Overcoming Challenges in Neuroinflammation with a Single-Cell Intracellular Proteome (Part 4)

To conclude our June blog series (Part 1, Part 2, Part 3) in honor of Alzheimer’s and Brain Awareness month, we are taking a deeper look into how our single-cell intracellular proteome solution can address common challenges when studying neuroinflammation and its effect in neurodegenerative diseases.

It’s evident that neuroinflammation plays a critical role in neurodegenerative diseases. With IsoPlexis’ cellular functional phenotyping, cellular differences can be uncovered and help identify functional mechanisms in neuroinflammation and neurotoxicity.

Our Single-Cell Intracellular Proteome solution provides a simple, integrated solution for monitoring simultaneous protein signaling networks that are missed by methods such as western blot, mass spectrometry, and flow cytometry. What’s more, it uses proteomic barcoding to characterize phosphoprotein signaling cascades targeting up to 1,500 single cells per chip.1

By understanding the entire network of cellular signaling pathways, we hope to help researchers reveal the effects of aberrant pathways typically missed in rare subsets of cells, which can support the advancement of more comprehensive treatments for cancer.1

Below we highlight a case study in which IsoPlexis technology was used to identify a mechanism of resistance in glioblastoma.

Application: Informing Targeted Combination Therapy to Overcome Resistance in Glioblastoma (GBM) with Single-Cell Intracellular Proteomics Single-Cell Phosphoproteomics Identifies Adaptive Mechanism of Resistance

Intraturmoral heterogeneity of signaling networks could be one of the causes of targeted cancer therapy resistance. In this study, single cell phosphoproteomics was performed on a patient-derived in vivo glioblastoma model of mTOR kinase inhibitor (mTORki) resistance and combined  with an analytical approach to detect changes in signaling coordination. Changes in the protein signaling coordination were resolved in as little as 2.5 days after treatment, thus predicting drug resistance before it was clinically manifested. In this particular case, combination therapies were discovered and resulted in complete and sustained tumor suppression in vivo. The researchers concluded that this approach could be useful in identifying actionable changes in signal coordination that underlie adaptive resistance, which could then be suppressed through combination therapies.2

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor (mTORki) resistance and coupled it to 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. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.

Highlights of the study included:3

  • Single-cell intracellular proteomics uncovers rewiring of signaling pathways, revealing dominant mechanism of resistance.
  • Single-cell intracellular proteomics identifies changes in signaling nodes missed by genomic analysis.
  • Targeting these signaling nodes before treatment blocks resistance, demonstrating the importance of single-cell intracellular proteomics and network rewiring for predicting cancer treatment responses

A Breakthrough Technological Innovation – Single-Cell Intracellular Proteome

Researchers are able to analyze signaling cascades of many phosphoproteins directly from each single cell, across thousands of single cells in parallel. Unlike traditional technologies, our Single-Cell Intracellular Proteome Solution can quantify and multiplex 15+ intracellular analytes simultaneously from each cell, and therefore detect critical protein to protein interactions and signaling networks in rare cells and cell subsets.

To learn more about this publication or any of the publications referenced in our June Blog Series, download our Neuroinflammation Application Note.

 

References

  1. (2020, December 2). The Scientist Names IsoPlexis Single Cell Intracellular Proteome a Top 10 Innovation of 2020. PR Newswire. https://www.prnewswire.com/news-releases/the-scientist-names-isoplexis-single-cell-intracellular-proteome-a-top-10-innovation-of-2020-301183200.html
  2. Wei W, Shin YS, Xue M, et al. Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma. Cancer Cell. 2016;29(4):563-573. doi:10.1016/j.ccell.2016.03.012
  3. Proteomic Product Suite for Neuroinflammation. https://isoplexis.com/literature/isoplexis-proteomic-product-suite-for-neuroinflammation/

 

 

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