Title: Reprogramming pancreatic cancer to discover early diagnosis biomarkers
Funder: Cancer Research UK

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, mainly because the tumors are diagnosed too late for effective treatment or for developing suitable therapeutics. The pancreatic intraepithelial neoplasias (PanIN) lesions are putative PDAC precursors, which progressively increase the risk of malignant transformation. Studying PanIN stages will therefore provide the best opportunity for discovering early diagnostics. However, current human cancer models including patient-derived xenograft, organoid cultures, or cancer stem cells provide a static end-point state of PDAC and do not recapitulate the PanIN stages. This lack of a suitable PanIN model is hampering our efforts to discover early-detection-biomarkers for this devastating disease. To this end, we have previously created a human PDAC-derived induced pluripotent stem cell (iPSC) line, which, when injected into immunodeficient mice, progresses to invasive PDAC through PanIN stages. We have successfully isolated these PanIN lesions, which can be grown as 3D organoids, secreting proteins into the culture media. This led to the discovery of early biomarkers that were further validated in three independent plasma cohorts derived from patients with PDAC and benign pancreatic diseases. THBS2 is one promising biomarker that can discriminate early resectable stage-I as well as all stages of PDAC patients from healthy subjects. Thus, our data demonstrated as a proof-of-concept that the PDAC-iPSC system provide unprecedented experimental access to the PanIN precursors. Thus far, we have generated a single PDAC-iPSC-line, which led to the discovery of biomarkers with limited representation of all the diverse PDAC cases. For example, THBS2 can classify about 20% or 50% of all stages PDAC patients with 100% or 99% specificity, respectively. Further investment in developing PDAC-iPSC-lines from more patients will significantly improve our ability to assemble a panel of early-detection-biomarkers that cover most PDAC patients with high specificity. Herein, we aim to use our improved reprogramming technology and exploit our access to a large PDAC tissue-bank as well as to pancreas tissue from healthy donors to streamline the generation of more PDAC-iPSC-lines and discover early biomarkers that represent the majority of PDAC cases. These iPSCs will also give us unprecedented access to the early PanIN stages. By reprogramming PDAC at different stages, we plan to reveal the early epigenetic changes that drive the transition from PanIN to PDAC, which can be used as biomarkers. Altogether we aim to establish the PDAC-iPSC system as a tool for the discovery of early-detection-diagnostic markers, which will ultimately reduce the burden of PDAC.

Lay abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, mainly because the tumors are diagnosed too late for effective treatment or for developing suitable therapeutics. The pancreatic intraepithelial neoplasias (PanIN) lesions are putative PDAC precursors, which progressively increase the risk of malignant transformation. Studying PanIN stages will therefore provide the best opportunity for discovering early diagnostics. However, current human cancer models including patient-derived xenograft, organoid cultures, or cancer stem cells provide a static end-point state of PDAC and do not recapitulate the PanIN stages. This lack of a suitable PanIN model is hampering our efforts to discover early-detection-biomarkers for this devastating disease. To this end, we have previously created a human PDAC-derived induced pluripotent stem cell (iPSC) line, which, when injected into immunodeficient mice, progresses to invasive PDAC through PanIN stages. We have successfully isolated these PanIN lesions, which can be grown as 3D organoids, secreting proteins into the culture media. This led to the discovery of early biomarkers that were further validated in three independent plasma cohorts derived from patients with PDAC and benign pancreatic diseases. THBS2 is one promising biomarker that can discriminate early resectable stage-I as well as all stages of PDAC patients from healthy subjects. Thus, our data demonstrated as a proof-of-concept that the PDAC-iPSC system provide unprecedented experimental access to the PanIN precursors. Thus far, we have generated a single PDAC-iPSC-line, which led to the discovery of biomarkers with limited representation of all the diverse PDAC cases. For example, THBS2 can classify about 20% or 50% of all stages PDAC patients with 100% or 99% specificity, respectively. Further investment in developing PDAC-iPSC-lines from more patients will significantly improve our ability to assemble a panel of early-detection-biomarkers that cover most PDAC patients with high specificity. Herein, we aim to use our improved reprogramming technology and exploit our access to a large PDAC tissue-bank as well as to pancreas tissue from healthy donors to streamline the generation of more PDAC-iPSC-lines and discover early biomarkers that represent the majority of PDAC cases. These iPSCs will also give us unprecedented access to the early PanIN stages. By reprogramming PDAC at different stages, we plan to reveal the early epigenetic changes that drive the transition from PanIN to PDAC, which can be used as biomarkers. Altogether we aim to establish the PDAC-iPSC system as a tool for the discovery of early-detection-diagnostic markers, which will ultimately reduce the burden of PDAC.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS