NuMAP-TNBC · Nuclear Metabolism Mapping to Predict Therapeutic Response in Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options and poorer survival. PARP inhibitors (PARPi) are the only approved targeted therapy but are restricted to ~15% of patients with homologous recombination deficiencies (HRD), underscoring the urgent need for functional biomarkers to expand their clinical reach.Our recent work points to nuclear metabolism as a regulator of genome function and therapy response. We identified that inosine monophosphate dehydrogenase 2 (IMPDH2), a purine biosynthesis enzyme, relocates to chromatin during DNA damage, where it interacts with PARP1 and consumes nuclear NAD⁺. In TNBC, we found that nuclear IMPDH2 is enriched and correlates with tumour aggressiveness, and that its activity modulates sensitivity to PARPi, supporting its potential as a predictive biomarker in a spatially defined tumour context.NuMAP-TNBC will test the hypothesis that nuclear IMPDH2 can guide PARPi response beyond HRD through four objectives:(1)Define molecular programmes linked to nuclear IMPDH2 by combining spatial transcriptomics and protein mapping in patient-derived xenograft tumours.(2)Characterise the distribution of nuclear IMPDH2 in patient breast cancer tissue and determine how it associates with cell types of the tumour microenvironment.(3)Build an integrated spatial atlas of nuclear IMPDH2 that connects protein features, transcriptional states, and cellular neighbourhoods to uncover biomarker signatures.(4)Develop and validate predictive models of therapy response based on nuclear IMPDH2, enabling patient stratification for PARPi treatment beyond HRD status.By bridging nuclear metabolism, spatial biology, and computational pathology, NuMAP-TNBC will provide mechanistic insight into chromatin-associated metabolic enzymes and deliver a practical, spatially resolved biomarker strategy. Its impact will be to expand PARPi eligibility and improve outcomes for patients with TNBC.