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.

DNA strand and cancer cell 3D rendering
Credit: CI Photos/Shutterstock
  • Developing immunotherapies for cancers is made more difficult by how different tumors are from each other.
  • Some cancers are actually made worse by immunotherapy.
  • A piece falls into place on the complicated puzzle of genetic interactions of cancer cells.

    • 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

      IV drip

      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.

      It's complicated

      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.


      What does kindness look like? It wears a mask.

      Northwell Health CEO Michael Dowling has an important favor to ask of the American people.

      Sponsored by Northwell Health
      • 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.
      Keep reading Show less

      Science confirms: Earth has more than one 'moon'

      Two massive clouds of dust in orbit around the Earth have been discussed for years and finally proven to exist.

      J. Sliz-Balogh, A. Barta and G. Horvath
      Surprising Science
      • 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.
      Keep reading Show less

      Scientists stumble across new organs in the human head

      New cancer-scanning technology reveals a previously unknown detail of human anatomy.

      Credit: Valstar et al., Netherlands Cancer Institute
      Surprising Science
      • 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.
      Keep reading Show less

      Millennials reconsidering finances and future under COVID-19

      A new survey found that 27 percent of millennials are saving more money due to the pandemic, but most can't stay within their budgets.

      Personal Growth
    • Millennials have been labeled the "unluckiest generation in U.S. history" after the one-two financial punch of the Great Recession and the pandemic shutdowns.
    • A recent survey found that about a third of millennials felt financially unprepared for the pandemic and have begun saving.
    • To achieve financial freedom, millennials will need to take control of their finances and reinterpret their relationship with the economy.
    • Keep reading Show less
      Personal Growth

      6 easy ways to transition to a plant-based diet

      Your health and the health of the planet are not indistinguishable.

      Scroll down to load more…
      Quantcast