Special Issue I Am Editing for the Journal *Genes*: Cancer Cell Plasticity and Therapeutic Resistance

How Do Cancer Cells Escape Treatment?

The international peer-reviewed journal Genes (MDPI) has launched a special issue on how cancer cells survive treatment pressure by changing their identity and how they become resistant to drugs: "Genomic and Epigenomic Drivers of Cancer Cell Plasticity and Therapy Resistance". Genetic Engineer Dr Muharrem Okan Çakır and I are the guest editors of this special issue. Submissions are open until 5 August 2027. In this article, I explain what the special issue covers, why it matters to me and how researchers can contribute. You can read about the basic biology of cancer in our article on cancer biology.

Why does this matter?

Targeted drugs and immunotherapies have transformed treatment in many cancers. Yet, as I see in the clinic every day, the main limitation of these treatments remains the same: a substantial proportion of tumours that respond well at first start growing again after a while despite the drug. For many years, this resistance was thought to arise mainly from new mutations, that is, permanent changes in the DNA (how do cancer cells become resistant to treatment?).

Research in recent years has broadened this picture. Some cancer cells can escape a drug without any change in their DNA sequence, by altering the epigenetic settings that determine which genes stay switched on or off. Some enter a temporary, "dormant"-like state and resume proliferating once treatment stops; others take on an entirely different cell identity. In EGFR-mutated lung cancer, for example, part of the tumour is known to be able to transform into small cell lung cancer under treatment, and resistance to RAS inhibitors in pancreatic cancer involves similar adaptive mechanisms (EGFR-mutated lung cancer, resistance to a RAS inhibitor).

This capacity to adapt is called cell plasticity. Understanding plasticity is one of the keys to predicting resistance before it emerges and to developing treatment combinations that prevent it. Together with Dr Çakır, I designed this special issue around precisely this question.

What is cancer cell plasticity?

Cancer cell plasticity is the ability of tumour cells to change their gene expression programmes and cell identity under the pressure of treatment or their environment. This change often occurs through epigenetic settings, without a permanent mutation in the DNA sequence. The result can be temporary drug tolerance, transformation into a different cell type or stable therapy resistance.

Some of these processes are linked to changes in chromatin structure, which determines how DNA is packaged, and some to regulatory networks formed by non-coding RNAs. The immune cells, blood vessels and connective tissue surrounding the tumour also influence which state the cells move into. Understanding therapy resistance therefore requires more than a list of mutations; we also need to see which programme a cell is running, how it changes over time and how it communicates with its surroundings (next-generation sequencing, uncovering resistance mechanisms with CRISPR).

What does the special issue cover?

The special issue addresses the genomic and epigenomic mechanisms that govern cancer cell plasticity and their effects on treatment response and relapse, in both solid tumours and blood cancers. The main topics within its scope are:

• Chromatin remodelling: how changes in the way DNA is packaged affect cell identity.
• Transcriptional and non-coding RNA networks: the regulatory systems that determine which genes are switched on and off, and when (RNA sequencing and the transcriptome).
• Clonal evolution: which groups of cells are selected and expand under treatment pressure.
• Tumour–microenvironment interactions: how immune cells, connective tissue and blood vessels contribute to cell plasticity.
• Virus-associated cancers: for example, plasticity and resistance in HPV-associated cancers (HPV and head and neck cancers).
• Mitochondria–nucleus communication: the role of the cell's powerhouse in resistance and identity switching.

Which methods are in focus?

The special issue particularly invites studies using methods that make it possible to see plasticity over time and in its tissue context: single-cell analyses that examine each cell individually, spatial methods that measure gene expression while preserving the position of cells in the tissue, lineage tracing techniques that reconstruct the family tree of cells, CRISPR screens that test which genes are truly required, and organoids grown in the laboratory from a patient's tumour. What these methods have in common is the aim of following the tumour not as a single snapshot but as a film that changes with treatment (an example of a single-cell atlas, a transcriptome atlas from Türkiye, what is CRISPR?).

As editors, we place particular emphasis on one point: priority will be given to studies that can distinguish causation from mere association, that reveal therapeutically targetable vulnerabilities or that validate markers of adaptive cell states. Our aim is to build a bridge between fundamental genetic mechanisms and clinical oncology and to contribute to strategies for predicting and overcoming resistance before it emerges (the functional meaning of mutations, resistance in genetic test reports).

How can researchers contribute?

Original research articles, reviews and short communications can be submitted to the special issue. Manuscripts are uploaded by registering with MDPI's online system and selecting the special issue. For a planned paper, a title and an abstract of about 250 words can be sent to the editorial office in advance for a preliminary assessment of suitability. All manuscripts that pass the initial check undergo single-blind peer review; accepted papers are published without delay and listed together on the special issue page.

Genes is an international, peer-reviewed, open-access monthly journal published by MDPI. Because it is open access, published articles can be read free of charge anywhere in the world; in return, authors pay an article processing charge (2600 Swiss francs). Author guidelines and further details are available on the journal's instructions for authors page.

What does it mean for patients?

A special issue of a scientific journal does not directly mean a new treatment. However, therapy resistance is one of the most difficult problems that people with cancer and their doctors face. A better understanding of how resistance develops may help predict in which patients resistance will appear early, decide in which order or combinations drugs should be given, and identify which new targets can be tried once resistance has developed. Today, in some cancers, searching for new genetic changes with a repeat biopsy or a blood test when resistance develops is an example of this kind of research reaching clinical practice (advanced genomic tests, sequencing technologies, castration-resistant prostate cancer).

A large share of the studies in the special issue will be basic research carried out in laboratory and animal models or on patient samples. For these findings to become treatments, they need to be tested in clinical trials. Patients' participation in clinical trials and their donation of tissue samples to scientific research also play an important role in this process (what is a clinical trial?, resistance research from laboratory to clinic).

Frequently Asked Questions

What is a special issue in a scientific journal?

A special issue is a collection of articles focusing on a specific topic, which a journal brings together under the direction of guest editors. The articles go through the journal's standard peer review and are published as they are accepted, then listed together on the special issue page.

What is the topic of this special issue?

How cancer cells become resistant to drugs by changing their gene expression programmes and identity under treatment pressure, and the role of genetic alterations, epigenetic reprogramming, non-coding RNAs and the tumour microenvironment in this process.

Who can submit, and what is the deadline?

Any researcher with original research, a review or a short communication on the topic can submit through the MDPI system. The deadline is 5 August 2027. The article processing charge is 2600 Swiss francs.

What does this special issue mean for patients?

It does not offer a new treatment directly, but it adds to the body of knowledge on how therapy resistance develops. In the future, this knowledge may help in developing treatment strategies to predict and overcome resistance.

Glossary

Cell plasticity

The ability of a cancer cell to change its gene expression programme and identity.

Therapy resistance

Continued or renewed growth of a cancer despite a drug that was initially effective.

Drug-tolerant "persister" cell

A cell that temporarily survives under drug pressure and can become sensitive again once the drug is withdrawn.

Lineage switching

The transformation of tumour cells into a different cell type under treatment; for example, lung adenocarcinoma transforming into small cell cancer.

Epigenetics

Mechanisms that regulate whether genes are switched on or off without changing the DNA sequence.

Chromatin

DNA packaged together with proteins; the way it is packaged determines how accessible genes are.

Non-coding RNA

RNA molecules that do not produce proteins but regulate gene expression.

Single-cell analysis

Measurement of the gene expression of each cell in a tumour individually.

Spatial transcriptomics

Measurement of gene expression while preserving the position of cells in the tissue.

Organoid

A small three-dimensional tissue model grown in the laboratory from a patient's tumour tissue.