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Wednesday, March 20th, 2019

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    12:00a
    How tumors behave on acid

    Scientists have long known that tumors have many pockets of high acidity, usually found deep within the tumor where little oxygen is available. However, a new study from MIT researchers has found that tumor surfaces are also highly acidic, and that this acidity helps tumors to become more invasive and metastatic.

    The study found that the acidic environment helps tumor cells to produce proteins that make them more aggressive. The researchers also showed that they could reverse this process in mice by making the tumor environment less acidic.

    “Our findings reinforce the view that tumor acidification is an important driver of aggressive tumor phenotypes, and it indicates that methods that target this acidity could be of value therapeutically,” says Frank Gertler, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.

    Former MIT postdoc Nazanin Rohani is the lead author of the study, which appears in the journal Cancer Research.

    Mapping acidity

    Scientists usually attribute a tumor’s high acidity to the lack of oxygen, or hypoxia, that often occurs in tumors because they don’t have an adequate blood supply. However, until now, it has been difficult to precisely map tumor acidity and determine whether it overlaps with hypoxic regions.

    In this study, the MIT team used a probe called pH (Low) Insertion Peptide (pHLIP), originally developed by researchers at the University of Rhode Island, to map the acidic regions of breast tumors in mice. This peptide is floppy at normal pH but becomes more stable at low, acidic pH. When this happens, the peptide can insert itself into cell membranes. This allows the researchers to determine which cells have been exposed to acidic conditions, by identifying cells that have been tagged with the peptide.

    To their surprise, the researchers found that not only were cells in the oxygen-deprived interior of the tumor acidic, there were also acidic regions at the boundary of the tumor and the structural tissue that surrounds it, known as the stroma.

    “There was a great deal of tumor tissue that did not have any hallmarks of hypoxia that was quite clearly exposed to acidosis,” Gertler says. “We started looking at that, and we realized hypoxia probably wouldn’t explain the majority of regions of the tumor that were acidic.”

    Further investigation revealed that many of the cells at the tumor surface had shifted to a type of cell metabolism known as aerobic glycolysis. This process generates lactic acid as a byproduct, which could account for the high acidity, Gertler says. The researchers also discovered that in these acidic regions, cells had turned on gene expression programs associated with invasion and metastasis. Nearly 3,000 genes showed pH-dependent changes in activity, and close to 300 displayed changes in how the genes are assembled, or spliced.

    “Tumor acidosis gives rise to the expression of molecules involved in cell invasion and migration. This reprogramming, which is an intracellular response to a drop in extracellular pH, gives the cancer cells the ability to survive under low-pH conditions and proliferate,” Rohani says.

    Those activated genes include Mena, which codes for a protein that normally plays a key role in embryonic development. Gertler’s lab had previously discovered that in some tumors, Mena is spliced differently, producing an alternative form of the protein known as MenaINV (invasive). This protein helps cells to migrate into blood vessels and spread though the body.

    Another key protein that undergoes alternative splicing in acidic conditions is CD44, which also helps tumor cells to become more aggressive and break through the extracellular tissues that normally surround them. This study marks the first time that acidity has been shown to trigger alternative splicing for these two genes.

    Reducing acidity

    The researchers then decided to study how these genes would respond to decreasing the acidity of the tumor microenvironment. To do that, they added sodium bicarbonate to the mice’s drinking water. This treatment reduced tumor acidity and shifted gene expression closer to the normal state. In other studies, sodium bicarbonate has also been shown to reduce metastasis in mouse models.

    Sodium bicarbonate would not be a feasible cancer treatment because it is not well-tolerated by humans, but other approaches that lower acidity could be worth exploring, Gertler says. The expression of new alternative splicing genes in response to the acidic microenvironment of the tumor helps cells survive, so this phenomenon could be exploited to reverse those programs and perturb tumor growth and potentially metastasis.

    “Other methods that would more focally target acidification could be of great value,” he says.

    The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the Howard Hughes Medical Institute, the National Institutes of Health, the KI Quinquennial Cancer Research Fellowship, and MIT’s Undergraduate Research Opportunities Program.

    Other authors of the paper include Liangliang Hao, a former MIT postdoc; Maria Alexis and Konstantin Krismer, MIT graduate students; Brian Joughin, a lead research modeler at the Koch Institute; Mira Moufarrej, a recent graduate of MIT; Anthony Soltis, a recent MIT PhD recipient; Douglas Lauffenburger, head of MIT’s Department of Biological Engineering; Michael Yaffe, a David H. Koch Professor of Science; Christopher Burge, an MIT professor of biology; and Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science.

    1:59p
    “Particle robot” works as a cluster of simple units

    Taking a cue from biological cells, researchers from MIT, Columbia University, and elsewhere have developed computationally simple robots that connect in large groups to move around, transport objects, and complete other tasks.

