Posted November 19, 2018

Edna Cukierman, Ph.D., Fox Chase Cancer Center

The early stages of pancreatic cancer often cause no noticeable signs or symptoms, which makes it difficult to detect and diagnose. When symptoms eventually develop, they are often non-specific and can be mistaken for other illnesses. Pancreatic cancer can develop in exocrine or neuroendocrine cells in the pancreas.¹ Exocrine cell tumors make up the majority of pancreatic cancers, with pancreatic ductal adenocarcinoma (PDAC) the most common type of exocrine pancreatic cancer.² PDAC develops from the cells lining the ducts of the pancreas that are responsible for carrying digestive juices from the pancreas into the small intestine.² Surgery followed by either chemotherapy or chemoradiation is standard treatment for pancreatic cancer. Individuals with advanced disease are also given palliative treatment to improve quality of life.³ However, the 5-year survival rate for people diagnosed with PDAC ranges from 1% to 12%, depending on the stage of the cancer at diagnosis.³

PDAC is characterized by desmoplasia, a fibrous-like stroma reaction associated with tumorigenesis, resistance to treatments, and a high degree of innervation. The innervation of parasympathetic nerves, called neurogenesis, is implicated in metastasis and neuropathic pain syndrome. Previous research has shown that an increased amount of parasympathetic neurogenesis is correlated with an aggressive phenotype in PDAC and increased tumor budding, thus it is a critical prognostic factor for patients.⁴

Dr. Edna Cukierman is an associate professor at Fox Chase Cancer Center and the co-leader of the Marvin & Concetta Greenberg Pancreatic Cancer Institute. Supported by a Fiscal Year 2014 Idea Award with Special Focus, she has been investigating NetrinG1, a member of the Netrin family of neuronal extracellular proteins. The main hypothesis of Dr. Cukierman’s work was to determine if specific variants of NetrinG1 promote and stabilize neuronal recruitment to PDAC tumors in a desmoplastic environment. It is known that NetrinG1 is associated with providing chemotropic guidance for migrating cells and axons, directing cell migration, and mediating cell-cell interactions in pancreatic tissue.

Dr. Cukierman used a novel simultaneous multi-channel immunofluorescence imaging technique for formalin-fixed paraffin-embedded human tissue⁵ that she developed and found that tumor-associated fibroblasts (TAFs) overexpress NetrinG1. NetrinG1 and its receptor, NetrinG L1 (NGL1) could be differentially stained and identified in cancer and nerve cells. Her research team went on to explore the mechanistic role of NetrinG1 by creating a cell line of TAFs with a knockout of NetrinG1 isoform C (NetrinG1C), the only form of NetrinG1 detected in TAFs. Neurons co-cultured with control TAFs grew without issue on three-dimensional desmoplastic extracellular matrices, suggesting that NetrinG1 is necessary for neuronal survival in the desmoplastic environment. Interestingly, neurons co-cultured with NetrinG1 knockout TAFs grown under the same conditions were unable to survive. A NGL1 knockout strain of TAFs did not interact with co-cultured neuronal spheres after 48 hours, supporting the notion that NetrinG1 and NGL1 are required for TAF-neuronal interactions. Based on these findings, Dr. Cukierman co-cultured dorsal root ganglions, which are a cluster of neurons located in the spinal cord that carry signals to the rest of the body, with spheres of benign pancreatic epithelial cells and PDAC cells on TAF-derived extracellular matrices. PDAC cells were observed to move more quickly toward the dorsal root ganglions than normal pancreatic cells. TAF spheroids co-cultured with dorsal root ganglions on desmoplastic extracellular matrices exhibited similar behavior. These results suggest that nerve cells play a role in attracting cancer and TAF cells by establishing a cancer-associated fibroblasts-nerve bridge. These provide evidence for how TAFs mediate interactions between nerves and PDAC cells and participate in the progression of PDAC neurogenesis. Mechanistically understanding NetrinG and its role in desmoplasia will open up a new series of therapeutics that may be used in the future to slow the progression of PDAC, decrease cancer pain, and improve patient outcomes.

References/Works cited:

¹ https://www.cancer.gov/types/pancreatic

² https://www.pancreaticcancer.org.uk/types

³ https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html

⁴ Zhang L, Guo L, Tao M, et al. 2016. Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma. Chin J Cancer Res. doi: 10.21147/j.issn.1000-9604.2016.02.05.

⁵Franco-Barraza J, Francescone R, Luong T, et al. 2017. Matrix-regulated integrin αvβ5 maintains α5β1-dependent desmoplastic traits prognostic of neoplastic recurrence. eLife 6:e20600.

Link:

Public and Technical Abstracts: Pancreatic Cancers Desmoplasia: The Possible Bridge Impending Nerve Infiltration and Neoplastic Escape

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