Loss of MTSS1 results in increased metastatic potential in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 7%. This dismal prognosis is largely due to the inability to diagnose the disease before metastasis occurs. Tumor cell dissemination occurs early in PDAC. While it is known that inflammation facilitates this process, the underlying mechanisms responsible for this progression have not been fully characterized. Here, we functionally test the role of metastasis suppressor 1 (MTSS1) in PDAC. Despite evidence showing that MTSS1 could be important for regulating metastasis in many different cancers, its function in PDAC has not been studied. Here, we show that loss of MTSS1 leads to increased invasion and migration in PDAC cell lines. Moreover, PDAC cells treated with cancer-associated fibroblast-conditioned media also have increased metastatic potential, which is augmented by loss of MTSS1. Finally, overexpression of MTSS1 in PDAC cell lines leads to a loss of migratory potential in vitro and an increase in overall survival in vivo. Collectively, our data provide insight into an important role for MTSS1 in suppressing tumor cell invasion and migration driven by the tumor microenvironment and suggest that therapeutic strategies aimed at increasing MTSS1 levels may effectively slow the development of metastatic lesions, increasing survival of patients with PDAC.

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

“…Having previously established that stable MTSS1 expression levels are correlated with decreased metastatic potential in PDAC [10] and now having uncovered a potential novel connection between the PTEN tumor suppressor and MTSS1 status, we next investigated the potential molecular mechanism that could be responsible for the loss of PTEN correlating to loss of MTSS1. We hypothesized that PTEN might regulate both the MTSS1 protein level and stability.…”

“…One of the molecular mechanisms that has recently been shown to be critical for preventing tumor cell dissemination is the regulation of metastasis suppressor protein 1 (MTSS1) [10] . Also known as Missing in Metastasis (MIM), MTSS1 is believed to prevent metastasis by increasing Rac-GTP levels in order to inhibit cell-cell junction disassembly, thereby elevating actin assembly at the cell-cell contacts and preventing cellular dissemination [11] .…”

“…Also known as Missing in Metastasis (MIM), MTSS1 is believed to prevent metastasis by increasing Rac-GTP levels in order to inhibit cell-cell junction disassembly, thereby elevating actin assembly at the cell-cell contacts and preventing cellular dissemination [11] . While very little is known about the mechanism of action and molecular relationships of MTSS1, it has been found to play a role in combatting cellular migration and invasion in PDAC [10] . However, while the functional role of MTSS1 in PDAC has recently been uncovered, the regulation of MTSS1 in PDAC is still an enigma.…”

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

“…The induction of the self‐renewal potential in these cells indicated a definite CAF‐driven CSC enrichment in these cells. Although studies on interactions between autologous niche‐dysplastic cells are few, niche‐dependent CSC enrichment has been reported to increase malignancy, migration and invasion in breast, hepatic, oral, and pancreatic cancer, with multiple pathways being implicated . Further, Notch1 inhibition could only lead to a minimal effect on CAF‐induced proliferation suggesting the involvement of multiple pathways in the dysplastic cell‐niche cross talk and the redundancy of the Notch1 pathway.…”

Reduced Expression of Metastasis Suppressor-1 (MTSS1) Accelerates Progression of Human Bladder Uroepithelium Cell Carcinoma

“…In addition, patients with low MTSS1 expression had a significantly worse outcome (14). Zeleniak et al demonstrated that primary pancreatic ductal adenocarcinoma displayed higher MTSS1 expression levels than did metastatic pancreatic ductal adenocarcinoma (15). Another report also showed that loss of MTSS1 expression was associated with lymph node metastasis and poor differentiation of hilar cholangiocarcinoma (16), and high expression of MTSS1 suppressed the invasive, migratory, growth and adhesive properties of breast cancer cell lines (17).…”