Â鶹´«Ã½

News — New research from Memorial Sloan Kettering Cancer Center (MSK) provides a clearer understanding of glioblastoma heterogeneity to aid development of new therapies; sheds light on mechanisms of cellular plasticity; presents a new imaging technique that could improve the diagnosis of brain diseases by revealing how different parts of the brain are metabolizing nutrients; describes a new method to aid the study of rare but influential cell populations; and identifies a potential treatment for malignant peripheral nerve sheath tumors.

New understanding of glioblastoma heterogeneity will aid development of new therapies

The incurable brain tumor glioblastoma is traditionally known by its longer name — glioblastoma multiforme, which is often shortened to GBM. This is in recognition of its highly variable appearance, which reflects the wide molecular and cellular variation within the tumors, which scientists call “heterogeneity.”

A recent study — led by Xuanhua Peter Xie, PhD, a senior research scientist in the lab of senior study author Luis F. Parada, PhD, Director of MSK’s Brain Tumor Center — sheds new light on the heterogeneity of GBM tumors and on the role of the small population of cancer stem cells that initiate and drive tumor growth. “Understanding this heterogeneity is crucial for developing effective treatments,” Dr. Parada says.

Using advanced single-cell transcriptomics in mice implanted with patient-derived tumors, the research team identified six distinct transcriptional states, each with its own unique gene signature. Five of these transcriptional states correspond to different cell lineages found in the central nervous system, such as neural stem cells, glia, and neurons. The research additionally emphasized the critical role played by cancer stem cells in tumor recurrence and resistance to chemotherapy.

The findings of this study have important implications for the development of new treatments for GBM, Dr. Parada notes. A more detailed understanding of the heterogeneity of GBM tumors and the role of cancer stem cells provides guidance for future research to develop targeted therapies. The study also reinforced the fidelity of the patient-derived-xenograft models for studying new therapies and combination treatments. Read more in . 

Stem cell study sheds light on mechanisms of cellular plasticity

Plasticity is the ability of a cell to change its identity. During embryonic development, cells have high plasticity, as they need to differentiate and generate our bodies. By contrast, cells in adults usually have greatly reduced plasticity, because it is important to keep cell identities — and by extension the organ they make up — stable. In cancer, however, as cells progress from a primary tumor toward becoming metastatic, they acquire increased plasticity, and gain the ability take on new, flexible cell states that often resemble those seen in early development — and that help the cancer evolve to resist treatment. An overarching question in biology and medicine concerns the regulation of plasticity at the molecular level.

A new collaboration between the labs of developmental biologist Anna-Katerina Hadjantonakis, PhD, and computational biologist Dana Pe’er, PhD, at MSK’s Sloan Kettering Institute, and , at Weill Cornell Medicine, examined the big-picture question of how cell identity is forged during development and how plastic cells are — that is, how easily they can their change their identity.

The research team used a novel bidirectional reprogramming strategy in mouse stem cells representing two sister cell types — epiblast (EPI) and primitive endoderm (PrE) cells — that arise in the embryo from a common ancestor. They combined high-resolution imaging and cell sorting along with single-cell RNA and ATAC sequencing to study how easily cells could be converted from one identity to their sister identity, identifying drivers and roadblocks as cells transitioned between states.

The team found that EPI-to-PrE conversion was rapid and efficient, while PrE-to-EPI conversion was slow and inefficient — despite being sister cell types — suggesting that cells acquiring a PrE identity quickly “lock” into a stable, less plastic state. Moreover, they uncovered specific molecular barriers that promoted or counteracted plasticity, which could inform future anti-cancer strategies. Overall, the research provides new insights into the mechanisms regulating the differential plasticities of cells and transitions between them. Read more in . 

Hyperpolarized MRI reveals different types of brain metabolism simultaneously

A research team led by biochemist and engineer Kayvan Keshari, PhD, has developed a new imaging technique that could improve the diagnosis of brain diseases by revealing how different parts of the brain are metabolizing nutrients. The approach uses hyperpolarized MRI (HP MRI), which provides important information about how a tumor is metabolizing an injected substance.

In HP MRI, the molecules of a substance are oriented to the MRI’s magnetic field prior to injection into the patient, boosting the signal more than 10,000-fold. As the substance is metabolized by the cancer cells, doctors get an immediate, clear snapshot of a tumor’s metabolic activities.

In mice, the researchers used HP MRI coupled with two tracing substances —  dehydroascorbate and pyruvate. This enabled them to study different types of metabolic activity across the brain, simultaneously. This real-time imaging of brain metabolism will shed light on how brain diseases develop and progress.

“In addition to improving diagnoses, this approach could help determine if a therapy is working in a patient across different lesions and aid in the development of new therapies,” Dr. Keshari says. Read more in . 

Technique sheds light on rare cells

An MSK research team and their collaborators have developed a new method to aid the study of rare but influential cell populations. The technique is called PERFF-seq — for Programmable Enrichment via RNA Flow-FISH by sequencing. It enables scientists to profile rare cells based on specific RNA markers.

“Single-cell RNA sequencing has revolutionized our understanding of cell heterogeneity, but it can be challenging to study rare cell populations due to their low frequency,” says study senior author Caleb Lareau, PhD, who began the research as a postdoctoral fellow at Stanford University and expanded upon it after launching an independent lab at MSK’s Sloan Kettering Institute. “Our new approach will facilitate the study of rare and important cell populations that initiate tumor evolution and metastasis, resist therapeutic intervention, and drive complications during treatment.”

MSK’s Single-cell Analytics Innovation Lab (SAIL) was a key collaborator on the project, Dr. Lareau notes. By collaborating with SAIL, the team demonstrated PERFF-seq could isolate rare endothelial cells from glioblastoma tumor tissues. These cells may play a role in the development of these tumors and in treatment response. Read more in . (10x Genomics also covered the paper’s preprint in a .) 

A potential treatment for malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors are a type of aggressive sarcoma without good treatment options. In a new study, however, laboratory researchers at MSK and NYU Langone Health, have identified a new potential treatment approach. The team — overseen by Luis Parada, PhD, an investigator at MSK’s Sloan Kettering Institute, and , of NYU — used mouse models to uncover that the cancer was vulnerable to SHP2 inhibition (reducing RAS signaling and suppressing tumor growth), and they additionally found that combining SHP2 inhibition with hydroxychloroquine (reducing autophagy) overcame resistance that developed when targeting SHP2 alone. The efficacy across multiple genetically engineered models and using patient-derived xenografts justify a clinical trial to further evaluate the approach, the authors write. Read more in the .