Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer.

The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding.

KSR1 regulates small-cell lung carcinoma tumor initiation and cisplatin resistance.

Small-cell lung cancer (SCLC) is designated a recalcitrant cancer due to its five-year relative survival rate of less than 7%. First line SCLC treatment has changed modestly in the last 40 years. The NeuroD1 subtype of SCLC (SCLC-N) commonly harbors MYC amplifications and other hallmarks of aggressive behavior.

Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20.

Background: The repurposing of FDA-approved drugs for anti-cancer therapies is appealing due to their established safety profiles and pharmacokinetic properties and can be quickly moved into clinical trials. Cancer progression and resistance to conventional chemotherapy remain the key hurdles in improving the clinical management of colon cancer patients and associated mortality.

Methods: High-throughput screening (HTS) was performed using an annotated library of 1,600 FDA-approved drugs to identify drugs with strong anti-CRC properties.

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.

KRAS is the most commonly mutated oncogene. Targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance.

Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer.

Therapy resistance is the primary problem in treating late-stage colorectal cancer (CRC). Claudins are frequently dysregulated in cancer, and several are being investigated as novel therapeutic targets and biomarkers. We have previously demonstrated that Claudin-1 (CLDN1) expression in CRC promotes epithelial-mesenchymal transition, metastasis, and resistance to anoikis.

Differential methylation patterns in lean and obese non-alcoholic steatohepatitis-associated hepatocellular carcinoma.

Background: Nonalcoholic fatty liver disease affects about 24% of the world's population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood.

PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.

Background: Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival.

Methods: In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β and inducible PGC-1β mutants to show that amino acid motif LRELL on PGC-1β is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1β & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes.

Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice.

Background: Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.

Splenic and PB immune recovery in neoadjuvant treated gastrointestinal cancer patients.

In recent years, immune therapy, notably immune checkpoint inhibitors (ICI), in conjunction with chemotherapy and surgery has demonstrated therapeutic activity for some tumor types. However, little is known about the optimal combination of immune therapy with standard of care therapies and approaches. In patients with gastrointestinal (GI) cancers, especially pancreatic ductal adenocarcinoma (PDAC), preoperative (neoadjuvant) chemotherapy has increased the number of patients who can undergo surgery and improved their responses.

KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition.

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells.

A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer.

Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products.

High-throughput identification of protein functional similarities using a gene-expression-based siRNA screen.

A gene expression-based siRNA screen was used to evaluate functional similarity between genetic perturbations to identify functionally similar proteins. A siRNA library (siGenome library, Dharmacon) consisting of multiple siRNAs per gene that have been pooled in to one well per gene was arrayed in a 384-well format and used to individually target 14,335 proteins for depletion in HCT116 colon cancer cells. For each protein depletion, the gene expression of eight genes was quantified using the multiplexed Affymetrix Quantigene 2.

The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC.

Experimental Design: A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics.

MnTnBuOE-2-PyP treatment protects from radioactive iodine (I-131) treatment-related side effects in thyroid cancer.

Treatment of differentiated thyroid cancer often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. However, there is morbidity associated with I-131 therapy, which can result in both acute and chronic complications. Currently, there are no approved radioprotectors that can be used in conjunction with I-131 to reduce complications in thyroid cancer therapy.

A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery.

Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs).

ERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells.

The cell cycle is under circadian regulation. Oncogenes can dysregulate circadian-regulated genes to disrupt the cell cycle, promoting tumor cell proliferation. As a regulator of G2/M arrest in response to DNA damage, the circadian gene Timeless Circadian Clock (TIMELESS) coordinates this connection and is a potential locus for oncogenic manipulation.

RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications.

The RAS family is among the most commonly mutated genes in all human malignancies including colon cancer. In normal cells, RAS proteins act as a link in the intracellular signal transduction initiated by binding of growth factors to cell membrane receptors mediating cell survival. RAS isoproteins have great morphological similarities, but despite that, they are thought to have different functions in different tissues.

WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage.

Background: KMT2/MLL proteins are commonly overexpressed or mutated in cancer and have been shown to support cancer maintenance. These proteins are responsible for methylating histone 3 at lysine 4 and promoting transcription and DNA synthesis; however, they are inactive outside of a multi-protein complex that requires WDR5. WDR5 has been implicated in cancer for its role in the COMPASS complex and its interaction with Myc; however, the role of WDR5 in colon cancer has not yet been elucidated.

Use of Endoscopic Ultrasound in a Diagnostic Dilemma: Metastatic Breast Cancer to the Stomach.

A 55-year-old woman presented with persistent nausea, vomiting, and weight loss previously attributed to Ménétrier's disease. On further workup, she was found to have metastatic lobular breast carcinoma causing gastric outlet obstruction, diagnosed by endoscopic ultrasound with fine needle aspiration after previous gastric mucosal biopsies were unremarkable. In most reported cases of gastric metastasis from breast cancer, a diagnosis was established by mucosal biopsy.

A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells.

AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death.

Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer.

Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases.

KSR as a therapeutic target for Ras-dependent cancers.

Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers. Areas covered: Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins.

TMPRSS2-ERG gene fusion is rare compared to PTEN deletions in stage T1a prostate cancer.

T1a prostate cancers (cancer found incidentally in transurethral resection, <5% of the tissue) are indolent tumors of the transition zone. The overexpression of ERG and the inactivation of PTEN have been shown to be important drivers of carcinogenesis in large series of prostate cancer, but the genetics of transition zone tumors have not been well characterized. We evaluated the status of ERG and PTEN in formalin-fixed paraffin-embedded tissue using immunohistochemical and FISH analysis in 54 T1a transition zone tumors.