Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.

Abstract Purpose: The National Breast Cancer Coalition (NBCC), established in 1991, is a collaboration of activists, survivors, grassroots groups and national organizations united to end breast cancer through action and advocacy. Despite progress in certain areas, neither breast cancer incidence nor global mortality have significantly declined. In response, NBCC launched the Artemis Project in 2010, an advocate-led initiative focused on primary prevention of breast cancer and prevention of metastasis, designed to foster new collaborations among researchers and advocates. The project is a response to the fact that despite billions of dollars invested in research that has led to some effective treatments, we still do not know how to prevent or cure breast cancer. Artemis process: The Artemis Project is a collaboration to identify urgent gaps, set milestones, and co-develop research solutions to primary and metastasis prevention. Unlike traditional research development pipelines, Artemis integrates trained patient advocates as equal partners in priority setting, research design and oversight. Advocates identify the participants and choose the issues. Collaborations form at the annual meeting among researchers and advocates who often would not have met otherwise.The annual Artemis meeting brings participants together to explore new ideas, develop innovative projects towards Artemis’s goals, and outline work plans for 12-18 months after the meeting. Online meetings are held throughout the year for the groups to interact and to report progress. Seed funding for some projects has been provided by NBCC. NBCC schedules webinars throughout the year on relevant topics for Artemis participants. Selected Artemis outcomes: The first Artemis project led to an ongoing initiative to develop a breast cancer prevention vaccine, with a plan in place to move to a Phase I trial by mid-2026. The vaccine, consisting of 6 self-antigens overexpressed in breast cancer, is being developed under a contract with the NCI Prevent Program. DNA Land, an effort stemming from another Artemis project, has recruited over 33,000 individuals who have consented and contributed genomic and matched phenotypic data to underpin bioinformatics studies supporting prevention-focused breast cancer research.Additionally, researchers participating in Artemis have formed many collaborations that have grown into externally funded research efforts, including a project to eliminate disseminated tumor cells. Conclusions: Now 15 years in, the Artemis Project has created a durable, advocate-led ecosystem that unites researchers, clinicians, and advocates to pursue transformative prevention solutions rather than incremental advances. This model is adaptable across disease research areas. Citation Format: Fran M. Visco, Jayanta Debnath, Daniel Douek, Stephen J. Elledge, Silvia C. Formenti, Michele S. Garfinkel, Cyrus M. Ghajar, Patricia K. Haugen, Christopher I. Li, Herbert Kim Lyerly, Michelle Tregear, Alana L. Welm, Frank J. Calzone. The Artemis Project: A patient-led global research consortium advancing prevention-focused breast cancer innovation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3695.

Supplementary Figure 1 shows (A) spider plots of Log 2 of individual tumor volumes, (B) growth curves representing average Log 2 tumor volumes, (C) spider plots of Log 2 of proportional changes in tumor volume, and (D) growth curves showing Log2 proportional changes in tumor volume of the data shown in Figures 1 and 2.

Abstract Background: Disseminated tumor cells (DTCs) can persist despite systemic therapy and drive distant recurrence, a major cause of breast cancer-related mortality. Objective: To identify biologic processes enriched in the primary tumors of invasive breast cancer patients with DTCs detected at the time of their breast cancer diagnosis. Methods: We performed tumor-normal whole-genome sequencing and bulk RNA sequencing on matched tumor and blood specimens from 65 patients with newly diagnosed invasive breast cancer who underwent bone marrow biopsy at diagnosis to assess DTC status. Mutational signatures were identified using SigProfilerExtractor. Differential expression and gene set enrichment analyses were conducted with DESeq2. Pathways were defined using MSigDB hallmark gene sets. Genes with Bonferroni-adjusted p < 0.05 and |log2 fold change| > 1 were considered significantly differentially expressed. Analyses were adjusted for tumor purity, tissue source, stage, age, and neoadjuvant therapy. Results: Among 41 DTC-positive and 24 DTC-negative patients, DTC-positive tumors were more likely to harbor intronic somatic mutations in MARCHF1 (78.7% vs 56%, p = 0.001) and MARCHF4 (31.9% vs 4%, p = 0.007). Mutations in genes within the WNT and RTK-RAS signaling pathways were more frequent in DTC-positive tumors (WNT: 43.5% vs 27.1%, p = 0.037; RTK-RAS: 43.5% vs 27.1%, p = 0.011). Gene set enrichment revealed upregulation of E2F targets and G2M checkpoint pathways in DTC-positive tumors (normalized enrichment score = 2.12, p = 0.01; 2.04, p = 0.01, respectively). Individual genes enriched in DTC-positive patients included HAVCR1, TRIM55, MUC13, and KCNJ12. Recurrent somatic mutations in canonical breast cancer genes (PIK3CA, TP53, GATA3, CHD1, MAP3K1) and mutational signatures associated with APOBEC activity and homologous recombination deficiency occurred similarly across DTC-positive and DTC-negative patients. Conclusion: Primary tumors of patients with bone marrow DTCs at diagnosis exhibit upregulation of proliferative programs and increased mutation burden in WNT and RTK-RAS signaling genes. These findings highlight candidate biological pathways in the primary tumor that may facilitate early dissemination and persistence of DTCs. Citation Format: Katherine Anne Lawson-Michod, Taleb Ahsan, Keara Malone, Bailey Harmon, Megan Stackouse, Paul Seth, Michael C. Haffner, Matthew Fitzgibbon, Alexander Zevin, Arun Paul Wiita, Jayanta Debnath, Katherine E. Varley, Alana L. Welm, Stanley Riddell, Cyrus M. Ghajar, Christopher I. Li. Biologic processes enriched in the primary tumors of invasive breast cancer patients with disseminated tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6815.

