Biomedical subjects

Morag Park

Publications and source records attributed to Morag Park.

3 recordsLinked to original sources

PubMed2026

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Ferroptosis↗

PubMed2026

A chromatin-informed transcriptional regulatory framework to stratify patients and guide therapy selection in triple-negative breast cancer.

Triple-negative breast cancer is an aggressive and heterogeneous breast cancer subtype with few effective targeted therapies and frequent resistance to chemotherapy. Here, we integrate transcriptional regulatory network inference with chromatin accessibility across a large-scale multi-system collection of primary tumors, patient-derived xenografts and model cell lines to quantify transcription factor activity and identify regulators that underpin triple-negative breast cancer identity. This approach prioritizes 94 high-confidence triple-negative breast cancer transcription factors whose activity capture inter-tumor heterogeneity and independently stratify patient outcome across clinical endpoints. Linking transcription factor activity to pharmacogenomic drug sensitivity profiles identifies reproducible drug-transcription factor associations across independent datasets, including NFE2L3 and CBFB activity as predictors of sensitivity to mTOR inhibition, which we validate in everolimus-treated triple-negative breast cancer patient-derived xenograft models. Collectively, we provide a transcriptional and chromatin-informed framework to capture triple-negative breast cancer regulatory state and expand transcription factor guided precision medicine to this breast cancer subtype.

Humans↗

PubMed2026

Distinct immune landscapes characterize highly versus minimally invasive brain metastases.

Brain metastases (BrMs) occur in approximately 30% of cancer patients, causing nearly one-fifth of cancer deaths. While immune checkpoint inhibitors (ICIs) benefit some BrM patients, responses remain highly variable. This variability partly reflects distinct histopathological growth patterns that include minimally invasive (MI) and highly invasive (HI) brain BrMs. Here we show that MI BrMs exhibit robust immune infiltration, whereas HI lesions are immunosuppressed. However, histological differentiation between MI and HI can be challenging because of subjective margin assessment. Here, using highly multiplexed spatial proteomics on 119 tumor sections from 46 patients with BrMs, we identify CHI3L1 as a key mediator of the immunosuppressive microenvironment in HI BrMs. In preclinical models, genetic deletion of CHI3L1 converts immune-cold metastases into lymphocyte-rich, ICI-responsive lesions infiltrated by granzyme B+ CD8+ T cells. In BrM patients treated with ICI, immunohistochemical quantification of CHI3L1 expression was a stronger predictor of ICI response than traditional MI/HI classification. Thus, CHI3L1 represents a promising biomarker and therapeutic target for BrMs.

Humans↗