reprogramming-pancreatic-ductal-adenocarcinoma-to-pluripotency

Reprogramming Pancreatic Ductal Adenocarcinoma to Pluripotency

The generation of induced pluripotent stem cells (iPSCs) using transcription factors has been achieved from almost any differentiated cell type and has ...

Oregon Health & Science University

Although genetic mutations are required for cancer development, reversible non-genetic alterations also play a pivotal role in cancer progression. Failure of well-orchestrated gene regulation by chromatin states and master transcription factors can be one such non-genetic etiology for cancer development. Master transcription factor-mediated cellular reprogramming of human cancer cells allows us to model cancer progression. Here I cover the history and recent advances in reprogramming cancer cells, followed by lessons from cellular reprogramming of normal cells that may apply to cancer. Lastly, I share my perspective on cellular reprogramming for studying epigenetic alterations that have occurred in tumorigenesis, discuss the current limitations, and propose ways to overcome the obstacles in the reprogramming of cancer.

Cellular reprogramming to model and study epigenetic alterations in cancer.

Previous transcriptome studies of human pancreatic ductal adenocarcinoma (PDAC) compare non-cancerous pancreatic intraepithelial neoplasias (PanIN) with late-stage PDAC obtained from different patients, thus have limited ability to discern network dynamics that contribute to the disease progression. We demonstrated previously that the 10-22 cell line, an induced pluripotent stem cell-like line reprogrammed from late-stage human PDAC cells, recapitulated the progression from PanINs to PDAC upon transplantation into NOD/LtSz-scid/IL2R-gamma mice. Herein, we investigated the transition from precursor to PDAC using the isogenic model. We analyzed transcriptomes of genetically tagged 10-22 cells progressing from PanINs to PDAC in mice and validated the results using The Cancer Genome Atlas PDAC dataset, human clinical PanIN and PDAC tissues, and a well-established murine PDAC model. We functionally studied candidate proteins using human normal (H6C7) and cancerous (Miapaca2, Aspc1) pancreatic ductal epithelial cell lines. 10-22 cell-derived PDAC displayed the molecular signature of clinical human PDAC. Expression changes of many genes were transient during PDAC progression. Pathways for extracellular vesicle transport and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. HMG-box transcription factor 1 (HBP1) and BTB domain and CNC homolog 1 (BACH1) were implicated in regulating dynamically expressed genes during PDAC progression, and their expressions inversely correlated with PDAC patients' prognosis. Ectopic expression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells, indicating that HBP1 may confer the cell dissemination capacity in early PDAC progression. This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis. IMPLICATIONS: Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.

Longitudinal Analysis of Human Pancreatic Adenocarcinoma Development Reveals Transient Gene Expression Signatures.

Pancreatic cancer is a disease notorious for its high frequency of recurrence and low survival rate. Surgery is the most effective treatment for localized pancreatic cancer, but most cancer recurs after surgery, and patients die within ten years of diagnosis. The question persists: what makes pancreatic cancer recur and metastasize with such a high frequency? Herein, we review evidence that subclinical dormant pancreatic cancer cells disseminate before developing metastatic or recurring cancer. We then discuss several routes by which pancreatic cancer migrates and the mechanisms by which pancreatic cancer cells adapt. Lastly, we discuss unanswered questions in pancreatic cancer cell migration and our perspectives.

Jungsun Kim

Cancer Early Detection Advanced Research Center,
Knight Cancer Institute,
Department of Molecular & Medical Genetics,
Cancer Early Detection Advanced Research Center, Knight Cancer Institute

Oregon Health & Science University

Reprogramming Pancreatic Ductal Adenocarcinoma to Pluripotency

Jungsun Kim

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Cancer Early Detection Advanced Research Center,Knight Cancer Institute,Department of Molecular & Medical Genetics,Cancer Early Detection Advanced Research Center, Knight Cancer Institute

Oregon Health & Science University

Reprogramming Pancreatic Ductal Adenocarcinoma to Pluripotency

Cancer Early Detection Advanced Research Center,
Knight Cancer Institute,
Department of Molecular & Medical Genetics,
Cancer Early Detection Advanced Research Center, Knight Cancer Institute