C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer.

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.

Mass Cytometry of Follicular Lymphoma Tumors Reveals Intrinsic Heterogeneity in Proteins Including HLA-DR and a Deficit in Nonmalignant Plasmablast and Germinal Center B-Cell Populations.

BACKGROUND: Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that has a risk of transformation to more aggressive lymphoma. Relatively little is known about the nonmalignant B-cell and T-cell subset composition within the tumor microenvironment and whether altered phenotypes are associated with patterns of lymphoma B-cell heterogeneity. METHODS: Two mass cytometry (CyTOF) panels were designed to immunophenotype B and T cells in FL tumors. Populations of malignant B cells, nonmalignant B cells, and T cells from each FL tumor were identified and their phenotypes compared to B and T cells from healthy human tonsillar tissue. RESULTS: Diversity in cellular phenotype between tumors was greater for the malignant B cells than for nonmalignant B or T cells. The malignant B-cell population bore little phenotypic similarity to any healthy B-cell subset, and unexpectedly clustered closer to naïve B-cell populations than GC B-cell populations. Among the nonmalignant B cells within FL tumors, a significant lack of GC and plasmablast B cells was observed relative to tonsil controls. In contrast, nonmalignant T cells in FL tumors were present at levels similar to their cognate tonsillar T-cell subsets. CONCLUSION: Mass cytometry revealed that diverse HLA-DR expression on FL cells within individual tumors contributed greatly to tumor heterogeneity. Both malignant and nonmalignant B cells in the tumor bore little phenotypic resemblance to healthy GC B cells despite the presence of T follicular helper cells in the tumor. These findings suggest that ongoing signaling interactions between malignant B cells and intra-tumor T cells shape the tumor microenvironment. © 2016 International Clinical Cytometry Society.