable means of locating prostate cancer metastasis. A <a href="https://www.cancer.gov/news-events/cancer-currents-blog/2020/prostate-cancer-psma-pet-ct-metastasis" target="_blank" rel="noopener noreferrer">study</a> published last spring suggests it may be the most accurate way to diagnose prostate cancer metastasis than any method previously available.</p><p>Prior to PSMA PET/CT, the primary way to look for metastatic prostate cancer was to image the body using x-ray-based CT scans and to perform bone scans, since bone is where prostate cancer often spreads. CT scans, however, often miss small tumors, and bone scans can generate false positives as a result of other damage or abnormalities that have nothing to do with prostate cancer.</p><p>PSMA PET/CT scans track the travels of an intravenously administered radioactive glucose tracer throughout the body. For hunting down prostate cancer, this tracer contains a molecule that binds to the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472940/" target="_blank">PSMA</a> protein that's present in large amounts in prostate tumors. The molecule is linked to a radioisotope, <a href="https://netrf.org/2018/11/13/gallium-68-scan-for-neuroendocrine-tumors/" target="_blank" rel="noopener noreferrer">gallium-68</a> (Ga-68).</p><p>In last spring's research, PSAM PET/CT was shown to be 27 percent more accurate than previous methods at finding metastases (92 percent accuracy as opposed to 65 percent). In addition, it was found to be much less likely to produce false positives, and it was particularly good at detecting tumors far removed from the prostate.</p>
A good kind of avoidance behavior<p>"Radiation therapy can damage the salivary glands," says Vogel, "which may lead to complications. Patients may have trouble eating, swallowing, or speaking, which can be a real burden."</p><p>The researchers looked back through the cases of 723 patients who had undergone radiation treatment, interested in seeing if inadvertent radiation of the tubarial glands was associated with the complications experienced by the patients. It turned out that this <em>was</em> the case: In cases where more radiation had been delivered to this area, patients did indeed report more in the way of complications of the type one would expect when salivary glands are radiated.</p><p>Now that we know the tubarial salivary glands exist, therapists can stay out of their way. Vogel says, "For most patients, it should technically be possible to avoid delivering radiation to this newly discovered location of the salivary gland system in the same way we try to spare known glands."</p><p>He's hopeful that that things may be about to get at least a bit better for cancer patients: "Our next step is to find out how we can best spare these new glands and in which patients. If we can do this, patients may experience less side effects which will benefit their overall quality of life after treatment."</p>
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