Fornetti, J. | bioRxiv Science

bioRxiv2026

Loss of short-form Ron promotes B and T cell cooperation to prevent outgrowth of breast cancer bone metastasis

While immunotherapy has great potential to eradicate tumors, success in metastatic breast cancer is limited. Bone metastasis, the most common site for breast cancer metastasis, has been associated with weakened anti-tumor immunity, both in the bone and in other metastatic sites. Additional strategies promoting anti-tumor immunity are needed. Using the MMTV-PyMT intratibial model of breast cancer bone metastasis, we discovered that deletion of host short-form Ron (Ron SF-/-) protected against bone metastatic outgrowth by promoting strong infiltration of lymphocytes, including B cells, into tumors at the micrometastasis stage. Transcriptionally, Ron SF-/- B cells were more active and inflammatory compared to wildtype. Elimination of mature B cells (JH-/-) rescued tumor growth in Ron SF-/- mice, indicating that mature B cells were necessary for anti-tumor immunity and protection against bone metastasis. In Ron SF-/- hosts, T follicular helper (Tfh) cells were abundant in tumor-enriched regions of bone, suggesting interactions between B and T cells. B-T cell cooperation was further supported by attenuation of CD4 and CD8 T cell tumor infiltration in Ron SF-/-JH-/- hosts and, conversely, diminished B cell tumor infiltration and rescue of tumor growth in Ron SF-/- hosts lacking CD4 or CD8 T cells. B cells were not required to protect Ron SF-/- mice from lung metastasis, indicating a tissue-dependent anti-tumor role for B cells. These data support a positive feedback loop between B and T cells regulated by SF-Ron and reveal the anti-tumor potential of B cells in the bone.

cancer biology↗

bioRxiv2024

Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model

Young women have increased risk of vitamin D deficiency, which may increase breast cancer incidence. Here, we assessed the anti-cancer efficacy of vitamin D in mouse models of young-onset breast cancer. In never-pregnant mice, vitamin D supplementation increased serum 25(OH)D and hepatic 1,25(OH)2D3, reduced tumor size, and associated with anti-tumor immunity. These anti-tumor effects were not replicated in a mouse model of postpartum breast cancer, where hepatic metabolism of vitamin D was suppressed post-wean, which resulted in deficient serum 25(OH)D and reduced hepatic 1,25(OH)2D3. Treatment with active 1,25(OH)2D3 induced hypercalcemia exclusively in post-wean mice, highlighting metabolic imbalance post-wean. RNAseq revealed suppressed CYP450 expression postpartum. In sum, we provide evidence that vitamin D anti-tumor activity is mediated through immunomodulatory mechanisms and is ineffective in the post-wean window due to altered hepatic metabolism. These findings have implications for suppressed xenobiotic metabolism in postpartum women beyond vitamin D. Statement of SignificanceIn a rodent model of postpartum breast cancer, weaning suppresses hepatic CYP450 activity and renders vitamin D supplementation ineffective, with implications for xenobiotic drug efficacy and safety. A tailored approach to therapy based on reproductive history is crucial for young breast cancer patients, and for healthcare strategies for postpartum women.

cancer biology↗