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Publications of the Week

The Landscape of Tumor Cell States and Spatial Organization in H3-K27M Mutant Diffuse Midline Glioma Across Age and Location

By January 16, 2023No Comments

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This week we profile a recent publication in Nature Genetics from the labs of Dr. Mariella Filbin (pictured, front row, center) at Dana-Farber Boston Children’s Cancer and Blood Disorders Center and the Broad Institute, Dr. Michelle Monje from Stanford University, and Dr. Mats Nilsson from Stockholm University.

Can you provide a brief overview of your lab’s current research focus?

My lab is interested in how pediatric brain tumors recapitulate certain aspects of normal brain development – what are similar behaviors and programs that are hijacked, but also what are the differences so we can target brain tumor cells specifically. Indeed, all pediatric brain tumor cells can differentiate to some degree, despite their mutations and DNA copy number variations, and thereby exit the cell cycle and no longer feed tumor growth.

What is the significance of the findings in this publication?

In this paper we look at the intra-tumoral cell programs across tumors of all ages and all locations in the brain, all unified by the same mutation – the pathognomonic histone 3 K27M mutation of “Diffuse midline gliomas”. We find that tumors occurring in the brain stem contain cancer cells from earlier stem cell stages than tumors of the higher brain regions. We also show that adult tumors are shaped by the aging immune cells, particularly by aging microglia and macrophages that induce a mesenchymal tumor cell state. Finally, we show that by spatial single cell transcriptomics the cancer stem cells all cluster together in mitogenic “niches”, while the differentiating cancer cells surround them and shield off immune attacks. The cancer stem cell niches are also rich in blood vessels and normal neurons, while again the immune cells seem to be “stuck” in the differentiating cancer cell walls.

What are the next steps for this research?

We are now looking into the communication lines between all these cells – who is telling cells to differentiate and move away, versus others to stay and divide. The step after that is to block this communication and destroy the architecture these tumors form, with the hopes of thereby cutting off the communication lines that drive these vicious tumors.

If you’d like to mention your funding sources, please list them.

This work was supported by generous funding from the Hope/Care project NIH CCSG cancer center (grant P30CA124435 to M.G.F.), the Sajni Fund (M.G.F.), the Claudia Adams Barr Program in Innovative Cancer Research (DFCI) (M.G.F.), the Cuming Family Fund for Pediatric Brain Tumor Research (M.G.F.), Andruzzi Foundation (M.G.F.), the Anita, Sophia and Athena Fund to Advance DIPG Research and Care (M.G.F.), Prabal Chakrabarti & Vanessa Ruget (M.G.F.), Hyundai Hope on Wheels (M.G.F.), Liv Like A Unicorn (M.G.F.), Alex’s Lemonade Stand Foundation Crazy 8 Initiative (M.G.F.) and Solving Kids’ Cancer/The Bibi Fund (M.G.F.). M.G.F. holds an NIH director’s New Innovator (award DP2NS127705), a Career Award for Medical Scientist from the Burroughs Wellcome Fund, the Distinguished Scientist Award from the Sontag Foundation and the A-Award from the Alex’s Lemonade Stand Foundation. M.G.F. was also supported by National Cancer Institute SPORE (grant 2P50CA165962).

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