Michael N Vansaun

University of Miami | UM · Division of Surgical Oncology

Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer death in the US by 2025, with rising incidence. Mutant KRAS in >90% of PDAC cases promotes activation of the MAPK pathway, yet targeting the MAPK pathway clinically has failed to improve patient outcomes. SHP2 canonically promotes KRAS activation and is es...

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the United States and has an abysmal 5-year overall survival of 12%. A major risk factor for PDAC is obesity- which has increased 12% between 1999-2018 in the United States. This rise correlates with the projection that PDAC is to become the second leading cause of...

Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease with a 5-year survival rate of just 12%. Poor survival is due in part to late detection of aggressive disease coincident with distant metastases, most often in the liver. While multiple proteins have been implicated in driving PDAC metastasis, effective targeted therapeutics h...

Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS as well as its target MAPK pathway effectors have shown limited success due to the difficulty to pharmacologically target KRAS, inherent drug resistance in PDAC cells, and acquired resistance through activation of alter...

CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. Cytokines responsible for stimulating these receptors include CXCL ligands, typically secreted by activated immune cells, fibroblasts, and even adipocytes. Obesity has been linked to poor patient outcome and altered anti-tumor immunity. Adipose-derived cytokines...

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the United States. PDAC is an aggressive disease with a poor survival rate of <10%. Hence, there is an urgent need to find novel drug targets for the clinical management of PDAC. Altered sphingolipid metabolism (SM) is a hallmark of cancer. The major sphingolipid...

Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify nove...

The 5-year overall survival for pancreatic ductal adenocarcinoma (PDAC) patients is an abysmal 12% with local disease and 3% for metastatic disease. Obesity is a major risk factor for PDAC showing a three-month decrease in overall survival when compared to lean PDAC patients. The causal relationship between obesity and cancer has driven seminal fin...

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death in the US, due to late detection and limited therapeutic options. While the main cause of PDAC remains unknown, obesity has been shown to be a major risk factor. However, the molecular mechanisms behind adipose-tumor crosstalk are still being elucidated. Therefore, understan...

Adipocytes are the most abundant cell type in the adipose tissue, and their dysfunction is a significant driver of obesity-related pathologies, such as cancer. The mechanisms that (1) drive the maintenance and secretory activity of adipocytes and (2) mediate the cancer cellular response to the adipocyte-derived factors are not fully understood. To...

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor and is the seventh cause of death for cancer worldwide, fifth in the US. The highly malignant profile is mainly caused by the constitutive activation of mutant KRAS - found in approximately 90% of PDAC cases. The undruggability of genetic KRAS mutations has led to efforts to find...

Pancreatic cancer is one of the deadliest cancers, due to late diagnosis and very few available therapeutic treatments. The Kras gene is frequently mutated in pancreatic cancer, but previous clinical trials using RAS inhibitors have proven ineffective. Additionally, many drug treatments targeting the MAPK pathway have shown little success due to th...

Obesity creates a localized inflammatory reaction in the adipose, altering secretion of adipocyte-derived factors that contribute to pathologies including cancer. We have previously shown that adiponectin inhibits pancreatic cancer by antagonizing leptin-induced STAT3 activation. Yet, the effects of adiponectin on pancreatic cancer cell metabolism...

Activating KRAS mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDKs) that induce cell cycle progression. p16INK4a (p16), encoded by the gene CDKN2A, is a potent inhibitor of CDK4/6 and serves as a critical checkpoint of cell proliferation. Mu...

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, stromal desmoplasia, and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/RAF/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi/STAT3i) overcomes th...

The Src family of non-receptor tyrosine kinases are frequently activated in pancreatic ductal adenocarcinoma (PDAC), contributing to disease progression through downregulation of E-cadherin and induction of epithelial-to-mesenchymal transition (EMT). The purpose of this study was to examine the efficacy of Src kinase inhibition in restoring E-cadhe...

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therap...

Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher level...

Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance i...

Background: Alcohol abuse is a major risk factor for pancreatitis. Alcohol addiction-induced molecular pathogenesis of pancreatitis remains obscure, and no current effective treatment exists. Therefore, approaches to investigate pathogenesis, prevention and cellular mechanisms by which alcohol causes pancreatitis are necessary for establishing ther...

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Chronic alcohol (>60 grams/day) consumption is strongly associated with the risk of PDAC development. The metabolites generated from alcohol have been shown to cause significant pancreatic injury. Although the association of...

Obesity is a significant risk factor for pancreatic cancer, harboring a chronic inflammatory condition characterized by dysregulation of the adipokines, leptin and adiponectin, that in turn alter oncogenic signaling pathways. We and others have shown that leptin promotes the proliferation and an invasive potential of pancreatic cancer cells through...

Introduction: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. HCC typically arises in patients with chronic liver disease or cirrhosis, yet it is increasingly associated with non-alcoholic fatty liver disease (NAFLD), specifically nonalcoholic steatohepatitis (NASH) in the absence of cirrhosis. NAFLD is associa...

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related mortality in the United States. Most patients present with an advanced disease and the majority die within five years, many surviving less than six months. Cytotoxic chemotherapy including Gemcitabine (Gem), FOLFIRINOX, nab-paclitaxel offer modest improvement in surv...

High fat diet increases development of hepatocellular carcinoma in glycine N-methyltransferase deficient mice

Demethylation and PPARγ activation independently restore adiponectin receptors in pancreatic cancer’

Combined MEK and STAT3 inhibition reprograms tumor microenvironment for improved anti-tumor efficacy of PD-1 blockade in PDAC

5-Azacytidine and PPARγ restore adiponectin receptors in PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains a major therapeutic challenge. Cytotoxic chemotherapy remains the standard approach in PDAC, but results in minimal survival benefit for patients, highlighting a desperate need for novel treatment strategies. Epidermal growth factor receptor (EGFR) is overexpressed in 25-90% of PDACs and has been show...

Introduction: The increasing incidence of pancreatic cancer is associated with a rising prevalence of obesity, a documented risk factor for the disease. Obesity harbors a systemic chronic inflammatory disorder characterized by increased production and secretion of pro-inflammatory adipokines leptin, TNF-α, and IL-6; while exhibiting a decrease in t...

Introduction: Mutations in the KRAS oncogene occur in the majority of pancreatic ductal adenocarcinomas (PDAC), resulting in aberrant activation of the MAPK (RAS-RAF-MEK-ERK) pathway, driving malignant progression. Targeting KRAS has remained an elusive goal. Therefore, efforts have focused on targeting downstream effectors of RAS. The clinical eff...

AdipoRon suppresses cytokine mediated STAT3 activation through SOCS3 to inhibit pancreatic cancer growth

Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucida...

Introduction: Cyclic AMP (cAMP) response element binding (CREB) overexpression in pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcome, however, the mechanism(s) driving CREB overexpression in PDAC are not fully understood. We investigated the association of CREB activation with oncogenic KRAS, MEK-ERK and AKT signaling pathways....

AdipoRon suppresses ERK and STAT3 to inhibit pancreatic cancer growth

Introduction: Activating KRAS mutations are commonly found in PDAC and lead to constitutive downstream activation of MEK, which results in uncontrolled proliferation. We have previously shown that MEK inhibition results in activation of STAT3 signaling which confers drug resistance and continued cancer cell growth while combined STAT3 and MEK inhib...

Introduction: Cell survival after DNA damage relies on DNA repair processes to protect the integrity of the genome. The repair process involves DNA homologous recombination system that requires numerous factors including the recombinase RAD51 and BRCA2, which co-localize to replication centers within the damaged cell nucleus. The defective DNA repa...

