Dasatinib and Trametinib Promote Anti-Tumor Metabolic Activity.

Thyroid cancer is the most common endocrine neoplasm, and despite its overall high survival rate, patients with metastatic disease or tumors that resist radioactive iodine experience a significantly worse prognosis. Helping these patients requires a better understanding of how therapeutics alter cellular function. Here, we describe the change in metabolite profiles after treating thyroid cancer cells with the kinase inhibitors dasatinib and trametinib.

Recommendations on ELISpot assay validation by the GCC.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays.

Mechanisms of breast cancer metastasis.

Invasive breast cancer tends to metastasize to lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth of the disease in the breast/chest wall, and at metastatic sites, initially by surgery alone, then by a combination of surgery with radiation, and later by adding systemic treatments in the form of chemotherapy, hormone manipulation, targeted therapy, immunotherapy and other treatments aimed at inhibiting the proliferation of cancer cells. It would be valuable for us to know how breast cancer metastasizes; such knowledge would likely encourage the development of therapies that focus on mechanisms of metastasis and might even allow us to avoid toxic therapies that are currently used for this disease.

Roles of mitochondria in the hallmarks of metastasis.

Although mitochondrial contributions to cancer have been recognised for approximately a century, given that mitochondrial DNA (mtDNA) is dwarfed by the size of the nuclear genome (nDNA), nuclear genetics has represented a focal point in cancer biology, often at the expense of mtDNA and mitochondria. However, genomic sequencing and advances in in vivo models underscore the importance of mtDNA and mitochondria in cancer and metastasis. In this review, we explore the roles of mitochondria in the four defined 'hallmarks of metastasis': motility and invasion, microenvironment modulation, plasticity and colonisation.

Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5.

Background: Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC.

Mitochondrial Haplotype of the Host Stromal Microenvironment Alters Metastasis in a Non-cell Autonomous Manner.

Mitochondria contribute to tumor growth through multiple metabolic pathways, regulation of extracellular pH, calcium signaling, and apoptosis. Using the Mitochondrial Nuclear Exchange (MNX) mouse models, which pair nuclear genomes with different mitochondrial genomes, we previously showed that mitochondrial SNPs regulate mammary carcinoma tumorigenicity and metastatic potential in genetic crosses. Here, we tested the hypothesis that polymorphisms in stroma significantly affect tumorigenicity and experimental lung metastasis.

The second genome: Effects of the mitochondrial genome on cancer progression.

The role of genetics in cancer has been recognized for centuries, but most studies elucidating genetic contributions to cancer have understandably focused on the nuclear genome. Mitochondrial contributions to cancer pathogenesis have been documented for decades, but how mitochondrial DNA (mtDNA) influences cancer progression and metastasis remains poorly understood. This lack of understanding stems from difficulty isolating the nuclear and mitochondrial genomes as experimental variables, which is critical for investigating direct mtDNA contributions to disease given extensive crosstalk exists between both genomes.

Meeting report: Metastasis Research Society (MRS) 17th Biennial conference and associated Young Investigator Satellite Meeting (YISM) on cancer metastasis.

The Metastasis Research Society (MRS) 17th Biennial conference on metastasis was held on the 1st to the 5th of August 2018 at Princeton University, NJ, USA. The meeting was held around themes addressing notable aspects of the understanding and treatment of metastasis and metastatic disease covering basic, translational, and clinical research. Importantly, the meeting was largely supported by our patient advocate partners including Susan G.

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer.

Mitochondrial DNA (mtDNA) encodes for only a fraction of the proteins that are encoded within the nucleus, and therefore has typically been regarded as a lesser player in cancer biology and metastasis. Accumulating evidence, however, supports an increased role for mtDNA impacting tumor progression and metastatic susceptibility. Unfortunately, due to this delay, there is a dearth of data defining the relative contributions of specific mtDNA polymorphisms (SNP), which leads to an inability to effectively use these polymorphisms to guide and enhance therapeutic strategies and diagnosis.

Src-mediated regulation of the PI3K pathway in advanced papillary and anaplastic thyroid cancer.

Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients.

Sustained activation of the AKT/mTOR and MAP kinase pathways mediate resistance to the Src inhibitor, dasatinib, in thyroid cancer.

New targeted therapies are needed for advanced thyroid cancer. Our lab has shown that Src is a key mediator of tumorigenic processes in thyroid cancer. However, single-agent Src inhibitors have had limited efficacy in solid tumors.

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer.

Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-SRC is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However, clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies.

eIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells.

Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance.

PVT1 dependence in cancer with MYC copy-number increase.

'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.

Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation.

Aberrant activation of fibroblast growth factor receptors (FGFR) contributes to breast cancer growth, progression, and therapeutic resistance. Because of the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan within the extracellular matrix and that blocking hyaluronan synthesis decreases proliferation, migration, and therapeutic resistance.

Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner.

Tumor formation is an extensive process requiring complex interactions that involve both tumor cell-intrinsic pathways and soluble mediators within the microenvironment. Tumor cells exploit the intrinsic functions of many soluble molecules, including chemokines and their receptors, to regulate pro-tumorigenic phenotypes that are required for growth and progression of the primary tumor. Previous studies have shown that activation of inducible FGFR1 (iFGFR1) in mammary epithelial cells resulted in increased proliferation, migration, and invasion in vitro and tumor formation in vivo.

Duration of expression and activity of Sleeping Beauty transposase in mouse liver following hydrodynamic DNA delivery.

The Sleeping Beauty (SB) transposon system can direct integration of DNA sequences into mammalian genomes. The SB system comprises a transposon and transposase that "cuts" the transposon from a plasmid and "pastes" it into a recipient genome. The transposase gene may integrate very rarely and randomly into genomes, which has led to concerns that continued expression might support continued remobilization of transposons and genomic instability.