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Murine models for triple-negative breast cancer with differential responsiveness to immunotherapy [scRNA-Seq]

ABSTRACT: Breast cancer is the most common cancer diagnosis in women. Clinical studies with triple-negative breast cancer (TNBC) are encouraging for immunotherapy combined with chemotherapy (aPD-1 with paclitaxel and/or carboplatin). However, additional clinical advances may be pursued more rapidly with assistance from preclinical TNBC models including syngeneic mammary tumor cell lines. Here, we report two mammary tumor cell lines that exhibit differential responsiveness to immunotherapy in vivo. Spontaneous mammary tumors from C57BL/6J MMTV-Cre Trp53fl/+ animals were passaged serially in cell culture and in vivo in the mammary fat pad of fully wildtype animals. The resulting lines, MM001i and MM008i, lost Trp53 and formed 1000 mm3 tumors in the mammary fat pad within 21-28 days. Despite originating from the same genetic background, these lines exhibit differential responses to immunotherapy. For aPD-1 therapy, MM001i is poorly responsive and MM008i is strongly responsive with near-complete tumor regression. In comparison, both MM001i and MM008i respond rapidly to aCTLA-4 therapy. Both models express unique tumor antigens as evidenced by immunity to subsequent engraftments. Primary MM008i tumors exhibit greater T cell infiltration, and CD8-positive T lymphocytes are required for aPD-1 responses. These TNBC models are promising for further mechanistic studies and testing future single and combinatorial therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE305842 | GEO | 2026/01/30

REPOSITORIES: GEO

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Murine models for triple-negative breast cancer with differential responsiveness to immunotherapy

Project description:Breast cancer is the most common cancer diagnosis in women. Clinical studies with triple-negative breast cancer (TNBC) are encouraging for immunotherapy combined with chemotherapy (aPD-1 with paclitaxel and/or carboplatin). However, additional clinical advances may be pursued more rapidly with assistance from preclinical TNBC models including syngeneic mammary tumor cell lines. Here, we report two mammary tumor cell lines that exhibit differential responsiveness to immunotherapy in vivo. Spontaneous mammary tumors from C57BL/6J MMTV-Cre Trp53fl/+ animals were passaged serially in cell culture and in vivo in the mammary fat pad of fully wildtype animals. The resulting lines, MM001i and MM008i, lost Trp53 and formed 1000 mm3 tumors in the mammary fat pad within 21-28 days. Despite originating from the same genetic background, these lines exhibit differential responses to immunotherapy. For aPD-1 therapy, MM001i is poorly responsive and MM008i is strongly responsive with near-complete tumor regression. In comparison, both MM001i and MM008i respond rapidly to aCTLA-4 therapy. Both models express unique tumor antigens as evidenced by immunity to subsequent engraftments. Primary MM008i tumors exhibit greater T cell infiltration, and CD8-positive T lymphocytes are required for aPD-1 responses. These TNBC models are promising for further mechanistic studies and testing future single and combinatorial therapies.

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Microarray-based gene expression data from BPLER tumor explants.

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MSLN-mediated activation of EGFR-ERK1/2 signaling drives liver metastasis in breast cancer

Project description:To facilitate the study of organ metastasis of triple-negative breast cancer (TNBC), liver metastatic models of TNBC were developed using 4T1 cell lines via repeated fat pad injections and the selection and growth of metastatic clones in vivo . The obtained cell lines were designated based on their source organs and injection cycles. Through ex vivo bioluminescence imaging (BLI) and metastatic nodule quantification, liver metastasis potential was validated in HM3 (third-passage liver metastatic cells). These cells exhibited preferential metastasis to the liver. Metastatic burden progressively increased across serial transplantations, as evidenced by escalating nodule counts in target organs. For the liver-specific metastasis mouse model, 100 μl of PBS containing 1×10⁶ 4T1 (BALB/c mice) cells was injected in situ into mammary fat pad of mice. Cells from primary tumors and liver metastases were separately isolated and cultured (cells isolated from mouse primary tumors were named 4T1-Pri, the metastatic tumor cells isolated from liver organs were named HM). After stable clones were established, liver organ metastatic cells were reinoculated into new mice to generate metastatic tumors. After at least three rounds of screening, highly liver organotropic metastasis cells were successfully established, designated as 4T1/HM3 (liver-preferential metastases). The firefly luciferase reporter gene (for bioluminescence tracking) retrovirus was infected with 4T1-derived cells and puromycin (1 μg/mL, Sigma Aldrich, USA) was selected for 14 days.

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Project description:Triple negative breast cancer (TNBC) is an aggressive subtype that lack targeted clinical therapies. In addition, TNBC is heterogeneous and was recently further sub-classified into seven TNBC subtypes that displayed unique gene expression patterns. To develop therapeutic treatment regimens, we established seven patient-derived xenograft models from TNBC tumors. These xenograft models not only retained the histology and clinical markers of the corresponding patient tumors, but also bearing the same mutations and deletions identified in the patient tumors. Moreover, as part of evaluation of these models, we performed microarrays on the xenograft tumors to assess their TNBC subtypes. After obtaining IRB-approved informed written patient consent, breast cancer tissues were obtained fresh from Stanford Hospital and transplanted into the number 2 mammary fat pads of female NOD SCID mice (NOD.CB17-Prkdcscid/J, Jackson Laboratory West, Sacramento, CA, USA). Mice were maintained in pathogen-free animal housing. The established xenografts were subsequently passaged from mouse to mouse. Xenograft tumor tissues were frozen on dry ice for RNA isolation and microarray analysis.

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Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

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