Genetically engineered mouse mannequin of inducible acinar-specific KLF4 expression for induction of acinar-ductal metaplasia (ADM). A Schematic of Ptf1a-rtTA, TRE-KLF4 (AK) mannequin and doxycycline administration schedule. TRE: Tet-response component. IP: Intraperitoneal. B Consultant hematoxylin and eosin staining of regular management, and day 2, day 4, and day 7 pancreata as in administration schedule in A. Blue arrows: regular ducts. Yellow arrows: ADM. Scale bar: 200 µm. C Relative mRNA expression of murine Krt19 and human KLF4 as quantified by qRT-PCR. n = 2 mice. p-values: two-sided t-test. Error bars: SD. Credit score: Genome Drugs (2025). DOI: 10.1186/s13073-025-01452-6
Johns Hopkins Drugs scientists say they’ve discovered a sample of so-called epigenetic “marks” in a transition state between regular and pancreatic most cancers cells in mice, and that the traditional cells might maintain a minimum of a short lived “memory” of these cancer-linked marks.
Epigenetic marks are chemical modifications that assist regulate genetic expression with out straight altering DNA sequence within the make-up of genes. Whereas the genetic code is like a pc’s {hardware}, epigenetics entails chemical marks on prime of the genetic code that act as software program programming in a pc.
The brand new analysis, revealed on-line March 28 within the journal Genome Drugs, helps efforts to raised perceive how regular cells morph into most cancers, together with the roles of irritation and mobile harm in that course of.
“Epigenetic changes have long been a focus of research seeking to explain how cells transition from normal to cancer,” says Andrew Feinberg, M.D., Bloomberg Distinguished Professor within the Johns Hopkins College colleges of medication, engineering and public well being.
“The transition begins when cells acquire an altered or hybrid identity, because of inflammation or damage that can potentially predispose them to a cancerous state, even without cancer-driving mutations,” he says.
Scientists have identified that, when the pancreas turns into infected, acinar cells, which produce digestive enzymes, start to rework into ductal cells, which transport digestive juices within the pancreas. This transformation helps acinar cells shield themselves from harm attributable to the irritation.
As a result of the epigenome decides which genes are turned on and off to provide cells their identification, its function within the transformation of acinar cells warranted research, Feinberg says.
Joint gene expression signatures at a single-cell decision. A Instance ADM cells co-expressing markers of acini (Pnliprp2, Gp2), ducts (Tff1, Krt19), panINs (Muc5ac), the PI3K pathway (Akt1, Pip5k1c, Pik3r2, Itpr3), and the AP1 advanced (Jund). B Violin plots of normalized gene pair co-expression proportion in every cell for the 2 labeled classes. n = 19,776 cells. p-values: Wilcoxon rank sum take a look at. Credit score: Genome Drugs (2025). DOI: 10.1186/s13073-025-01452-6
Feinberg, who co-led the brand new research with Patrick Cahan, Ph.D., affiliate professor of biomedical engineering at Johns Hopkins, due to this fact took a more in-depth take a look at the remodeling or hybrid pancreatic cells in mice, which the scientists say, have traits much like human pancreatic cells.
The scientists, together with first writer Emily Lo, who was co-mentored by Cahan and Feinberg, did so by sequencing the entire genome of mouse pancreatic cells transitioning between acinar and ductal cells, in a course of referred to as acinar-to-ductal metaplasia. They discovered epigenetic marks, however no mutations (alterations within the DNA sequence itself), on genes linked with pancreatic most cancers, together with two teams referred to as PI3K and R/R/C GTPase.
That they had earlier proven the identical kind of epigenetic adjustments in these genes in human pancreatic precancers termed PanINs, that are attributable to a mutation in a gene referred to as KRAS, though there was no such mutation within the mouse cells. This steered that the transitioning cells took on epigenetic traits of precancerous cells with out requiring a mutation, and inch nearer to turning into most cancers, says Feinberg.
When the transitioning cells returned to their unique identification as acinar cells, the scientists discovered that a few of the epigenetic marks on pancreatic cancer-linked genes remained for a minimum of seven extra days, forming a “memory” of the epigenetic signature.
“This work shows a key role for epigenetic memory in the transition to cancer even without a genetic mutation,” says Feinberg.
“This transition state is probably a normal way that the pancreas protects itself from the corrosive impact of inflammation and other stressors,” says Cahan.
Feinberg speculates that additional research might reveal that the epigenetic adjustments taking place in a cell’s transition state might clarify the rising frequency of most cancers in younger individuals, since they could not have acquired age-associated mutations to the genetic code itself.
Further Johns Hopkins researchers who contributed to the research embrace Adrian Idrizi, Rakel Tryggvadottir, Weiqiang Zhou, Wenpin Hou and Hongkai Ji.
Extra info:
Emily Okay.W. Lo et al, DNA methylation reminiscence of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling within the absence of Kras mutation, Genome Drugs (2025). DOI: 10.1186/s13073-025-01452-6
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