Developmental Biology - Pancreatic Cancer|
Gene Removal Prevents Pancreatic Cancer
A new study finds ATDC gene is required for pancreatic cancer to develop...
This research builds on the theory that many cancers arise when adult cells - to resupply cells lost to injury and inflammation - switch back into more 'primitive' high-growth cell types such as those driving fetal development.
When this reversion happens in the presence of other genetic mistakes, a repair process — meant to start and stop quickly — continues on unchecked.
New details of this cancer-causing switch back to primitive cells, and of the role of ATDC in pancreatic cancer formation, are revealed in a study on mice and human patient tissue samples published online May 2 in the journal Genes & Development.
The study led by researchers from NYU School of Medicine and the University of Michigan, Ann Arbor, found ATDC must be active if injured pancreatic cells are to regress into a primitive stem-cell state and undergo those early steps leading to pancreatic cancer.
"We found deleting the ATDC gene in pancreatic cells results in one of the most profound blocks of tumor formation ever observed. A well-known mouse model was engineered to develop pancreatic ductal adenocarcinoma — or PDA — which mimics the human disease. We thought this deletion would slow cancer growth, but it completely prevented it."
Diane Simeone MD, Director, Pancreatic Cancer Center, New York University (NYU), Langone Health's Perlmutter Cancer Center.
Simeone says the search for better treatment for PDA cases is especially urgent given it has the worst prognosis of any major malignancy and is on track to become the second leading cause (after lung cancer) of cancer deaths by 2030.
Healing Gone Awry
The study focused on acinar cells in the pancreas. Through a network of ducts, acinar cells secrete digestive enzymes into the small intestine to digest food particles, causing low level tissue damage in the process. In a counter response, acinar cells can also quickly switch back into stem cells — their high-growth ancestors — and stop their digestive function.
Researchers believe this ability to regenerate comes at a price. Dual purposed cells are prone to become cancerous, acquiring random DNA changes. Included amongst this gene type is the KRAS gene, known to drive aggressive cell growth in more than 90 percent of pancreatic cancers.
Specifically, stressed acinar cells are known to temporarily undergo acinar-to-ductal metaplasia or ADM, a step back to a primitive cell type which resupplies cells. This sets the stage for another shift into pancreatic intra-epithelial neoplasia (PanIN) — where cells no longer multiply under normal controls.
In the current study, the researchers found that mutant KRAS and other genetic abnormalities induced aggressive pancreatic cancer in 100 percent of study mice when the ATDC gene was present, but in none of the same cancer-prone mice lacking the gene. Neither did acinar cells in the ATDC "knock-out" mice undergo ADM or transformation to PanIN.
To get a better look at the early steps in pancreatic cancer formation, the research team artificially caused pancreatitis in mice by treating them with a signaling protein fragment — cerulein — that damages pancreatic tissue. ATDC gene expression did not rise immediately after the damage, but increased a few days later, in line with the timeframe required for acinar cells to reprogram genetically into their ductal cell forebears.
Further experiments confirmed the expression of ATDC triggers beta-catenin, a cell-signaling protein which will, upon receiving the right trigger, activate genes that include SOX9. Earlier studies link SOX9 to development of ductal stem cells and to aggressive cell growth seen in PDA. Consistent with this work, the current study found an inability of cells lacking ATDC to become cancerous was due to their inability to induce SOX9 expression.
The authors also examined ATDC expression in ADM lesions from 12 samples of human pancreatic tissue. The team found it to be more active in human ADM lesions along with beta-catenin and SOX9, and its activation increased further during the transition of ADM into human pancreatic ductal adenocarcinoma.
These findings, says Simeone, identify ATDC, beta catenin, SOX9, and their signaling partners as potential targets in the design of new treatment and prevention strategies for pancreatic cancer.
Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar–ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of ?-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.
Along with Simeone, study authors from NYU School of Medicine were first author Lidong Wang, Andrea Zamperone, Daniel Diolaiti, and Vinee Purohit from the Department of Surgery and Perlmutter Cancer Center; Christina Hadju in the Department of Pathology, Dafna Bar-Sagi in the Department of Biochemistry and Molecular Pharmacology; and Igor Dolgalev of the Bioinformatics Core of the Perlmutter Cancer Center. Study authors from the University of Michigan, Ann Arbor, were Mats Ljungman and Huibin Yang of the Department of Radiation Oncology; Howard Crawford and Phillip Palmbos in the Department of Internal Medicine; Christopher Halbrook and Ethan Abel in the Department of Molecular and Integrative Physiology; and Marina Pasca di Magliano in the Department of Surgery. Also a study author was Andrew Rhim in the Department of Gastroenterology, Hepatology and Nutrition at MD Anderson Cancer Center.
The work was supported by funding from National Cancer Institute grants 2R01CA131045 and 1R01CA174836, and by the Sky Foundation.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
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May 3 2019 Fetal Timeline Maternal Timeline News
Pictured are pancreatic acinar cells
in which the (RED) ATDC gene is abnormally activated, turning on the (GREEN) SOX9 protein signal during an early step in their becoming cancerous.
CREDIT: NYU School of Medicine