Projects

The Cell and Molecular Biology of Carcinogenesis Laboratory is involved in multiple projects that support pancreatic cancer research and therapeutic techniques.

The lab focuses on characterizing the genes involved in the initiation and progression of pancreatic cancer, including several protein kinase C (PKC) isozymes. The goals include improving cancer-screening methods, developing new therapies and facilitating advanced treatment of pancreatic cancer.

Project 1: Defining a role for PKC iota in oncogenic K-ras-mediated initiation and progression of pancreatic cancer

The specific aims of this project are to:

  • Dissect the PKC iota-regulated signaling mechanisms required for K-ras-mediated, acinar-to-ductal metaplasia
  • Assess the role of PKC iota in oncogenic K-ras-mediated initiation of pancreatic carcinogenesis and mouse pancreatic preneoplastic lesion formation in vivo
  • Determine the role of PKC iota in oncogenic K-ras-mediated pancreatic cancer

Dr. Murray's lab has determined that PKC iota is required for K-ras-induced acinar-to-ductal metaplasia. The lab has demonstrated that PKC iota regulates acinar-to-ductal metaplasia by mediating induction of matrix metalloproteinase 7 (MMP-7) and Notch activation. This signaling has previously shown to be required for pancreatic acinar-to-ductal metaplasia.

These studies are significant to patient care because they characterize a signaling pathway involved in the initiation of pancreatic cancer. In addition, the studies may yield information about more-effective therapeutic targets for the prevention of pancreatic cancer or about biomarkers for pancreatic cancer screening.

Project 2: Role of PKC zeta in pancreatic cancer cells

The specific aims of this project are to:

  • Determine the mechanism by which PKC zeta promotes pancreatic ductal adenocarcinoma (PDAC) cell cancer phenotype
  • Characterize the role of PKC zeta in PDAC cell oncogenic signaling

Dr. Murray's lab is investigating the mechanism by which PKC zeta expression regulates STAT3 phosphorylation. Inhibition of PKC zeta expression in pancreatic cancer cells significantly reduces STAT3 Y705 phosphorylation. The lab is also studying the effects on STAT3 downstream signaling in pancreatic cancer cells.

Inhibition of PKC zeta expression significantly reduces in vitro transformed growth invasion and migration of pancreatic ductal adenocarcinoma cell lines. In addition, signal transducer and activator of STAT3 signaling is often dysregulated in pancreatic cancer. However, STAT3 plays a crucial role in both pancreatic cancer development and maintenance of the transformed phenotype of pancreatic cancer cells.

Characterization of the mechanism by which PKC zeta promotes the cancer phenotype might eventually provide new targets for pancreatic cancer therapy.

Project 3: Atypical PKCs in pancreatic cancer stem cells

Specific aims of this project are to:

  • Investigate the functional role of atypical PKCs in pancreatic cancer stem cells
  • Evaluate atypical PKCs in pancreatic cancer stem cell tumor initiation and maintenance

Investigators in the lab are evaluating the effect of inhibition of atypical PKCs on the aggressive phenotype of pancreatic cancer stem cells in tumor formation and metastasis. Preliminary results suggest that PKC zeta is required for pancreatic cancer stem cell phenotype in vitro. Researchers will characterize the requirement for atypical PKCs in pancreatic cancer stem cells in vitro phenotypes.

Significant evidence has been generated in support of a cancer stem cell hypothesis. This hypothesis suggests that the pancreatic tumor cells are heterogeneous, with a distinct population of cells exhibiting stem-like, initiator or progenitor cell properties that play a crucial role in tumor development and maintenance resistance to chemotherapy. These are two of the characteristics of pancreatic cancer that contribute to its high mortality rates.

Identification and characterization of therapeutic targets specific to cancer stem cells has the potential to identify more specific and lasting chemotherapy for pancreatic cancer patients.

Project 4: Development of primary pancreatic cancer tumor grafts for translational pancreatic cancer research

The specific aims of this project are to:

  • Evaluate tumor grafts established from human pancreatic tumors for their ability to faithfully maintain the specific characteristics of the original human tumor
  • Evaluate tumor grafts and isolated tumor graft cells for sensitivity to conventional and novel cancer chemotherapy
  • Isolate pancreatic cancer stem-like cells from tumor grafts and characterize the role of stem cells in chemoresistance and tumor phenotype

The Cell and Molecular Biology of Carcinogenesis Lab has begun isolating primary pancreatic cancer tissue and expanding surgical specimens in immunodeficient mice. The goal of this project is to gain a greater understanding of the utility of tumor grafts to evaluate chemotherapy sensitivity and guide selection of chemotherapy for pancreatic cancer patients.

This research is intended to help facilitate the advanced treatment of pancreatic cancer, including late-stage tumor events, including pancreatic cancer metastasis and complex interactions with the tumor microenvironment.