Origin, diversification and function of pancreatic cancer associated fibroblasts

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Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest cancers due to a lack of effective treatment options. One hallmark of PDAC is the expansion of cancer associated fibroblasts (CAFs). CAFs play critical and complex roles in PDAC microenvironment to modulate tumor progression and therapeutic response. The long-term objective of my research program is to determine the cellular origin, heterogeneity and function of CAFs in pancreatic cancer. To identify the tissue origin of CAFs in PDAC, I performed lineage tracing experiments using genetically engineered mouse models. The splanchnic mesenchyme is a particular type of mesenchyme adjacent to the pancreatic epithelium during fetal development. My studies demonstrated that the splanchnic mesenchyme is the fetal origin of CAFs in PDAC (Han et al, Nat Commun, in press). In this current proposal, I aim to further investigate whether splanchnic-derived CAFs maintain certain molecular signatures of their fetal progenitors. The Hedgehog pathway is a critical paracrine signal between the epithelium and mesenchyme during fetal development and is reactivated during tumorigenesis of the pancreas. The Hedgehog signal modulates PDAC progression, but its downstream targets in CAFs have not been identified. My graduate study showed that transcription factors FOXF1 and GATA6 are downstream targets of the Hedgehog pathway in the fetal splanchnic mesenchyme. My preliminary studies suggested that these factors are also expressed in PDAC CAFs in a regionally distinct pattern within the tumor microenvironment. In Aim 1, I will determine whether FOXF1/GATA6 patterning in CAFs is regulated by the Hedgehog pathway activity. Hedgehog agonist or antagonist will be utilized in in vitro cell or organoid culture and in vivo mouse models. In Aim 2, I will determine the function of FOXF1+ CAFs and GATA6+ CAFs in PDAC by deleting these genes specifically in CAFs both in vitro and in vivo as well as in patient correlation studies. The completion of this study will provide critical insights in PDAC CAF biology, including novel cellular heterogeneity defined by selective persistence of fetal signatures in coordination with the epithelium, and certain fetal signatures playing tumor-suppressing roles in a non-cell autonomous manner. Ultimately, such knowledge in tumor microenvironment may reveal critical targets and therapeutic avenues to inhibit tumor progression and prolong PDAC patient survival. I received rigorous training in developmental biology during my graduate study. Four years ago, I started my training in cancer biology as a postdoctoral fellow in the Hollings Cancer Center. During the K99 phase, I aim to further enhance my expertise in pancreatic cancer research and to acquire several additional skills, which are essential to launch my independent research program during the R00 phase. I aspire to draw from paradigms in both embryology and oncology to develop novel perspectives and to tackle fundamental biological questions.