    This so-called “particle robotics” system — based on a project by MIT, Columbia Engineering, Cornell University, and Harvard University researchers — comprises many individual disc-shaped units, which the researchers call “particles.” The particles are loosely connected by magnets around their perimeters, and each unit can only do two things: expand and contract. (Each particle is about 6 inches in its contracted state and about 9 inches when expanded.) That motion, when carefully timed, allows the individual particles to push and pull one another in coordinated movement. On-board sensors enable the cluster to gravitate toward light sources.

    In a Nature paper published today, the researchers demonstrate a cluster of two dozen real robotic particles and a virtual simulation of up to 100,000 particles moving through obstacles toward a light bulb. They also show that a particle robot can transport objects placed in its midst.

    Particle robots can form into many configurations and fluidly navigate around obstacles and squeeze through tight gaps. Notably, none of the particles directly communicate with or rely on one another to function, so particles can be added or subtracted without any impact on the group. In their paper, the researchers show particle robotic systems can complete tasks even when many units malfunction.

    The paper represents a new way to think about robots, which are traditionally designed for one purpose, comprise many complex parts, and stop working when any part malfunctions. Robots made up of these simplistic components, the researchers say, could enable more scalable, flexible, and robust systems.

    “We have small robot cells that are not so capable as individuals but can accomplish a lot as a group,” says Daniela Rus, director of the Computer Science and Artificial Intelligence Laboratory (CSAIL) and the Andrew and Erna Viterbi Professor of Electrical Engineering and Computer Science. “The robot by itself is static, but when it connects with other robot particles, all of a sudden the robot collective can explore the world and control more complex actions. With these ‘universal cells,’ the robot particles can achieve different shapes, global transformation, global motion, global behavior, and, as we have shown in our experiments, follow gradients of light. This is very powerful.”

    Joining Rus on the paper are: first author Shuguang Li, a CSAIL postdoc; co-first author Richa Batra and corresponding author Hod Lipson, both of Columbia Engineering; David Brown, Hyun-Dong Chang, and Nikhil Ranganathan of Cornell; and Chuck Hoberman of Harvard.

    At MIT, Rus has been working on modular, connected robots for nearly 20 years, including an expanding and contracting cube robot that could connect to others to move around. But the square shape limited the robots’ group movement and configurations.

    In collaboration with Lipson’s lab, where Li was a postdoc until coming to MIT in 2014, the researchers went for disc-shaped mechanisms that can rotate around one another. They can also connect and disconnect from each other, and form into many configurations.

    Each unit of a particle robot has a cylindrical base, which houses a battery, a small motor, sensors that detect light intensity, a microcontroller, and a communication component that sends out and receives signals. Mounted on top is a children’s toy called a Hoberman Flight Ring — its inventor is one of the paper’s co-authors — which consists of small panels connected in a circular formation that can be pulled to expand and pushed back to contract. Two small magnets are installed in each panel.

    The trick was programming the robotic particles to expand and contract in an exact sequence to push and pull the whole group toward a destination light source. To do so, the researchers equipped each particle with an algorithm that analyzes broadcasted information about light intensity from every other particle, without the need for direct particle-to-particle communication.

    The sensors of a particle detect the intensity of light from a light source; the closer the particle is to the light source, the greater the intensity. Each particle constantly broadcasts a signal that shares its perceived intensity level with all other particles. Say a particle robotic system measures light intensity on a scale of levels 1 to 10: Particles closest to the light register a level 10 and those furthest will register level 1. The intensity level, in turn, corresponds to a specific time that the particle must expand. Particles experiencing the highest intensity — level 10 — expand first. As those particles contract, the next particles in order, level 9, then expand. That timed expanding and contracting motion happens at each subsequent level.

    “This creates a mechanical expansion-contraction wave, a coordinated pushing and dragging motion, that moves a big cluster toward or away from environmental stimuli,” Li says. The key component, Li adds, is the precise timing from a shared synchronized clock among the particles that enables movement as efficiently as possible: “If you mess up the synchronized clock, the system will work less efficiently.”

    In videos, the researchers demonstrate a particle robotic system comprising real particles moving and changing directions toward different light bulbs as they’re flicked on, and working its way through a gap between obstacles. In their paper, the researchers also show that simulated clusters of up to 10,000 particles maintain locomotion, at half their speed, even with up to 20 percent of units failed.

    “It’s a bit like the proverbial ‘gray goo,’” says Lipson, a professor of mechanical engineering at Columbia Engineering, referencing the science-fiction concept of a self-replicating robot that comprises billions of nanobots. “The key novelty here is that you have a new kind of robot that has no centralized control, no single point of failure, no fixed shape, and its components have no unique identity.”

    The next step, Lipson adds, is miniaturizing the components to make a robot composed of millions of microscopic particles.

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