Rosa Rubicondior: Malevolent Design - How Epigenetics Helps Pancreatic Cancer To Spread

Representation of KLF5 expression patterns in lab-grown human pancreatic cancer cells (left) and their patterns of migration from the primary tumor (right). Credit: Andrew Feinberg laboratory, Johns Hopkins Medicine. Originally published in Molecular Cancer.

Growth of Spreading Pancreatic Cancer Fueled By “Under-Appreciated” Epigenetic Changes | Johns Hopkins Medicine

A new paper in Molecular Cancer from Johns Hopkins Medicine describes yet another discovery that should be deeply uncomfortable for Intelligent Design creationists. The researchers found that the spread of pancreatic cancer is driven not chiefly by fresh mutations in DNA sequence, but by epigenetic reprogramming — changes in chromatin organisation and gene activity. In particular, they identified KLF5 as a major driver of metastatic growth, with higher expression in most metastatic lesions than in the matched primary tumours. The paper in Molecular Cancer shows that KLF5 promotes metastatic proliferation through epigenetic modifier genes including NCAPD2 and MTHFD1, helping switch on programmes involved in migration, plasticity and invasion. [1]

What makes this especially important is that epigenetics is not some magical extra layer of “specified information” inserted into life by a supernatural designer. Its roots are ancient. In bacteria, DNA methylation is a major form of epigenetic regulation, involved in gene expression, chromosome replication and DNA repair. In archaea, histone-based chromatin already exists in a form strikingly similar to that of eukaryotes, and studies show that chromatin architecture and its role in regulating gene expression long predate complex multicellular life. In other words, the basic machinery was already there in simpler organisms, doing ordinary cellular housekeeping long before animals and plants ever appeared. [2]

Multicellular organisms did not receive a brand-new control system from an intelligent agent; they inherited this ancient molecular toolkit and elaborated it. As multicellularity evolved, epigenetic regulation expanded and became central to cell differentiation, allowing cells with the same DNA to adopt different stable identities by opening some regions of the genome and closing others. Work on the transition from unicellular to multicellular states in Dictyostelium, for example, shows that chromatin reorganisation and histone modifications are closely tied to the shift into multicellularity, while evolutionary reviews note that epigenetic diversity expanded rapidly with multicellular life and that epigenetic marks are crucial in development and long-lived cell lineages. [3]

And that is exactly why this Johns Hopkins work is such bad news for ID creationists. The same ancient, repurposed system that multicellular organisms rely on for cell specialisation can also be subverted to drive one of the deadliest features of cancer: metastasis. That is what evolved systems do. They are modified from older parts, good enough to work, but never perfect and never immune to catastrophic failure. What this study reveals is not elegant, flawless engineering, but the vulnerability of a historically evolved regulatory system — one that natural selection adapted for development and tissue specialisation, but which disease can hijack with lethal consequences. That is entirely consistent with evolution, and profoundly at odds with the notion of a competent, benevolent designer. [1]

The evolutionary origins of epigenetics.

Epigenetics is not “extra DNA information” magically added to the genome. It refers to chemical marks on DNA and its associated proteins, plus changes in chromatin packing, that alter how easily genes can be switched on or off without changing the DNA sequence itself. These marks help control which parts of the genome are accessible and active in any given cell.
Its roots are far older than animals, plants, or even multicellular life. In bacteria, DNA methylation is a major form of epigenetic regulation, involved in transcription, chromosome replication and DNA repair. In other words, long before there were bodies to build, cells were already using chemical marking systems to manage their genomes. [2]
Another major part of the story comes from the archaea. Histones — the DNA-packaging proteins central to eukaryotic chromatin — have their evolutionary origins in archaea. Archaeal histone-like proteins share the same basic fold as eukaryotic histones and can regulate gene expression as well as DNA organisation, showing that core components of chromatin regulation predate true eukaryotes.
Eukaryotes did not invent epigenetic regulation from scratch; they elaborated an older toolkit. Comparative work shows that DNA methylation is widespread across the tree of life, while several components of nucleosomes and histone-based regulation predated the emergence of eukaryotes. What changed with eukaryotes was the scale, complexity and integration of these systems.
That ancient toolkit became crucial when multicellular organisms evolved. A multicellular organism needs cells with the same genome to behave differently: some become muscle, some neurons, some skin, some blood. Epigenetic mechanisms such as DNA methylation, histone modification and chromatin accessibility provide the means to lock different cells into different patterns of gene activity. [4]
This works because epigenetic states can be copied when cells divide. Reviews of developmental epigenetics note that DNA methylation and some histone marks are transmitted through mitotic cell divisions, so descendant cells tend to retain their lineage identity. That is how a fertilised egg can give rise to many specialised tissues without changing the underlying DNA sequence in each one.
But evolved systems are not flawless; they are vulnerable to misuse and breakdown. The Johns Hopkins team found that in metastatic pancreatic cancer, a gene called KLF5 promotes growth and invasion not mainly by new DNA mutations, but by altering chromatin organisation and other epigenetic controls. In 10 of 13 patients examined, at least one metastatic lesion showed increased KLF5 expression compared with the primary tumour. [1]
That is why this is such bad news for Intelligent Design creationists. What we see is not a perfect, purpose-built control system, but an ancient regulatory machinery adapted and repurposed over evolutionary time — useful for cell specialisation, yet also vulnerable to catastrophic failure in diseases such as cancer. That is exactly what we would expect from a historically evolved system assembled by modification of older parts, not from an all-wise and benevolent designer. [1]

