Rosa Rubicondior: Malevolent Design - How Some Cancers Are Designed to Win

Cancer cells dividing

Shapeshifting cancers’ masters, unmasked | Cold Spring Harbor Laboratory

Scientists led by Cold Spring Harbor Laboratory (CSHL) Professor Christopher Vakoc have uncovered a mechanism by which certain cancers manage to evade modern medical treatments: they can disguise themselves as ordinary cells from entirely different tissues, such as those of the skin. In two recent papers — one in Nature Communications and another in Cell Reports — Vakoc’s team identify the proteins that determine whether pancreatic cancer cells retain their pancreatic identity or slip into a skin-cell-like state. They also highlight a different set of proteins with a pivotal role in tuft-cell lung cancer.

Proteins, of course, are specified by genetic information, and if that information is altered, so too is the protein’s function. In the language of ID creationists, proteins are products of “complex, specified genetic information”.

This presents intelligent design creationists with a familiar problem — one they usually address, as with parasites and pathogens, by ignoring it and relying on the scientific illiteracy of their followers. If complex, specified information were genuinely evidence of an intelligent designer, then that same designer would be implicated in the origin of the proteins that maintain and diversify cancers. Their “specified information” is neither less complex nor less specific than the proteins involved in cognition, immunity, or embryonic development.

Only by refusing to define “complex specificity” in scientific terms — or to explain how it might be distinguished from information that is supposedly non-complex or non-specified — do ID advocates manage to maintain the fiction that all beneficial traits are the work of their designer, while harmful traits must arise from some other agency. This selective attribution, based entirely on subjective human preference, underscores the religious foundations of intelligent design creationism and its distance from genuine science.

The team’s findings are summarised in a Cold Spring Harbor Laboratory news release by Jen A. Miller.

The Takeaway
Research from the Vakoc lab, published in Nature Communications and Cell Reports, provides new insights into the master regulators of two severe forms of lung and pancreatic cancer, which can morph in response to treatment. The discoveries could someday lead to safer therapies with fewer and less harmful side effects.
Shapeshifting cancers’ masters, unmasked
A new study from the Vakoc lab reveals how tuft cell lung cancer’s master regulator, POUF23, binds to DNA and the OCA-T1 protein. The crystal structure of this three-part interface, seen here from the front and back, allows scientists to consider how and which kinds of drugs might target it. The study’s first author, former postdoc Aktan Alpsoy, is now a faculty member at Middle East Technical University.
Some tumors are almost impossible to treat. That’s especially true for carcinomas, which don’t behave like other malignancies. Some of these tumors act as shapeshifters and start to resemble cells from other organs of the human body, such as skin. This bizarre behavior presents a challenge for existing therapies. “The tumors are notoriously plastic in their cellular identity,” says Cold Spring Harbor Laboratory (CSHL) Professor Christopher Vakoc. Some may even change to escape cancer treatment.

Recent studies from the Vakoc lab shine a new light on two hard-to-treat carcinomas, revealing vulnerabilities that could “tee up targets for therapy,” he says.

In a study published in Nature Communications, CSHL researchers identify a protein that determines whether pancreatic cancer cells maintain their classical form or begin to look and act more like skin cells. Meanwhile, in Cell Reports, they uncover the crystal structure of another group of proteins that plays a key role in tuft cell lung cancer.

This latest finding represents a full-circle moment for the lab, Vakoc explains. When he and his colleagues discovered tuft cell lung cancer in 2018, they were searching for epigenetic factors that drive tumor growth. In other words, they were looking beyond the genes themselves and into the processes of transcription and gene regulation. Now, in collaboration with CSHL Director of Research Leemor Joshua-Tor, they’ve found what could someday become an epigenetic therapy designed to stop the cancer’s growth.

CSHL Professor Chris Vakoc discusses cancer cells’ shifting identities and his lab’s search for the regulators of these transformations.

Together, the two new studies continue to build on one of Vakoc’s main goals of the last 17 years. “We aim to identify the master regulators of cellular identity,” he says. The hope is that these “master regulators” could someday become the targets of new medicines, much like hormone therapies now used against breast and prostate cancers that were once difficult to treat. Of course, there’s still a long way to go. Should the findings eventually lead to new drugs, Vakoc hopes they will be engineered to target the cancer without harming other parts of the patient’s body. That ethos is apparent in both of his lab’s latest studies. Whether going after mouse models of pancreatic cancer or lung cancer, they see no evidence of toxicity or damage to vital organs.  “We’re setting a higher bar for specificity when it comes to new cancer targets and treatments,” Vakoc says. They’re not just working toward new medicines. They’re coming to a deeper understanding of cellular identity, and in so doing, they’re helping establish a new and better standard of care.

