Solstara Research Report | 03-08-24

The latest in cancer science, summarized.

Author

Solstara Labs
March 08, 2024

The study presents a nanobiopsy platform that enables the injection of exogenous molecules and multigenerational longitudinal cytoplasmic sampling from a single cell and its progeny. The technique is based on scanning ion conductance microscopy (SICM) and was applied to longitudinally profile the transcriptome of single glioblastoma (GBM) brain tumor cells in vitro over 72 hours. The GBM cells were biopsied before and after exposure to chemotherapy and radiotherapy, and the results suggest that treatment either induces or selects for more transcriptionally stable cells. The study aims to transform standard single-cell transcriptomics from a static analysis into a dynamic assay. This assay could provide valuable insights into the effects of different interventions on cellular state transitions and the selection of more transcriptionally stable cells

The study investigates the role of leukocyte interaction with neoplastic and stromal cells in cancer immunity and how it contributes to immune evasion and immunotherapy resistance. It identifies a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). The study aims to understand the mechanisms underlying the formation of this vascular niche and its impact on GBM growth and immunotherapy response. The primary objective of the study is to identify potential targets for optimizing cancer immunotherapy.

The study's findings suggest that exploiting naturally occurring mutations can improve the efficacy of adoptive T cell therapies for cancer. The study identifies a gene fusion, CARD11-PIK3R3, that enhances the anti-tumor efficacy of therapeutic T cells in immunotherapy-refractory models in an antigen-dependent manner. It also highlights the potential of CARD11-PIK3R3 to be deployed safely, as CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. The study suggests future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches. For example, future studies could investigate the effects of other gene fusions or mutations on T cell signaling, cytokine production, and in vivo persistence in tumors, and explore their potential to improve T cell therapies for cancer.

The study investigates the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. It aims to understand the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells in actual therapeutic settings. The primary objective of the study is to identify subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. The study uses single-cell analyses to show that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. The study also identifies acquired mutations at the PRC2-compound interface that result in the propagation of clones with increased H3K27me3 expression. The study identifies subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. The study aims to provide opportunities for further sustained epigenetic cancer therapies.

The study investigates the use of cryo-electron tomography to quantify the nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. The study aims to identify potential therapeutical targets for GBMs by comparing the inter-mitochondrial features of GBM cells with cancer-free brain cells. The hypothesis being tested is that GBM cells have unique inter-mitochondrial features that can be used to distinguish them from cancer-free brain cells. The methodology used for the experiment includes cryo-electron tomography, which was used to obtain high-resolution images of mitochondria in GBM cells. The study also includes predictive modeling to analyze the inter-mitochondrial features and distinguish GBM cells from cancer-free brain cells. The primary objective of the study is to identify high-resolution inter-mitochondrial structural signatures that can be used for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.

The study's findings have significant implications for the field of research and clinical practice, as they highlight the importance of Wnt signaling in regulating early stages of tumor induction by homeostatic tissue macrophages. The study identifies a potential therapeutic target for Sonic hedgehog medulloblastoma, as targeting Wnt signaling in endothelial cells could suppress tumor induction. However, the study also identifies limitations, such as the need for further in vivo studies to validate the findings and the need to investigate the specific mechanisms by which Wnt signaling regulates CXCL4 expression in meningeal macrophages. Future research directions could include exploring the role of Wnt signaling in other types of tumors and investigating the potential therapeutic applications of targeting Wnt signaling in endothelial cells.

The study aims to comprehensively analyze the molecular determinants of mutational burden and signatures in 10,294 gliomas to understand the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy. The study delineates two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. The study experimentally recapitulates the mutational signature of post-treatment hypermutated gliomas by temozolomide-induced damage in cells with MMR deficiency. The study identifies that MMR-deficient gliomas are characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival, and a low rate of response to PD-1 blockade. The study also shows that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.