Science Impacting The Clinic
From the lab of Ken Zaret, Ph.D.
Director of the Institute for Regenerative Medicine
First Solid Cancer Reprogramming Reveals Biomarkers of Early Stage Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death by 2030. Early detection is perceived as being the most crucial breakthrough needed. The Zaret lab was the first to apply stem cell reprogramming to immortalize human patient PDAC cells (Figure steps 1-5), so that the resulting human cells in a nonimmune animal model undergo progression from early to invasive stage lesions. We have used the system to discover 107 secreted and released human proteins, as candidate biomarkers, that reflect distinct networks activated during PDAC progression (Figure step 6, and Kim/Zaret et al., Cell Reports 2013). The candidate markers were further evaluated for their low expression in normal human plasma proteomes and tissue expression databases and the most promising subset of 64 reflect the activation of multiple networks in PDAC progression. We have collaborated with the Mayo Clinic to screen human plasmas from PDAC patients and diverse control populations. We currently have a marker panel entering Phase III of biomarker validation that strongly exceeds the predictive capacity compared to the state-of-the-art. We own the intellectual property and are seeking corporate partners and funding to bring this promising method to the clinic. Expected markets for diagnostics include primary care physicians who would order the tests on individuals over age 50 and clinicians who see high risk patients such as healthy individuals with a family history of pancreatic cancer.
Discovery of the Basis for Cellular Reprogramming by Gene Regulatory Proteins
The ability to change a cell’s fate at will is an ultimate goal of the regenerative medicine field. The primary means of cell type control is by gene regulatory proteins that bind to sites on chromosomes and govern the expression of genes specific for a given cell type. Yet chromosomes consist of DNA packaged into “nucleosomes” which create physical barriers to regulatory protein binding and cellular reprogramming. We previously showed that a subset of transcription factors called “pioneer factors” can function in early development and are useful in cell reprogramming because they have the special ability to bind their DNA target sites on nucleosomes. We recently discovered that this feature is dictated by the ability of the DNA binding domain of pioneer factors to adapt to DNA on the nucleosome surface. This fundamental principle explains how pioneer factors reprogram skin cells into liver cells, neurons, blood cells, and pluripotent cells, and thus helps the field understand how to control cell fate at will (Soufi et al. 2015 Cell, in press).
On the Horizon
- We are creating new ways to reprogram human cancer cells for additional models of progression.
- We are discovering new proteins in chromosomes that can be antagonized to enhance reprogramming.
- We are partnering with tissue engineers to develop new ways of bringing together pancreatic insulin cells, blood vessels, connective cells, and neural cells into artificial islets for diabetics.