Publications:
Cunniff, P.J., Sivetz, N., Skopelitis, D. et al.
KLF5 enables dichotomous lineage programs in pancreatic cancer via the AAA+ ATPase coactivators RUVBL1 and RUVBL2.
Nat Commun 16, 9996 (2025). https://doi.org/10.1038/s41467-025-66007-0

Alpsoy, Aktan; Ipsaro, Jonathan J.; Skopelitis, Damianos
Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3
Cell Reports (2025) 44(11); DOI: 10.1016/j.celrep.2025.116572

Abstract
Lineage plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor heterogeneity and therapeutic resistance. Here, we identify KLF5 as a dynamic master regulator of epithelial lineage identity in PDAC, with dichotomous roles in promoting either classical or basal-like transcriptional programs. Through unbiased proteomic and genetic screens, we uncover the AAA+ ATPases RUVBL1 and RUVBL2 as essential coactivators of KLF5 across both lineage states. We demonstrate that ATP hydrolysis by RUVBL1/2 is required for the stable interaction with an intrinsically disordered region of KLF5, enabling its recruitment to lineage-specific enhancers and driving transcriptional regulation of identity-defining genes. Notably, small-molecule inhibitors of RUVBL1/2 ATPase activity, which have anti-PDAC activity in vivo, suppress KLF5-dependent transcription. These findings define a previously unrecognized mechanism of ATP hydrolysis-dependent transcriptional coactivation and highlight a potential therapeutic strategy for modulating aberrant lineage programs in cancer.

Cunniff, P.J., Sivetz, N., Skopelitis, D. et al.
KLF5 enables dichotomous lineage programs in pancreatic cancer via the AAA+ ATPase coactivators RUVBL1 and RUVBL2.
Nat Commun 16, 9996 (2025). https://doi.org/10.1038/s41467-025-66007-0

Copyright: © 2025The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Graphical abstract

Highlights

Validation of POU2F3 and OCA-T1 as tumor-maintenance dependencies
Crystal structures of DNA-dependent POU2F3 complexes with OCA-T1 and OCA-T2
Deep mutational scanning reveals functional hotspots of POU2F3 and OCA-T1
A role for OCA-T1 in stabilizing POU2F3 chromatin occupancy
Summary The transcription factor POU2F3 defines the identity of tuft cells and underlies a distinct molecular subtype of small cell lung cancer (SCLC). Although POU2F3 is considered undruggable, its activity critically depends on the coactivators OCA-T1 and OCA-T2. Here, we demonstrate that acute suppression of either POU2F3 or OCA-T1 induces regression of tuft cell-like SCLC xenografts in vivo. To explore the structural basis and druggability of this dependency, we determine crystal structures of POU2F3 bound to OCA-T1 or OCA-T2 in complex with DNA, revealing a tripartite, DNA-dependent interface. We further employ deep mutational scanning to assess the functional impact of 4,218 missense variants in POU2F3 and OCA-T1, uncovering both mutation-sensitive hotspots and structurally constrained regions critical for tumor cell fitness. These findings define a transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3-OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.

Alpsoy, Aktan; Ipsaro, Jonathan J.; Skopelitis, Damianos
Structural basis of DNA-dependent coactivator recruitment by the tuft cell master regulator POU2F3
Cell Reports (2025) 44(11); DOI: 10.1016/j.celrep.2025.116572

Copyright: © 2025The authors.
Published by Elsevier Inc. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Findings such as these expose a deep incoherence and intellectual dishonesty at the heart of intelligent design creationism. If ID advocates were genuinely committed to applying their own criteria consistently, they would be forced to acknowledge that the same “complex, specified information” they cite as evidence of purposeful engineering in healthy tissues is equally present in the molecular machinery that enables cancers to grow, spread, and evade treatment. The proteins identified by Vakoc and his colleagues are no less intricate, no less information-rich, and no less finely tuned to their function than those that support normal development or physiology.

A consistent application of ID logic would therefore require its proponents to credit their supposed designer with the innovation of these malign adaptations — including the ability of cancer cells to reprogramme themselves to mimic entirely different cell types. Unsurprisingly, they never do. Instead, they abandon their own standards the moment the implications become theologically uncomfortable, retreating into selective blindness and special pleading.

This double standard highlights what biologists have long recognised: intelligent design is not an evidence-based framework, but a religious apologetic layered with scientific jargon. Scientific research proceeds by following the evidence wherever it leads, even when the results are troubling or counterintuitive. ID, by contrast, begins with the conclusion it wants and discards anything that contradicts it.

Vakoc’s findings, and others like them, underscore the reality that life’s complexity is not the product of foresight or benevolence but the outcome of evolutionary processes that can generate both exquisite adaptations and devastating failures. When examined honestly and consistently, the molecular landscape of cancer becomes yet another demonstration of evolution’s explanatory power — and of intelligent design’s inability to account for the natural world on its own terms.

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