Identifying predictive and prognostic adipome biomarkers in obese TNBC mice for targeted therapy development - triple-negative breast cancer (TNBC) is an aggressive subtype characterized by rapid…

The National Cancer Institute awarded Hackensack University Medical Center $460,254 on July 16, 2026, under the Cancer Cause and Prevention Research program (CFDA 93.393, Assistance Listing Project Grant) to identify predictive and prognostic adipome biomarkers in obese triple-negative breast cancer mice for targeted therapy development.

The funded research investigates how obesity-modified adipomes—large extracellular vesicles derived from adipose tissue—regulate triple-negative breast cancer progression and metastasis in murine models. The work will characterize how adipomes from lean and obese adult TNBC mice regulate epithelial-mesenchymal transition, cellular stemness, and transcriptional reprogramming in normal epithelial and tumor cells; identify the lipid and RNA cargo within adipomes responsible for these effects; and map the HSPA1B pathway through which obesity-dependent adipome composition acts as a metabolic-state-dependent epigenetic regulator to promote TNBC progression, plasticity, and metastatic dissemination. Preliminary data demonstrate that lipid cargo differs significantly between adipomes derived from tumor-associated versus non-tumoral mammary fat, and that HSP70-2 expression increases up to 85-fold in cancer cells exposed to obese versus lean adipomes.

Performance occurs in Edison, New Jersey. The award runs through June 30, 2028.

Identifying predictive and prognostic adipome biomarkers in obese TNBC mice for targeted therapy development - triple-negative breast cancer (TNBC) is an aggressive subtype characterized by rapid metastasis, limited treatment options, and worse outcomes in obesity. Yet the mechanisms linking adiposity to tumor aggressiveness remain poorly understood. Our preliminary studies in murine TNBC models and plasma from breast cancer patients identify adipocytederived large extracellular vesicles, termed adipomes (>200 NM), as potent paracrine mediators that enhance invasion, EMT-related transcriptional programs, and cellular reprogramming in both malignant EO771 cells and non-malignant MCF-10A cells. We demonstrate that lipid cargo significantly differs between adipomes derived from tumor-associated mammary FAT and non-tumoral mammary FAT, indicating that adipome composition closely reflects host metabolic status, tumor pathology, and disease severity. BC-adipome exposure induces differential CPG methylation at HSPA1B regulatory loci in MCF-7 cells, and HSP70-2 expression is dramatically increased up to 85-fold in EO771 cells exposed to obese versus lean adipomes, consistent with HSPA1B's established role in proliferation, stemness, motility, and metastatic adaptation. These findings support a mechanistic model in which obesity-modified adipomes act as metabolic-state-dependent epigenetic regulators that activate an HSPA1B-driven transcriptional program promoting TNBC progression, plasticity, and metastatic dissemination. Our central hypothesis is that obesity and tumor pathology reshape adipome composition in ways that reprogram malignant and non-malignant mammary epithelial cells to promote TNBC progression and metastasis. Aim 1 will define how adipomes derived from lean and obese adult TNBC mice regulate EMT, stemness, and transcriptional reprogramming in normal epithelial and tumor cells, identify adipome lipid and RNA cargo responsible for these effects, and map HSPA1B-associated epigenetic remodeling using syngeneic EO771/C57BL/6 models and integrated multi-omics profiling. Because TNBC patients are highly heterogeneous and obesity-specific adipome effects are difficult to isolate in clinical cohorts, the controlled diet-induced obesity murine model provides a powerful platform to directly dissect how lean- and obese-derived adipomes reprogram epithelial and tumor cells. Aim 2 will identify circulating adipome-regulated CPG methylation signatures and transcriptomic pathways that distinguish early-stage from metastatic TNBC as a function of host BMI, using plasma adipomes from 40-50 DE-identified TNBC patients to establish clinically relevant biomarkers associated with progression risk, metabolic status, and metastatic potential. This study is highly innovative because IT introduces adipomes as a previously unrecognized stromal driver of TNBC aggressiveness, establishes the first mechanistic link between obesity, adipome cargo, and epigenetic reprogramming via HSPA1B, and integrates murine modeling with patient-derived adipomes to overcome clinical heterogeneity. The work is highly significant because IT will define a new adipocyte-tumor communication axis, generate metabolic and epigenetic biomarkers for risk stratification, and identify therapeutic vulnerabilities targeting adipomeregulated pathways, with direct relevance for improving prognosis and treatment strategies in obese TNBC patients