AdipoRon suppresses ERK and STAT3 to inhibit pancreatic cancer growth

Adiponectin is an anti-atherogenic hormone which is typically decreased in the setting of obesity, diabetes, and pancreatitis. Adiponectin and/or its receptor levels have been inversely correlated with risk for pancreatic cancer. The purpose of this study was to determine the effect of adiponectin on pancreatic cancer cells and to investigate the p...

Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients....

Non alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the United States and worldwide. Our studies have previously shown an increase in metastatic burden in steatotic vs. normal livers using a mouse model of diet induced steatosis. In the present study we aim to identify and evaluate the molecular factors responsible...

With the rising prevalence of obesity there has been a marked increase in the incidence of non alcoholic fatty liver disease (NAFLD). Epidemiologically, NAFLD has been linked to an increased risk for development of primary liver cancer (HCC), however the mechanisms involved are not known. The liver is also a frequent site of metastasis for several...

Nonalchoholic fatty liver disease (NAFLD) is a problem of increasing prevalence and clinical significance worldwide and is associated with increased risk of development of end stage liver disease and cirrhosis, and can be complicated by hepatocellular carcinoma (HCC). NAFLD is characterized by physical and molecular changes in the liver microenviro...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The expanding obesity epidemic has led to an escalation in the incidence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis, which are associated with an increase in incidence of primary and metastatic liver cancer. As NAFLD progresses, it is characterized by...

Unlabelled: Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutiv...

The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metas...

Pancreatic cancer is recognized as one of the deadliest forms of cancer; yet the underlying mechanistic cause of pancreatic cancer remains unknown. Risk factors for pancreatic cancer include smoking, chronic pancreatitis, obesity, and family history. Obesity is known to lead to alteration of serum adipokine levels, including the reduction of adipon...

Proteinases, including matrix metalloproteinases (MMPs), contribute to cancer progression and other pathologies. Selective MMP expression can be used to distinguish benign from malignant tumors and identify aggressive tumors associated with poor outcome. MMP9, a basement membrane-degrading type-IV collagenase/gelatinase, is associated with tumor in...

Introduction: Non-alcoholic fatty liver disease (NAFLD), encompassing steatosis and progression to non-alcoholic steatohepatitis (NASH) are liver disorders of increasing clinical significance. Studies in our lab have shown that hepatic steatosis establishes a permissive microenvironment for metastatic tumor seeding and tumor progression in the live...

Background: Pro-inflammatory processes associated with the early postoperative state are known to contribute to peritoneal metastases in patients with advanced diseases. This study aimed to determine whether the wound healing response after an abdominal incision leads to increased matrix metalloproteinase (MMP)-9 activity locally, contributing to...

Background: Pancreatic cancer is the fourth leading cause of cancer death with a five year survival rate around 5%, which has not changed in 30 years. Obesity and increased abdominal adipose tissue independently correlate with an increased relative risk for the development of pancreatic cancer. These conditions have been associated with altered lev...

Cell identity is determined by its gene expression programs. The ability of a cell to change its identity and produce cell types outside its lineage is achieved by the activity of transcription controllers capable of reprogramming differentiation gene networks. The synovial sarcoma (SS)-associated protein, SYT-SSX2, reprograms myogenic progenitors...

Fragmentation spectra of m/z 871 peak. MS/MS spectra of 38:4e PI from cirrhotic liver sample (eluting at 6.06 min). (TIF)

MS/MS spectra of 18:0e/20:4 PI synthetic standard. Fragmentation pattern of the liver sample PI yielded fragments consistent with those appearing in the synthetic standard. (TIF)

Total number of identified phospholipid species in each of the human liver (normal, steatotic, and cirrhotic) and murine groups. The number includes the identification of isobaric species (having the same total carbon number and number of double bonds but presented in different fatty acids combinations. I.e., 36:4 PC could be 16:0/20:4, 18:2/18:2,...

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The go...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Pancreatic cancer remains one of the eight deadliest cancers due to its late detection and high propensity to metastasize. Increased risk for the development of pancreatic cancer has been associated with obesity, type II diabetes and pancreatitis. The contribution of adipocyt...

