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Abstract Background: Metaplastic breast carcinoma is a heterogenous, highly aggressive and chemoresistant subtype of triple negative breast cancer (TNBC) with histological evidence of deregulated differentiation towards non-glandular components including spindle, squamous, and sarcomatoid. The role of the tumor microenvironment in the metastatic behavior and chemotherapy response of metaplastic carcinomas needs investigation to improve patient outcomes. Our lab has generated a model of spindle metaplastic breast carcinomas based on mammary epithelial cell-specific CCN6 knockout (MMTV-Cre;Ccn6fl/fl or CCN6KO). We have recently shown that a subset of TNBC cells engulf mesenchymal stem/stromal cells (MSC) generating a hybrid cell population with metastatic ability, which is detected in breast cancer tissue samples. In this study, we tested the hypothesis that hybrid cells may promote chemoresistant distant metastasis in spindle metaplastic breast carcinomas and that the tumor immune microenvironment may play a role in this function. Methods: Luc-GFP-CCN6KO cells were cultured with DsRED-MSCs for 7 days, yielding 90% of hybrid cells detected by flow cytometry. Hybrids or CCN6KO single cultures (1x10(5) cells) were injected intracardially in FVB/NJ syngeneic immune competent mice (n=20 mice per group). Four days after injection, each group was treated with Paclitaxel (PTX, 10 mg/kg twice a week, i.p.) or PBS control. The metastatic burden was evaluated by bioluminescence imaging twice a week. Mice were euthanized 23 days after heart injections, followed by necropsy and histopathological evaluation of the harvested organs. Results: All mice injected with single cultures of CCN6KO cells or hybrid cells formed distant metastasis. CCN6KO cells were highly invasive and spread to the lungs and lymph nodes in the chest,. We noted that 5 of 20 (25%) mice injected with hybrid cells showed metastasis in the liver (n=3 mice), pancreas (n=1), and abdominal lymph nodes (n=1). PTX treatment significantly reduced metastatic burden in mice injected with CCN6KO single cultures compared to vehicle (p=0.035) but had no effect on the metastatic burden of hybrid cells. Histologically, while the metastasis from CCN6KO cells and hybrids showed similar pathological features, consisting of spindle cancer cells with high grade nuclei and 10 mitoses/10 high power fields, hybrid-derived tumors had abundant infiltration by immune cells, mainly neutrophils, compared to single culture tumors. Conclusion: Our data show that hybrid cancer cell/MSC derived from CCN6KO spindle metaplastic carcinomas have higher ability to disseminate to distant organs, especially in the abdomen, compared to cancer cells. Our data show that hybrid cell-derived metastases have increased immune cell infiltration. We provide evidence that hybrid cells enhance Paclitaxel resistance in a mouse model of metaplastic breast carcinoma. Ongoing studies are aimed at elucidating the role of hybrids in the immune microenvironment of metaplastic breast carcinoma and clinical significance. Citation Format: Ahmad Eido, Maria Gonzalez, Celina Kleer. A hybrid breast cancer/mesenchymal stem cell population increases distant metastasis and chemoresistance of metaplastic breast carcinomas abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-25-06.
Eido et al. (Thu,) studied this question.