The research and its importance for understanding pancreatic cancer is the subject of a news item from Johns Hopkins Medicine:

Growth of Spreading Pancreatic Cancer Fueled By “Under-Appreciated” Epigenetic Changes
In a lab-grown cell study focused on potential new treatment targets for halting the spread of most pancreatic cancers, Johns Hopkins Medicine scientists report they have found that a gene called KLF5 (Krueppel-like factor 5) fuels the growth of such spreading tumors not by acquiring abnormal changes in the cancer cells’ DNA code itself but by altering chemical changes and organization of DNA, or epigenetics, that turns genes on and off.

Epigenetic alterations are underappreciated as a major route to developing and fueling the growth of cancer metastasis.

Professor Andrew Feinberg, M.D., corresponding author.
Center for Epigenetics
Johns Hopkins University School of Medicine,
Baltimore, MD, USA.

Feinberg led researchers in 2017 to show that people with the most common form of pancreatic cancer had widespread epigenetic alterations, as opposed to new changes in the DNA code itself, or mutations, in their primary tumor that drove the cancer to metastasize to other parts of the body.

The new findings, which have implications in the search for treatments for pancreatic and other cancers, led them to pursue the current study, funded in part by the National Institutes of Health and described today in Molecular Cancer.

For the current study, the scientists aimed to find the most impactful genes associated with cancer cell growth. To do so, they used a gene-altering technology known as CRISPR to make cuts in DNA that silenced the genes in their investigative crosshairs. Once turned off, the genes that caused the largest shutdown of cell growth were considered to be most influential in cell growth had they been turned on.

The scientists found that KLF5 had the greatest effect specifically promoting the growth and invasion of metastatic cells, and that 10 of 13 people with pancreatic cancer had increased KLF5 gene expression in at least one metastatic lesion compared with the primary tumors.

The research team also did other experiments to validate KLF5’s impact on metastatic cell growth and found that KLF5 controls the tight packaging of DNA, an epigenetic factor that enables genes to be turned on or off.

The scientists concluded that slight changes in KLF5 expression levels in the metastatic group of cells appeared to make relatively larger changes in the cells’ ability to grow and spread. “This could suggest that, to develop treatments for pancreatic cancer metastasis, the gene may not need to be entirely shut down to have a positive effect,” says Feinberg, who notes that several anti-cancer compounds targeting KLF5 are in development.

The scientists also found that KLF5 regulates at least two other genes, NCAPD2 and MTHFD1, in metastatic but not primary laboratory-grown pancreatic cancer cells. The two genes are known as epigenetic modifier genes, which turn genes on or off not through the genetic code but by adding chemical groups to the DNA and helping to alter its packaging.

We are adding to evidence that cancer metastases are not caused by additional mutations in the primary cancer, but by additional epigenetic changes, enabling the cancer to thrive and grow. KLF5 seems to be a master gene that drives such changes and impacts a pathway of genes known to control invasion and the ability to resist treatments.

Kenna Sherman, co-first author.
Center for Epigenetics
Johns Hopkins University School of Medicine,
Baltimore, MD, USA.

