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Northwestern University Feinberg School of Medicine
Youngblood Lab

Research

The Youngblood Lab studies the molecular mechanisms that drive brain tumor growth, aggressiveness and treatment resistance, translating these insights into better therapies for patients. Our projects span the full arc from discovery to translation — defining the genomic and epigenetic drivers of tumor behavior, dissecting how tumors interact with and reshape the immune microenvironment and developing novel therapeutic strategies for tumors that resist surgery. To do this, we integrate a broad range of approaches, including chromatin and epigenomic profiling (e.g., Hi-C, ChIP-seq, ATAC-seq, DNA methylation), spatial and single-cell transcriptomics, immunologic and preclinical modeling and liquid biopsy platforms for tracking tumors over time. Together, these efforts aim to uncover new biology across the spectrum of central nervous system (CNS) tumors and to convert that understanding into meaningful clinical advances.

Current Projects

Advancing Immunotherapeutic Approaches in Meningiomas

Meningiomas are infiltrated by abundant myeloid populations, particularly macrophages, that our lab and others have shown adopt immunosuppressive phenotypes and shape the tumor immune microenvironment. Our program develops preclinical and translational strategies to reprogram these cells from tumor-permissive to tumor-fighting states. A central effort leverages STING pathway activation to reawaken innate immune signaling, while a complementary approach targets the collagen–LAIR1 myeloid checkpoint to relieve inhibitory signaling within the microenvironment. In collaboration with the Dmello Lab, we are also exploiting CHEK2-deficient tumors as a means to remodel the immune landscape and enhance therapeutic response. Together, these projects aim to convert the meningioma myeloid compartment into a driver of anti-tumor immunity.

 Representative Papers

 Key Figure

Microscopy images of the meningioma tumor microenvironment showing tumor, endothelial and myeloid cells and STING pathway activation.

Fluorescence microscopy images of meningioma tissue showing STING protein expressed across neoplastic (SSTR+), endothelial (CD31+) and myeloid (CD163+) populations, with additional images showing activation of the downstream signaling marker pIRF3 in the nucleus of these same cell types.

Source: Youngblood MW, et al. Nat Commun. 2026; PMID 41680157.

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Decoding the Epigenetic Drivers of CNS Tumor Aggressiveness

Meningiomas and gliomas span a wide clinical spectrum, from indolent lesions cured by surgery to aggressive tumors that recur and resist treatment — yet the molecular basis for this divergence remains incompletely understood. Our lab applies a comprehensive suite of epigenomic technologies, including Hi-C, ChIP-seq, RNA profiling, DNA methylation and spatial epigenetic approaches to define the regulatory programs that drive tumor behavior. By integrating these layers, we aim to identify the epigenetic features that distinguish a benign lesion from one destined to progress despite surgical resection. Ultimately, this work seeks to translate molecular insight into improved prognostication and new therapeutic targets for the most aggressive CNS tumors.

 Representative Papers

 Key Figure

Scientific diagram illustrating tandem duplication involving IHH alters chromatin structure and creates neo-loops between DIRC3 super-enhancers and IHH.

A multi-panel genomic diagram of a region on chromosome 2 showing how a tandem duplication in meningioma tumors rearranges the 3D structure of the DNA, creating new chromatin loops and boundaries ('neo-loops' and 'neo-TADs') that bring enhancer elements near the DIRC3 gene into contact with the IHH gene. Supporting tracks below show the duplication's location, associated super-enhancer activity and nearby genes.

Source: Youngblood MW, et al. Nat Commun. 2023; PMID 3780562.

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Tracking Brain Tumor Evolution Through Circulating Extracellular Vesicles

Brain tumors continuously shed extracellular vesicles into the bloodstream, offering a minimally invasive window into tumor biology that conventional imaging and tissue sampling cannot provide. In collaboration with the Nagrath Lab at the University of Michigan, we apply microfluidic immunoaffinity platforms to isolate these tumor-derived vesicles from patient blood using tumor-specific surface markers. By characterizing the molecular cargo of these vesicles, we aim to track how tumors evolve over the course of treatment and to identify early signatures of therapeutic response or resistance. Ultimately, this liquid biopsy approach seeks to illuminate the biology of the tumor microenvironment in real time without the need for repeat surgery.

 Representative Papers

 Key Figure

Design and validation of GlioExoChip using EVPs from GBM cell lines.

A multi-panel figure showing a microfluidic chip designed to capture tumor-derived extracellular vesicles from blood or cell culture media. Panels show the physical device and its microwell structure, antibody validation by western blot, a diagram of how vesicles are captured and released using surface coatings, bar graphs comparing capture efficiency across different capture methods and cell types, fluorescence images confirming vesicle capture and particle-size measurements confirming the captured vesicles are exosome-sized.

Source: Youngblood MW, et al. Nat Commun. 2025; PMID 4140229762.

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Defining Therapeutic Vulnerabilities in Aggressive PitNETs

Pituitary neuroendocrine tumors (PitNETs) cause substantial morbidity through both hormone hypersecretion, which drives systemic endocrine dysfunction and local mass effect, which can produce neurological deficits such as vision loss. Surgery is curative for many patients, but others are left with residual or recurrent disease that remains difficult to control. Our lab applies advanced molecular profiling to define the epigenetic drivers of PitNET aggressiveness and to identify therapeutic vulnerabilities in surgically refractory tumors.

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Leveraging Meningioma Biology to Develop Better Therapies

For patients whose meningiomas recur or invade the brain after surgery and radiation, treatment options remain critically limited — there is currently no standard-of-care chemotherapy. Our lab works to close this gap by translating molecular insight into rational therapeutic strategies. In collaboration with the Horbinski and Rogers groups, we are developing local therapy approaches that deliver treatment directly to the surgical resection cavity, concentrating drug at the site of recurrence while sparing systemic toxicity. We have also shown that DNA methylation profiles can nominate effective chemotherapies, identifying docetaxel as an agent that selectively targets high-risk meningiomas and sensitizes them to radiation. Complementing these efforts, our studies of brain invasion biology have revealed the cellular reprogramming and microenvironmental interactions that allow tumors to breach the brain, exposing new vulnerabilities for therapeutic intervention.

 Representative Papers

 Key Figure

Microscopy images of the meningioma tumor microenvironment showing tumor, endothelial and myeloid cells and STING pathway activation.

A multi-panel figure showing a drug-screening pipeline that tested 147 FDA-approved compounds against patient-derived meningioma cell cultures to identify effective chemotherapy candidates. Panels show the experimental workflow, patient sample characteristics, the range of drug potency across different drug classes and scatter plots highlighting standout compounds, which include docetaxel, bortezomib and romidepsin, along with charts identifying which patient and tumor factors correlate with drug response.

Source: Youngblood MW, et al. In production.

The image is sourced from this abstract (which matches the study description of 147 FDA-approved compounds), but the image is not included in the paper.

 Collaborators & Support

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