Non-alcoholic fatty liver disease (NAFLD), encompassing steatosis and progression to non-alcoholic steatohepatitis (NASH) are liver disorders of increasing clinical significance. We have shown that hepatic steatosis establishes a permissive microenvironment for metastatic seeding and tumor progression in the liver. We have identified MMP-12 (macrop...

Non-alcoholic fatty liver disease (NAFLD), which includes steatosis and its progression to non-alcoholic steatohepatitis, is a liver disorder of increasing clinical significance. Here we characterize a murine model of high fat diet-induced NAFLD with progression from liver steatosis to histological features compatible with steatohepatitis and more...

By analogy, the study of metastasis is like a group of blind people studying an elephant. Each describes the pachyderm based on the part (s)he touches, but none comprehends the whole elephant because his/her exposure is limited. Likewise, the complexity of metastasis can only be appreciated when one either steps back from a specialized area and exa...

Matrix metalloproteinases (MMPs) are extracellular proteolytic enzymes involved in tumor progression. We present the in vivo detection and quantitation of MMP7 activity using a specific near-infrared polymer-based proteolytic beacon, PB-M7NIR. PB-M7NIR is a pegylated polyamidoamine PAMAM-Generation 4 dendrimer core covalently coupled to a Cy5.5-lab...

The extracellular matrix surrounding the neuromuscular junction is a highly specialized and dynamic structure. Matrix Metalloproteinases are enzymes that sculpt the extracellular matrix. Since synaptic activity is critical to the structure and function of this synapse, we investigated whether changes in synaptic activity levels could alter the acti...

The movement of cells and the accompanied remodeling of the extracellular matrix is a critical step in many developmental processes. The matrix metalloproteinases (MMPs) are well recognized as mediators of matrix degradation, and their activity as regulators of signaling pathways by virtue of the cleavage of nonmatrix substrates has been increasing...

Rapsyn is a synapse-specific protein that is required for clustering acetylcholine receptors at the neuromuscular junction. Analysis of the rapsyn promoter revealed a consensus site for the transcription factor Kaiso within a region that is mutated in a subset of patients with congenital myasthenic syndrome. Kaiso is a POZ-zinc finger family transc...

Matrix metalloproteinases are important regulators of extracellular matrix molecules and cell-cell signaling. Antibodies to matrix metalloproteinase 3 (MMP3) recognize molecules at the frog neuromuscular junction, and MMP3 can remove agrin from synaptic basal lamina (VanSaun & Werle, 2000). To gain insight into the possible roles of MMP3 at the neu...

Agrin is a heparan sulfate proteoglycan, which plays an essential role in the development and maintenance of the neuromuscular junction. Agrin is a stable component of the synaptic basal lamina and strong evidence supports the hypothesis that agrin directs the formation of the postsynaptic apparatus, including aggregates of AChRs, and junctional fo...

Agrin, a heparin sulfate proteogly-can, is an integral member of the synaptic basal lamina and plays a critical role in the formation and maintenance of the neuromuscular junction. The N-terminal region of agrin binds tightly to basal lamina, while the C-terminal region interacts with a muscle-specific ty-rosine kinase (MuSK) to induce the formatio...

Agrin, a heparin sulfate proteoglycan, is an integral member of the synaptic basal lamina and plays a critical role in the formation and maintenance of the neuromuscular junction. The N-terminal region of agrin binds tightly to basal lamina, while the C-terminal region interacts with a muscle-specific tyrosine kinase (MuSK) to induce the formation...

Agrin, a heparin sulfate proteoglycan, is an integral member of the synaptic basal lamina and plays a critical role in the formation and maintenance of the neuromuscular junction. The N-terminal region of agrin binds tightly to basal lamina, while the C-terminal region interacts with a muscle-specific tyrosine kinase (MuSK) to induce the formation...