Generation of Murine Cancer Cell Lines.

Cancer cell lines are important tools to investigate the biology of cancer and test hypotheses to improve cancer treatments. A major challenge in establishing epithelial cancer cell lines is the removal of cancer-associated fibroblasts (CAFs). CAFs are abundant within the tumor microenvironment.

Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.

Besides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGFβ transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus.

cProSite: A web based interactive platform for online proteomics, phosphoproteomics, and genomics data analysis.

We developed cProSite, a website that provides online genomics, proteomics, and phosphoproteomics analysis for the data of The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC). This tool focuses on comparisons and correlations between different proteins and mRNAs of tumors and normal tissues. Our website is designed with biologists and clinicians in mind, with a user-friendly environment and fast search engine.

Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration.

Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy.

STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential.

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5a) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize.

Low-dose carbon monoxide suppresses metastatic progression of disseminated cancer cells.

Low-dose carbon monoxide (CO) is under investigation in clinical trials to treat non-cancerous diseases and has an excellent safety profile. Due to early detection and cancer awareness, an increasing number of cancer patients are diagnosed at early stages, when potentially curative surgical resection can be done. However, many patients ultimately experience recurrence.

RHAMM-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment.

The incidence of pancreatic neuroendocrine tumor (PNET) has continued to rise. Due to their indolent feature, PNET patients often present with incurable, metastatic diseases. Novel therapies are urgently needed.

Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer.

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor.

Functional impact of cancer patient-associated Bcl-xL mutations.

Bcl-xL, an antiapoptotic protein, is frequently overexpressed in cancer to promote survival of tumor cells. However, we have previously shown that Bcl-xL promotes migration, invasion, and metastasis independent of its antiapoptotic function in mitochondria. The pro-metastatic function of Bcl-xL may require its translocation into the nucleus.

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer.

Pancreatic cancer has the lowest survival rate out of all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages, hence an urgent need for a better therapeutic development of this devastating disease. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET).

miR-431 Promotes Metastasis of Pancreatic Neuroendocrine Tumors by Targeting DAB2 Interacting Protein, a Ras GTPase Activating Protein Tumor Suppressor.

The incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations and an unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs.

Insights into the biology and treatment strategies of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are the second most common primary pancreatic neoplasms after pancreatic ductal adenocarcinoma. PNETs present with widely various clinical manifestation and unfavorable survival rate. The recent advances in next generation sequencing have significantly increased our understanding of the molecular landscape of PNETs and help guide the development of targeted therapies.

(-)-Oleocanthal and (-)-oleocanthal-rich olive oils induce lysosomal membrane permeabilization in cancer cells.

(-)-Oleocanthal (oleocanthal) is a phenolic compound found in varying concentrations in extra virgin olive oil oleocanthal has been shown to be active physiologically, benefiting several diseased states by conferring anti-inflammatory and neuroprotective benefits. Recently, we and other groups have demonstrated its specific and selective toxicity toward cancer cells; however, the mechanism leading to cancer cell death is still disputed. The current study demonstrates that oleocanthal, as well as naturally oleocanthal-rich extra virgin olive oils, induced damage to cancer cells' lysosomes leading to cellular toxicity in vitro and in vivo.

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression.

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMM promoted liver metastasis. It was unknown whether RHAMM is upregulated in pancreatic cancer or contributes to its progression.

Expression of the Receptor for Hyaluronic Acid-Mediated Motility (RHAMM) in Endometrial Cancer is Associated With Adverse Histologic Parameters and Tumor Progression.

Endometrial cancer is one of the most common gynecologic malignancies worldwide. Only 2 agents have been approved by Food and Drug Administration for endometrial cancer since 1971. There is a need to identify molecular targets to treat advanced endometrial cancer.

Alleles of Insm1 determine whether RIP1-Tag2 mice produce insulinomas or nonfunctioning pancreatic neuroendocrine tumors.

The two most common types of pancreatic neuroendocrine tumors (PanNETs) are insulinomas and nonfunctioning PanNETs (NF-PanNETs). Insulinomas are small, rarely metastatic tumors that secrete high amounts of insulin, and nonfunctioning PanNETs are larger tumors that are frequently metastatic but that do not secrete hormones. Insulinomas are modeled by the highly studied RIP1-Tag2 (RT2) transgenic mice when bred into a C57Bl/6 (B6) genetic background (also known as RT2 B6 mice).

UCHL1 loss alters the cell-cycle in metastatic pancreatic neuroendocrine tumors.

Loss of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) expression by CpG promoter hypermethylation is associated with metastasis in gastroenteropancreatic neuroendocrine tumors; however, the mechanism of how UCHL1 loss contributes to metastatic potential remains unclear. In this study, we first confirmed that loss of UCHL1 expression on immunohistochemistry was significantly associated with metastatic tumors in a translational pancreatic neuroendocrine tumor (PNET) cohort, with a sensitivity and specificity of 78% and 89%, respectively. To study the mechanism driving this aggressive phenotype, BON and QGP-1 metastatic PNET cell lines, which do not produce UCHL1, were stably transfected to re-express UCHL1.

Orthotopic Pancreatic Tumor Mouse Models of Liver Metastasis.

The survival from pancreatic cancer is poor because most patients are diagnosed after the cancer has metastasized. Liver is the most common site of pancreatic cancer metastasis. Orthotopic mouse models of liver metastasis by intrasplenically injecting the pancreatic tumor cells are useful in studying the molecular mechanisms of metastasis and evaluating therapeutic regimens.

Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation.

We reported that inactivation of menin (the protein product of MEN1) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation.

Immunohistochemical analysis of RHAMM expression in normal and neoplastic human tissues: a cell cycle protein with distinctive expression in mitotic cells and testicular germ cells.

Expression of Receptor for Hyaluronic Acid Mediated Motility (RHAMM) increases cellular motility and RHAMM overexpression promotes invasive phenotype and metastasis of cancer cells. RHAMM has been suggested as a biomarker for poor prognosis in several tumor types, including lung, breast, colorectal, gastric, pancreatic ductal, and ovarian cancers. RNA studies showed restricted RHAMM expression in normal tissues, but its protein expression data in tissues were limited.

Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model.

Metastatic cancer accounts for 90% of deaths in patients with solid tumors. There is an urgent need to better understand the drivers of cancer metastasis and to identify novel therapeutic targets. To investigate molecular events that drive the progression from primary cancer to metastasis, we have developed a bitransgenic mouse model, RIP-Tag; RIP-tva.

Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma.

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers, but its role in primary and metastatic non-small cell lung carcinoma (NSCLC) remains to be determined. Here, we investigate the clinical relevance of RHAMM expression in NSCLC. RHAMM protein expression correlates with histological differentiation stages and extent of the primary tumor (T stages) in 156 patients with primary NSCLC.

p53 and p16/p19 Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells.

In human studies and mouse models, the contributions of p53 and p16/p19 loss are well established in pancreatic ductal adenocarcinoma (PDAC). Although loss of functional p53 pathway and loss of Ink4a/Arf in human pancreatic acinar cell carcinoma (PACC) and pancreatic neuroendocrine tumor (PanNET) are identified, their direct roles in tumorigenesis of PACC and PanNET remain to be determined. Using transgenic mouse models expressing the viral oncogene polyoma middle T antigen (PyMT), we demonstrate that p53 loss in pancreatic Pdx1+ progenitor cells results in aggressive PACC, whereas Ink4a/Arf loss results in PanNETs.