Estrogen receptor alpha gene ESR1 mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 YS mutation induced an epithelial-mesenchymal transition EMT with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of YS ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. YS mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen Tam as well as to estradiol E 2 withdrawal.
Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis
In a clinical trial evaluating a novel immunotherapy option for cancer treatment, a child with rhabdomyosarcoma, a form of muscle cancer, that had spread to the bone marrow, showed no detectable cancer following treatment with chimeric antigen receptor CAR T cells that were engineered to target the HER2 protein on the surface of the cancer cells. As a result, this child was a candidate to receive a promising new CAR T cell therapy, a personalized form of immunotherapy that redirects the patient's own immune T cells to recognize and fight the tumor ," said first and corresponding author Dr. Meenakshi Hegde, assistant professor of pediatric hematology-oncology at Baylor College of Medicine and Texas Children's. About 75 percent of the tumor cells in this patient displayed a protein on their surface called HER2.
Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase ATGL activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis-lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities.
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