Our winter edition of From the Bench, our quarterly blog series showcasing creative basic science approaches to study cancer, is chock full of inspiring new advances to keep you warm until spring. This installment includes muffin tin-like molds to grow organoids with various shapes, an artificial intelligence (AI) model akin to “ChatGPT for genomes,” a yeast pill for oral immunotherapy, a mix-and-match platform for immune cell engagers, and urine-powered nanomotors to treat bladder cancer.
Organoids Get Into Shape
Getting into shape is a common New Year’s resolution, but it may be a useful goal for tumor models, too. In an article published in Advanced Materials, researchers explained that the spherical shape typical of organoid models is not always consistent with the morphology of tumors in the body and therefore may not accurately capture the various aspects of tumor biology, so developing models that better reflect tumor morphology is critical.
To this end, the researchers developed Recoverable-Spheroid-on-a-Chip with Unrestricted External Shape (ReSCUE), a platform that allowed them to create uniformly sized organoids with different shapes. The process relies on a microwell mold containing differently shaped wells—disk-, rod-, oval-, U-, and I-shaped. Cells are seeded in each well, and as they proliferate, they fill the well to form its respective shape. The resulting organoids can then be released from the mold and grown separately while mostly maintaining their shape.
The authors propose that the differently shaped organoids developed with the ReSCUE platform could be used to better understand cancer invasion, treatment response, and cell repopulation and reorganization after tumor clearance, among other applications.
Artificial Intelligence to Unravel the Biochemistry of Life Itself
Despite their progress in understanding human language, artificial intelligence (AI) models have not been as successful yet when it comes to comprehending the complex genomic and molecular libraries of living organisms. Nor can they accurately interpret the biological consequences of changes in these flows of information, all aspects of which influence—and are influenced by—the evolution of lifeforms.
Enter Evo, a new AI model with the potential to help uncover important insights into the nanoscale interactions involving DNA, RNA, and proteins.
In a recent study published in Science, researchers unveiled the capabilities of Evo, which was trained on data from 2.7 million different genomes. With this information, Evo can predict how small changes in a gene’s sequence, and the consequent alterations in protein structure, might impact the biology and overall health of an organism. The technology also demonstrated the ability to design novel CRISPR constructs, as well as genetic elements known as transposons that can “jump” around in a cell’s genome and induce a variety of changes.
Combined with other advances in synthetic biology and genome engineering, Evo’s ability to grasp the complex physical interactions underpinning biology—and design ways to manipulate it—could soon enable momentous strides in our understanding of life itself, the study authors note, and ultimately pave the way for previously unimaginable strategies against diseases like cancer.
Rising to the Challenge: Using Yeast to Crush Colorectal Cancer
The past decade has revealed the beneficial effects of certain types of probiotic microscopic organisms, especially bacteria, on the health of our gut. By boosting our immune system, they can even improve the effectiveness of cancer immunotherapy. But did you know that some fungi also have beneficial health effects, and can be engineered to deliver medicine directly to tumors?
A recently published study in Cell Chemical Biology highlighted the potential of a strain of fungal yeast known as Saccharomyces cerevisiae var. boulardii (Sb), which naturally possesses anticancer activity. Taking things a step further, the researchers modified the yeast to produce miniature versions of immune checkpoint inhibitors (ICIs) targeting the PD-1 pathway, which can improve the immune system’s ability to recognize and destroy cancer cells. Remarkably, when mice with a form of colorectal cancer that is resistant to traditional ICIs were fed these modified yeast, their tumors shrunk significantly. Unsurprisingly, these antitumor effects coincided with dramatic changes in the types of bacteria and immune cells in the intestinal tracts of the mice, most notably a reduction in the amount of regulatory T cells, which can suppress immune responses against cancer. No such changes were witnessed in mice treated with traditional ICIs.
Another potential advantage of this approach is that the therapy can be given orally, compared to currently approved ICIs that are either injected into the skin or the bloodstream. This enables the modified yeast and the ICIs they produce to reach cancers of the gastrointestinal tract directly, potentially limiting toxicities in other tissues. Furthermore, the highly adaptable and customizable nature of this platform, in which yeast can be engineered to express a variety of molecules with cancer-targeting or immune-modulating properties, allows for diverse new drug delivery opportunities targeting gastrointestinal cancers.
Mr. Potato TAC: An Interchangeable Triple Threat for Tumors
Bispecific engager molecules are a type of immunotherapy that bind to one protein on tumor cells and another protein on T cells, bringing the two together so the T cells can fight the cancer. While bispecific engagers have proven effective in several cancer types, with nine such drugs approved for cancer indications by the U.S. Food and Drug Administration (FDA), some researchers have hypothesized that engaging additional subsets of immune cells could further boost the efficacy of such molecules.
In a recent study in Cell, researchers designed a series of molecules they called multimodal targeting chimeras (multi-TACs) capable of binding to three different ligands. Anchored by a triple orthogonal linker (T-linker), the multi-TAC platform allows for the swapping of different targeting molecules at any of the linker sites. The researchers successfully produced multi-TACs with various combinations of T-cell engagers, natural killer cell engagers, dendritic cell engagers, and peptides, small molecules, or nucleotides that boost immune cell activity.
As a proof of concept, they designed a multi-TAC targeting EGFR (expressed on many cancer cells), CD3 (expressed on T cells), and PD-L1 (expressed on dendritic cells). In a coculture model consisting of lung cancer cells, T cells, and dendritic cells, the multi-TAC exhibited 39-fold better cell killing than bispecific antibodies. It also elicited robust responses in humanized mouse models and patient-derived cancer cells, with promising evidence of strong immune activation. The authors suggested that the modular nature of their system could allow for testing a wide variety of trispecific targeting methods.
Urine-powered nanoMotors to Drill Into Bladder Tumors
Immunotherapeutics instilled directly into the bladder have shown promising efficacy for the treatment of certain types of bladder cancer, including non-muscle invasive bladder cancer (NMIBC). Recently, groups have experimented with treating NMIBC using nanoparticles containing agonists of the immune activator STING. However, a significant proportion of these nanoparticles do not reach the tumor because they leave the bladder during urination and because the bladder’s mucus layer inhibits effective penetration.
In a study published in Nature Communications, researchers designed biodegradable nanomotors that swarm toward the bladder wall in the presence of urea, a component of urine. Chitosan, which has the ability to bind to and penetrate the bladder’s mucus layer, was included as a component of the nanomotor chassis, and the nanomotors were designed to encapsulate a STING agonist. The researchers showed that the nanomotors distributed themselves evenly throughout mouse bladders in the presence of urea and were retained in bladder cells even after multiple urinations. The nanomotors decreased bladder cancer growth in mice better than Bacillus Calmette-Guérin (BCG), the current standard of care for NMIBC, and stimulated the recruitment of T cells to the tumor.
In January 2023, a study in Nature Nanotechnology described a similar urease-powered nanomotor approach to deliver radioactive iodine to bladder tumors. Taken together, these studies represent a potential way to make urine work for patients instead of against them during bladder cancer treatment.
