Supervillain Cells: Functionally Resistant Cells Lead to Disease Progression
In our previous post we discussed “superhero” cells and their ability to create an anti-tumor response due to high functionality. While in the previous two cases the superpowered cells exhibited beneficial functions, that is not always the case. Here, we discuss cells that have high functionality and are performing many functions which are contributing to something adverse to the patient, such as resistance, suppression, or immune-related adverse events like cytokine release syndrome. These are considered supervillain cells and can lead to disease progression. Dr. Rong Fan of Yale University said that “polyfunctional cells are the subsets with ’superpowers.’” In various published studies, polyfunctional cells have correlated to increased anti-tumor response, immune persistence, etc. As discussed above, these superpowered cells can either have a positive or negative effect on the immune system, depending on their function.
Dr. Rong Fan expanded this concept: “If you want to develop a therapy with immune cells, you want to have highly functional cells. They are like ‘superheroes.’ However, in a disease mediated by an immune mechanism, cells with a lot of functions can act as ‘supervillains’ leading to disease progression.”
A study published in Cancer Cell demonstrated an example of how polyfunctional cells can be characterized as supervillain cells. When glioblastoma (GBM) cells start adapting functional changes to targeted therapies and become resistant, they become supervillains and lead to increased metastasis. While genomics has identified mutations in GBM tumors along druggable pathways, drugs created to target those pathways have not induced significant improvement for patients, and drug resistance occurs quickly and almost universally.1
When traditionally looking for resistance, researchers look at the genomic markers, but functional adaptations are occurring despite their genomic signatures. This leads to resistance to targeted inhibitors, and these cells that are able to change their function are considered “supervillains.” Measuring and identifying the functional adaptations are critically important here, but that is not possible with genomics. IsoPlexis’ single-cell proteomics is the only method available to obtain this information.
IsoPlexis’ Single-Cell Proteomics Predicts Success of Combination Therapy
Researchers used IsoPlexis’ single-cell intracellular proteomics “on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it with an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest[ed].”1
Using IsoPlexis’ single-cell proteomic barcoding technology, researchers were able to identify a solution to overcome resistant supervillain cells by analyzing the differential responses in signaling coordination. They showed “that drug resistance can proceed via a non-genetic (adaptive) mechanism that is activated within days of drugging. The measured adaptive response points to combination therapies that are tested in vivo and shown to halt tumor growth. This single-cell analytical approach appears to provide clinically actionable insights into designing combination therapy strategies for more effectively treating GBM patients.”1
The same single-cell proteomics technology from IsoPlexis was used to identify the adaptive response to mutant melanoma cells treated with a BRAF inhibitor and other targeted therapies. “The resulting analysis of changes in protein signaling coordination yielded a successful prediction of a combination targeted therapy that arrested the cellular dedifferentiation. This result demonstrates the applicability of [the researchers’] approach in models of other cancers, but this work, and work reported elsewhere, also highlights the facile ability of many cancers to adapt to targeted inhibitors.”1 Using IsoPlexis’ single-cell proteomics to measure signaling networks activated by different drugs can provide essential insights into the adaptive immune response, which is especially crucial for overcoming supervillain cells which develop drug resistance.1
It’s vital to identify superpowered cells when creating therapeutic strategies to overcome difficult to treat cancers. These cells dictate the function, whether that is beneficial and contributing to anti-tumor activity or negative and contributing to disease progression. In order to be sure that a potential therapy or vaccine will be effective and potent, researchers have to look at the function on a single-cell level. By identifying the highly functional supervillain cells, which lead to disease progression and adverse events, researchers can accelerate insights into overcoming these diseases. Using IsoPlexis’ single-cell proteomics platform, researchers can reveal these superpowered cell subsets and utilize this unique data for the development of better therapies.
To learn more about this superpowered cell concept, watch IsoPlexis’ webinar with Dr. Rong Fan of Yale University here.
- Wei W, et al. Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma. Cancer Cell 29: 563-573, 2016.