Abstract A017: Influenza virus-induced expansion of dormant metastatic breast cancer in the lung alters tumor collagen program

Abstract Metastatic relapse may occur long after eradication of the primary tumor in part due to dormancy of the disseminated cancer cells (DCCs). The treatment of metastases remains a relevant clinical challenge, as an estimated two-thirds of cancer-related deaths are caused by metastatic disease. Thus, investigating the basis for reactivation of dormant DCCs is pertinent to the treatment of metastatic cancers. Our lab previously demonstrated that viral infection induces expansion of dormant breast cancer cells in the lungs, with a marked upregulation of extracellular matrix (ECM) component-encoding mRNAs in proliferative lesions. Indeed, recent literature suggests that cell-extrinsic factors, including the immune microenvironment and ECM, influence dormancy status. Collagen, the major component of the ECM, can direct cell proliferation, migration, and invasion, as well as promote cancer immunoevasion. Here, we seek to disambiguate the roles of three major fibrillar collagen types – Collagen I, III, and V – thought to play a role in cancer cell dormancy. Mouse Mammary Tumor Virus (MMTV) Her2+ mouse models were utilized to model high-latency, dormant metastatic breast cancer and challenged with Influenza A virus. Lung tissue collected longitudinally over the course of infection was stained for the collagen subunit proteins Col3a1 and Col5a1 and the breast cancer cell marker Her2. Second Harmonic Generation (SHG) was performed to visualize Collagen I architecture. Images were evaluated in QuPath, and fluorescence intensity data were used to quantify and classify cell types for analysis.Induced bronchial-associated lymphoid tissue (iBALT) and immune infiltration are evident in lungs from mice challenged by influenza virus. Interestingly, proximity to the iBALT region is correlated with increased expression of Collagen III by DCCs, though this pattern of expression does not emerge in Collagen V. Fluorescence data suggest DCC production of both collagen subtypes increases over the course of infection and remains high following viral clearance. Correspondingly, bulk RNA-seq data demonstrate both Collagen III and V subunit transcription are elevated in DCCs from flu-infected lungs compared to control. However, this process does not appear to be interleukin 6 dependent. Preliminary SHG data also indicate extracellular matrix remodeling by proliferative lesions.Though Collagen III has been previously demonstrated to promote the dormancy niche, our data instead suggest an association with DCC awakening and expansion at immune-rich sites in the lung. Since this collagen signature is largely absent in spontaneous lesions, next steps involve investigating cytokine signaling in this apparently immune-directed expansion. Differential upregulation of ECM proteins may in part justify the mixed epithelial-mesenchymal cancer cell population seen in proliferative lesions and further our understanding of cell-extrinsic factors implicated in the adoption of, and exit from, the dormant phenotype. Citation Format: Bailey S. Kane, Bryan J. Johnson, James V. DeGregori. Influenza virus-induced expansion of dormant metastatic breast cancer in the lung alters tumor collagen program [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr A017.