Pancreatic ductal adenocarcinoma (PDAC) holds one of the worst prognoses in medicine, with a five-year survival of only six percent. In most cases PDAC is detected after it has metastasized, at which point no curative treatment exists. We are interested in understanding the initiating events and pathways that drive tumorigenesis and cancer growth, which may provide new targets for early intervention. Recently, we and others discovered that PDAC originates from differentiated acinar cells, despite the ductal tumor phenotype for which it is named. This proposal is based on our identification of the transcription factor PTF1A, a master regulator of acinar cell identity, as a new and potent gatekeeper of PDAC initiation. We find that PTF1A expression is lost in early stage pancreatic intraepithelial neoplasia (PanINs) in humans as well as in a mouse model of PDAC, leading us to hypothesize that PTF1A downregulation represents a rate-limiting step in pancreatic cancer initiation. This possibility is borne out in our preliminary data. To test whether PTF1A loss is a functionally important step in PanIN development, we deleted Ptf1a in mice using an acinar-specific inducible Cre (Ptf1a cKO). We find that Ptf1a-deficient acinar cells are dramatically more sensitive to transformation by oncogenic KRAS (KrasG12D), undergoing widespread PanIN formation on a time-frame of days rather than months. Furthermore, we find that Ptf1a heterozygosity increases susceptibility to KRAS-mediated PanIN formation, suggesting that transformation requires reduction of PTF1A activity below a critical autoregulatory threshold that maintains acinar identity. Additional experiments suggest that loss of PTF1A expression could actually be sufficient for at least the earliest stages of tumor development. We and others have shown that KRAS transformation of acinar cells is accelerated by inflammation, such as that stimulated by caerulein- induced pancreatitis, which potentiates both mutant and wild-type KRAS signaling activity. In the absence of Ptf1a, we find that pancreatitis is sufficient to induce initiation of PanIN-like lesions without oncogenic KrasG12D, potentially due to enhanced signaling through wild-type KRAS. Together, our results indicate that PTF1A has a critical role in guarding against genetic and environmental insults, and highlight the importance of studying the genetic program of differentiation as an endogenous safeguard against cancer.
In AIM 1 of this proposal, we will interrogate the role of PTF1A in suppressing KRAS-driven tumor initiation and progression, and determine the sufficiency of Ptf1a downregulation for the early stages of cancer initiation.
In AIM 2 we will use whole- genome approaches to identify and validate PTF1A target genes involved in KRAS signaling inhibition.
In AIM 3 we will utilize a Ptf1a gain-of-function mouse model to determine whether persistent PTF1A expression can prevent and/or reverse KRAS-driven acinar cell transformation. Defining how PTF1A inhibits KRAS-driven PDAC initiation could lead to a better understanding of the genetic and environmental risk factors for this deadly disease, as well as provide new and urgently-needed avenues for therapeutics.
Over 45,000 people are diagnosed with pancreatic ductal adenocarcinoma (PDAC) annually in the United States, of whom only 6% survive five years or more. Among the reasons that PDAC is such a terrible disease is that it is difficult to detect and diagnose at early stages, and often remains asymptomatic until it has metastasized. Therefore, understanding the initiation of this disease and the factors driving its progression are of the utmost importance. We have identified the rate-limiting step in PDAC initiation: loss of the master acinar cell regulator, PTF1A. Defining the molecular mechanism of how PTF1A acts to suppress tumor initiation and growth will lead to a better understanding of genetic and environmental risk factors for PDAC, as well as provide novel avenues for therapeutic targets.
| Krah, Nathan M; Murtaugh, L Charles (2016) Differentiation and Inflammation: 'Best Enemies' in Gastrointestinal Carcinogenesis. Trends Cancer 2:723-735 |
| Krah, Nathan M; De La O, Jean-Paul; Swift, Galvin H et al. (2015) The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Elife 4: |