The research in this study was supported by the National Institutes of Health (CA54358, R01HG010889, R01HG013409, T32GM148383), a Celgene License Pathway Agreement and a gift from the friends and family of Jasmine Lampadarios.

Additional scientists who contributed to the study are Masahiro Maeda, Weiqiang Zhou, Jiaqi Cheng, Yuta Nihongaki, Adrian Idrizi, Rakel Tryggvadottir, Oscar Camacho, Michael Koldobskiy, Barbara Slusher and Hongkai Ji from Johns Hopins; Xingbo Shang and Andre Levchenko from Yale University; and Jimin Min and Anirban Maitra from NYU Langone Health.

Publication:
Maeda, M., Sherman, K., Zhou, W. et al.
CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1. Mol Cancer 25, 75 (2026). https://doi.org/10.1186/s12943-026-02575-z

Abstract One of the major conundrums of cancer research and treatment is that the metastases that lead to death in most patients do not appear to involve additional driver mutations. Previously, we reported widespread loss of heterochromatin with activation of pro-metastatic genes in the subset of cells of primary pancreatic tumors that gave rise to liver and lung metastases. Here we hypothesized that this change in chromatin could create unique vulnerabilities in distant metastases. Using a CRISPR screen of human patient-derived xenografts from metastases and primary tumors, we identified KLF5 as essential for metastatic cell proliferation but not primary tumor growth. Further, we found that KLF5 induced epigenetic modifier genes, including NCAPD2 and MTHFD1, which themselves facilitated expression of specific genes driving migration and epithelial-mesenchymal transition, including TGFBR2, VIM, EMP1, and ITGB1. Inhibition of expression of these modifier genes restored heterochromatin in the specific regions that distinguish the primary and metastatic tumors. We backed up this causal chain of evidence with rigorous additional knockdown experiments with the modifier genes, and single cell RNA and chromatin experiments, and we also replicated the main findings in a second set of paired primary and distant metastasis xenograft lines. Finally, KLF5 expression was strongly associated with patient survival and human PDAC cell plasticity in a dataset of 70 PDAC patients and KLF5 expression was increased in the majority of lung, liver and peritoneal metastases compared to the matched primary tumor, confirming its importance in PDAC metastasis and mortality. In summary, we have identified a cascade of epigenetic modulators, modifiers and mediators that maintains the widespread heterochromatin loss supporting metastatic cell proliferation in human pancreatic cancer (see Graphical Abstract).
Graphical Abstract

KLF5 modulates epigenetic modifications driving PDAC metastatic proliferation and plasticity

Maeda, M., Sherman, K., Zhou, W. et al.
CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1. Mol Cancer 25, 75 (2026). https://doi.org/10.1186/s12943-026-02575-z

Copyright: © 2026 The authors.
Published by Springer Nature. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

This study shows yet again how much more sense biology makes when viewed through the lens of evolution than through the fantasies of Intelligent Design. What we are looking at is not a pristine, purpose-built system created by a flawless engineer, but an ancient regulatory machinery inherited from simpler ancestors, modified over immense spans of time, and adapted for new functions such as cell differentiation in complex multicellular life. That such a system can be turned against the organism it serves is exactly what we should expect of an evolved, contingent process, not of deliberate, benevolent design.

For ID creationists, this presents an impossible dilemma. If epigenetic regulation is supposed to be the product of intelligent foresight, then so too is its lethal susceptibility to corruption in cancers such as pancreatic adenocarcinoma. The same machinery that helps produce specialised tissues and organs can also be hijacked to drive invasion, metastasis and death. That is not evidence of wisdom or compassion in design; it is evidence of a system that works well enough to persist, but which remains vulnerable because evolution can only tinker with what already exists.

And that, of course, is the point creationists are so often desperate to evade. Time and again, biology reveals not elegant perfection but jury-rigged compromise, historical constraint and dangerous failure modes. Epigenetics now joins the long list of features that make perfect sense as the modified inheritance of an unguided evolutionary past, and no sense at all as the handiwork of an all-knowing designer.

So, once again, the facts are no friend to creationism. Far from uncovering signs of supernatural planning, research like this exposes the messy, makeshift and often tragic reality of living systems shaped by evolution. Science has no difficulty accommodating that reality. It is Intelligent Design that is left floundering, forced either to ignore the evidence or to attribute one of the deadliest forms of human suffering to the intentions of its supposed designer.

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