Pancreatic cancer

Summary

Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancreatic cancer are known. The most common, pancreatic adenocarcinoma, accounts for about 90% of cases, and the term "pancreatic cancer" is sometimes used to refer only to that type. These adenocarcinomas start within the part of the pancreas that makes digestive enzymes. Several other types of cancer, which collectively represent the majority of the non-adenocarcinomas, can also arise from these cells. About 1–2% of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormone-producing cells of the pancreas. These are generally less aggressive than pancreatic adenocarcinoma. Signs and sy

Official source

https://en.wikipedia.org/wiki/Pancreatic_cancer

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Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver onco-genes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. SIGNIFICANCE: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. (C) 2018 AACR.

2018

The pancreas is one of the major organs of the digestive tract. Its endocrine function, mainly regulating glucose blood level, is achieved by endocrine cells. These cells are organized in clusters, the so-called islets of Langerhans. During development, these cells are specified within the pancreatic epithelium, and will subsequently delaminate and migrate out of the epithelium in order to form the islets. Neurogenin3 (Ngn3) is a bHLH transcription factor that is responsible for the differentiation of all endocrine cell types, but whether or not it has a role in their migration is still an open question. By using the chicken embryo model organism, we found that the differentiation and migration programs are two different processes that are induced by Ngn3 and that can be uncoupled. Therefore, we tried to unravel the mechanisms by which Ngn3 can induce endocrine cell migration. We found that, in both chick and mouse models, over-expression of Ngn3 induces a loss of apico-basal polarity, a breakdown of basal lamina, and more importantly, a loss of the epithelial marker E-cadherin (E-cad). It seems that this is not a direct effect mediated by direct binding to E-boxes in the E-cad promoter. Therefore, we are currently trying to find targets of Ngn3 that could mediate repression of E-cad, focusing on the zinc-finger transcription factors Snail1 and Snail2. Moreover, we also used a pancreatic explant culture method, developed in the laboratory of Pr. Jonathan Slack, which allows us to do time-lapse imaging and describe precisely the migration of endocrine cells in a system similar to in vivo conditions. Taking advantage of our Pdx1::Ngn3ERTM transgenic line, we followed Ngn3 misexpressing cells to understand in a more physiological manner how they migrate in the developing pancreas. We found that endocrine cell migrate at an average speed of 11.35 µm/h and migrate through an average length of 132.30 µm in 12 hours. We also found that endocrine cells migrate in the three compartments we defined: in the mesenchyme, inside the epithelium and at the edge of the epithelium. Their average velocity significantly changes depending on the compartment cells are migrating in. We found that the fastest cells are the ones migrating at the edge of the epithelium. RNA profiling comparing Ngn3 knockouts rescued or not by the Pdx1::Ngn3ERTM transgene was also used to identify the genes that function in endocrine cell migration downstream of Ngn3. We identified new Ngn3 target genes, some of which are implicated in migration such as the Doublecortin family.

EPFL2010

Neurogenin3 Initiates Stepwise Delamination of Differentiating Endocrine Cells During Pancreas Development

Mathieu Gouzi, Anne Grapin-Botton, Keiichi Katsumoto, Yung Hae Kim

During development, pancreatic endocrine cells are specified within the pancreatic epithelium. They subsequently delaminate out of the epithelium and cluster in the mesenchyme to form the islets of Langerhans. Neurogenin3 (Ngn3) is a transcription factor required for the differentiation of all endocrine cells and we investigated its role in their delamination. We observed in the mouse pancreas that most Ngn3-positive cells have lost contact with the lumen of the epithelium, showing that the delamination from the progenitor layer is initiated in endocrine progenitors. Subsequently, in both mouse and chick newly born endocrine cells at the periphery of the epithelium strongly decrease E-cadherin, break-down the basal lamina and cluster into islets of Langerhans. Repression of E-cadherin is sufficient to promote delamination from the epithelium. We further demonstrate that Ngn3 indirectly controls Snail2 protein expression post-transcriptionally to repress E-cadherin. In the chick embryo, Ngn3 independently controls epithelium delamination and differentiation programs. Developmental Dynamics 240:589-604, 2011. (C) 2011 Wiley-Liss, Inc.

2011

EPFL2010