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"Welch, Danny"
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Afetna Point, Saipan : archaeological investigations of a Latte Period village and historic context in the Commonwealth of the Northern Mariana Islands
When Ferdinand Magellan first anchored off the island of Guam in 1521, the inhabitants of the small Chamorro village at Afetna Point on the southwest coast of Saipan were likely unaware. Archaeological investigations of the traditional village yielded Latte Period burials, ceramics, stone and shell tools, microfossils from food remains, and charcoal from cooking features dating between A.D. 1450 and 1700. No direct evidence of Spanish Contact before forced abandonment of the island circa 1730 was encountered, after which time Saipan remained virtually unpopulated until the arrival of Carolinian and Chamorro settlers from Guam nearly a century later. Spanish settlement in 1668, the German occupation from 1898-1914, and the Japanese sugarcane period from 1914-1944 left few traces at the site until WWII and subsequent American administration. Afetna Point and Saipan have therefore been a contested landscape for centuries, but the island's prehistory has deep roots that tie the Mariana Islands and its modern culture to ancestral SE Asia.
Book
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. Biochemical processes within the mitochondria of both cancer cells and the stromal cells with which they interact are critical for each metastatic hallmark. We unravel complex dynamics in mitochondrial contributions to cancer, which are context-dependent and capable of either promoting metastasis or being leveraged to prevent it at various points of the metastatic cascade. Ultimately, mitochondrial contributions to cancer and metastasis are rooted in the capacity of these organelles to tune metabolic and genetic responses to dynamic microenvironmental cues.
Journal Article
KISS1 metastasis suppressor in tumor dormancy: a potential therapeutic target for metastatic cancers?
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells.
Journal Article
KISS1 in metastatic cancer research and treatment: potential and paradoxes
The significance of KISS1 goes beyond its original discovery as a metastasis suppressor. Its function as a neuropeptide involved in diverse physiologic processes is more well studied. Enthusiasm regarding KISS1 has cumulated in clinical trials in multiple fields related to reproduction and metabolism. But its cancer therapeutic space is unsettled. This review focuses on collating data from cancer and non-cancer fields in order to understand shared and disparate signaling that might inform clinical development in the cancer therapeutic and biomarker space. Research has focused on amino acid residues 68-121 (kisspeptin 54), binding to the KISS1 receptor and cellular responses. Evidence and counterevidence regarding this canonical pathway require closer look at the covariates so that the incredible potential of KISS1 can be realized.
Journal Article
Functional inhibition of the RNA ‐binding protein HuR sensitizes triple‐negative breast cancer to chemotherapy
Chemotherapy remains the standard treatment for triple‐negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA‐binding protein Hu antigen R (HuR) could be a potential therapeutic target to enhance the chemotherapy efficacy. HuR is known to mainly stabilize its target mRNAs, and/or promote the translation of encoded proteins, which are implicated in multiple cancer hallmarks, including chemoresistance. In this study, a docetaxel‐resistant cell subline (231‐TR) was established from the human TNBC cell line MDA‐MB‐231. Both the parental and resistant cell lines exhibited similar sensitivity to the small molecule functional inhibitor of HuR, KH‐3. Docetaxel and KH‐3 combination therapy synergistically inhibited cell proliferation in TNBC cells and tumor growth in three animal models. KH‐3 downregulated the expression levels of HuR targets (e.g., β‐Catenin and BCL2) in a time‐ and dose‐dependent manner. Moreover, KH‐3 restored docetaxel's effects on activating Caspase‐3 and cleaving PARP in 231‐TR cells, induced apoptotic cell death, and caused S‐phase cell cycle arrest. Together, our findings suggest that HuR is a critical mediator of docetaxel resistance and provide a rationale for combining HuR inhibitors and chemotherapeutic agents to enhance chemotherapy efficacy.
Journal Article
BRMS1: a multifunctional signaling molecule in metastasis
Despite high mortality rates, molecular understanding of metastasis remains limited. It can be regulated by both pro- and anti-metastasis genes. The metastasis suppressor, breast cancer metastasis suppressor 1 (BRMS1), has been positively correlated with patient outcomes, but molecular functions are still being characterized. BRMS1 has been implicated in focal adhesion kinase (FAK), epidermal growth factor receptor (EGFR), and NF-κB signaling pathways. We review evidence that BRMS1 regulates these vast signaling pathways through chromatin remodeling as a member of mSin3 histone deacetylase complexes.
Journal Article
Synergistic anti-proliferative activity of JQ1 and GSK2801 in triple-negative breast cancer
Background
Triple-negative breast cancer (TNBC) constitutes 10–20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801.
Methods
RNASeq data sets of TNBC cell lines (MDA-MB-231, HCC-1806 and SUM-159) were analyzed to identify the differentially expressed genes in single and combined treatments. The topmost downregulated genes were characterized for their downregulated expression in the TNBC cell lines treated with JQ1 and GSK2801 under different dose concentrations and combinations. The optimal lethal doses were determined by cytotoxicity assays. The inhibitory activity of the drugs was further characterized by molecular modelling studies.
Results
Global expression profiling of TNBC cell lines using RNASeq revealed different expression patterns when JQ1 and GSK2801 were co-administered. Functional enrichment analyses identified several metabolic pathways (i.e., systemic lupus erythematosus, PI3K-Akt, TNF, JAK-STAT, IL-17, MAPK, Rap1 and signaling pathways) enriched with upregulated and downregulated genes when combined JQ1 and GSK2801 treatment was administered. RNASeq identified downregulation of
PTPRC, MUC19, RNA5-8S5, KCNB1, RMRP, KISS1
and
TAGLN
(validated by RT-qPCR) and upregulation of
GPR146, SCARA5, HIST2H4A, CDRT4, AQP3, MSH5-SAPCD1, SENP3-EIF4A1, CTAGE4
and
RNASEK-C17orf49
when cells received both drugs. In addition to differential gene regulation, molecular modelling predicted binding of JQ1 and GSK2801 with PTPRC, MUC19, KCNB1, TAGLN and KISS1 proteins, adding another mechanism by which JQ1 and GSK2801 could elicit changes in metabolism and proliferation.
Conclusion
JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.
Journal Article