Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or in-pipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice,...
Approximately 20% of colorectal cancer patients present with metastases at the time of diagnosis, and therapies that specially target these metastases are lacking. We present a novel approach for investigating transcriptomic differences between primary colorectal cancers (CRC) and distant metastases, which may help to identify primary tumors with high risk for future dissemination and to inform the development of metastasis-targeted therapies. To effectively compare the transcriptomes of primary...
The nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARdelta) is a ligand-dependent transcription factor involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Although PPARdelta has been shown to promote intestinal adenoma formation and growth, the molecular mechanisms underlying the contribution of PPARdelta to colorectal cancer (CRC) remain unclear. Here we demonstrate that activation of PPARdelta induces expansion of colonic cancer stem...
The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations....
To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (Engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin...
One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel...
Colorectal cancer (CRC) is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LVs) and tumor-associated macrophages (TAMs). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary CRC development. We found that both VEGFC and VEGFR3 were upregulated in human non-metastatic CRC, with VEGFR3 expressed on...
Tripartite motif (TRIM) family proteins participate in a variety of important cellular processes, including apoptosis, cell cycle arrest, DNA repair and senescence. In this study, we demonstrated that a novel TRIM family member, TRIM67, was commonly silenced in colorectal cancer (CRC) and its downregulation was associated with poor survival. Trim67 knockout in ApcMin/+ mice increased the incidence, multiplicity and burden of colorectal tumors. Similarly, colon-specific knockout of Trim67 significantly...
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