Functional precision oncology aims to guide therapy selection by directly measuring drug sensitivity in patient-derived cancer samples. However, most existing functional assays require prolonged cell expansion limiting their feasibility for time-sensitive clinical decision-making. We evaluated whether multiparametric quantitative phase imaging (mQPI), a label-free single-cell imaging approach, could enable rapid assessment of therapeutic response in patient-derived breast cancer models. We applied mQPI to cells derived from patient-derived xenograft organoid (PDXO) models and viably cryopreserved primary breast cancer samples. Quantitative phase imaging was used to extract multiple orthogonal biophysical parameters describing cellular growth and response dynamics following drug exposure. Drug sensitivity, intrapatient heterogeneity, and resistance-associated phenotypes were quantified and compared across models. mQPI resolved distinct drug response profiles among cells derived from different anatomical sites within the same patient and revealed heterogeneous response dynamics in models of acquired therapeutic resistance. Importantly, drug responses were detected in a high-purity cryopreserved patient sample immediately after thawing, whereas a more heterogeneous sample required a short-term (2-week) expansion to enrich the viable tumor population before a response could be resolved, indicating that sample composition determines whether a direct-from-thaw or short-term expansion workflow is required. Across sample types, mQPI enabled robust single-cell measurements without the need for labeling or extensive culture. These findings establish mQPI as a rapid, label-free functional assay capable of quantifying therapeutic response and heterogeneity in patient-derived breast cancer samples. By reducing assay time and material requirements while preserving single-cell resolution, mQPI has the potential to complement genomic profiling and advance the clinical translation of functional precision oncology.

Immunotherapy has significantly improved outcomes for some cancer patients, but many patients, including those with breast cancer, have minimal response to these therapies. Our long-term goal is to enhance the efficacy of immunotherapy in patients with metastatic breast cancer, specifically by targeting short-form Ron (SF-Ron). SF-Ron is one of two transcripts encoded by the Mst1r (Ron) gene and lacks the ligand-binding domain present in the full-length Ron isoform. We previously reported that deletion of host SF-Ron protects against breast cancer lung metastasis in mice by promoting a heightened immune response mediated by T cells. Given the increasing evidence that tissue-specific tumor microenvironments can impact the effectiveness of immunotherapies, we aim to determine whether the loss of host SF-Ron also enhances an immune response in the bone. This is important because bone is the most common site of breast cancer metastasis, and it has been shown that the presence of bone metastases weakens the response to immunotherapies not only in bone but also in other metastatic sites. Using an experimental model of breast cancer bone metastasis, we observed that tumors initially grow in both wild-type (WT) mice and mice lacking SF-Ron (Ron SF-/-), but are subsequently eliminated by the immune system in Ron SF-/-mice. This immune-mediated clearance was associated with increased infiltration of T cells, B cells, and dendritic cells into bone metastases in Ron SF-/- mice compared to WT controls. We also determined that T cells, B cells, and dendritic cells express SF-Ron. Unlike T cells and dendritic cells, the role of B cells in anti-tumor immunity is poorly understood, yet clinical evidence suggests that high infiltration of B cells is associated with improved prognosis in breast cancer. To investigate the importance of B cells in tumor elimination in mice lacking SF-Ron, we performed genetic depletion of B cells in Ron SF-/- mice. Loss of B cells strikingly rescued tumor growth in SF-Ron knockouts and had no effect on tumor growth in WT mice, confirming the necessity of B cells for the anti-tumor immune response in this model, and revealing a novel link between B cells and SF-Ron-mediated protection from tumor growth. RNA sequencing revealed that B cells from Ron SF-/- mice are more proliferative and active in the presence of tumors compared to wild-type B cells, suggesting a role for SF-Ron in regulating B cell activity against tumors. To our knowledge, this is the first study to show expression of SF-Ron in B cells and reveal a role for SF-Ron in B cell function, as well as the first to implicate B cell anti-tumor activity in breast cancer bone metastasis. Future work will assess the contributions of SF-Ron in B cells for tumor clearance using in vitro functional assays and single-cell RNA sequencing. Our data suggest that targeting host SF-Ron could improve outcomes for metastatic breast cancer patients by increasing anti-tumor immune responses, at least in part through stimulating infiltration and activity of B cells in bone metastases. Clint H. Valencia, Jaime Fornetti, Alana L. Welm. Short-form Ron regulates the B cell response in preclinical models of metastatic breast cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A002.

Supplementary Fig. S3. Summary of protein expression changes after 24 weeks of endocrine treatment (ET) and/or Palbociclib (palbo) treatment.