Strigolactone analogs act as new anti-cancer agents in inhibition of breast cancer in xenograft model

Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.R35 GM118173 - NIGMS NIH HHS; U01 TR002625 - NCATS NIH HHS; P30 CA008748 - NCI NIH HHS; FC010144 - Cancer Research UK; FC010144 - Medical Research Council; FC010144 - Wellcome TrustPublished versio

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling

Tumors initiate by mutations in cancer cells, and progress through interactions of the cancer cells with non-malignant cells of the tumor microenvironment. Major players in the tumor microenvironment are cancer-associated fibroblasts (CAFs), which support tumor malignancy, and comprise up to 90% of the tumor mass in pancreatic cancer. CAFs are transcriptionally rewired by cancer cells. Whether this rewiring is differentially affected by different mutations in cancer cells is largely unknown. Here we address this question by dissecting the stromal landscape of BRCA-mutated and BRCA Wild-type pancreatic ductal adenocarcinoma. We comprehensively analyze pancreatic cancer samples from 42 patients, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA Wild-type tumors. In particular, we detect an increase in a subset of immune-regulatory clusterin-positive CAFs in BRCA-mutated tumors. Using cancer organoids and mouse models we show that this process is mediated through activation of heat-shock factor 1, the transcriptional regulator of clusterin. Our findings unravel a dimension of stromal heterogeneity influenced by germline mutations in cancer cells, with direct implications for clinical research

Elevated Expression of Moesin in Muscular Dystrophies

International audienceFibrosis is the main complication of muscular dystrophies. We identified moesin, a member of the ezrin-radixin-moesin family, in dystrophic muscles of mice representing Duchenne and congenital muscular dystrophies (DMD and CMD, respectively) and dysferlinopathy, but not in the wild type. High levels of moesin were also observed in muscle biopsy specimens from DMD, Ullrich CMD, and merosin-deficient CMD patients, all of which present high levels of fibrosis. The myofibroblasts, responsible for extracellular matrix protein synthesis, and the macrophages infiltrating the dystrophic muscles were the source of moesin. Moesin-positive cells were embedded within the fibrotic areas between the myofibers adjacent to the collagen type I fibers. Radixin was also synthesized by the myofibroblasts, whereas ezrin colocalized with the myofiber membranes. In animal models and patients' muscles, part of the moesin was in its active phosphorylated form. Inhibition of fibrosis by halofuginone, an antifibrotic agent, resulted in a major decrease in moesin levels in the muscles of DMD and CMD mice. In summary, the results of this study may pave the way for exploiting moesin as a novel target for intervention in MDs, and as part of a battery of biomarkers to evaluate treatment success in preclinical studies and clinical trials

Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone

Absence of, or loss-of-function mutations in the dysferlin gene (dysf) result in dysferlinopathy, characterized by increased muscle inflammation, collagen deposition and deterioration in muscle function. We evaluated halofuginone efficacy in improving muscle histopathology in mice with deleted dysf transmembrane domain. Quadriceps sublumbar and longissimus muscles of 9-month-old dysf-/- mice treated with halofuginone for 4 months exhibited a reduction in centrally-nucleated myofibers, inflammatory infiltrates and collagen content. Late onset of dysferlinopathy makes it ideal for evaluating the efficacy of early treatments on late outcome. The dysf-/- mice were treated with halofuginone for 3 to 4 months starting at 1, 5 or 9 months of age, and quadricep muscle histopathology was evaluated at 12 months. Collagen content and number of centrally nucleated myofibers decreased after early halofuginone treatment, administered when myofibers with central nuclei and inflammatory infiltrates are evident, but there was almost no fibrosis. When administered at the beginning of fibrosis it resulted in a further decrease in the number of centrally-nucleated myofibers with no additional decrease in collagen levels. Cardiac fibrosis was almost completely abolished following early halofuginone treatment. Halofuginone inhibited Smad3 phosphorylation and its translocation to the nucleus and increased the activity of matrix metalloproteinases 9 and 2 responsible for resolution of pre-existing collagen. Macrophage and myofibroblast invasion into the dystrophic muscle at the site of myofibers with central nuclei was inhibited by halofuginone. These results suggest that early halofuginone treatment can prevent the late outcome of dysferlinopathy and can cause resolution of the established fibrosis when administered at later stages

Figure S1 from Breast Cancer–Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic Niche

Supplementary data to Figure 1</p

Figure S2 from Breast Cancer–Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic Niche

Supplementary data to Figure 4</p

Figure S3 from Breast Cancer–Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic Niche

Supplementary data to Figure 6</p

Table S1 from Breast Cancer–Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic Niche

Supplementary Table 1 showing list of proteins detected in protein array</p