Cell-cell transfer of genetic material may provide trophoblastic tumors with new functions.

Intercellular DNA transfer describes the movement of genetic material between cells. It can be achieved by various means, including extracellular vesicles,[1] tunneling nanotubes,[2] cell–cell fusion,[3] mitochondria transfer[4] and phagocytosis or efferocytosis of apoptotic bodies[5]. How these processes are triggered in vivo remain elusive.

Similarly, although it is demonstrated that transferred genetic material includes whole organelles such as mitochondria as well as genomic DNA, mitochondrial DNA, extrachromosomal DNA and DNA fragments, we are unsure whether cells may transfer multiple genetic material types at the same time or sequentially, or if there are any cellular determinant factors as to what to transfer.

Despite the ambiguities, intercellular DNA transfer in vivo is attracting growing attention because initial reports suggest that it may occur autonomously, and allow recipient cells to acquire new functions that support vitality, plasticity, and resistance, in other words, intercellular DNA transfer is like a shortcut for evolution.

Mechanisms of intercellular DNA transfer.

Cell–cell fusion is an interesting scenario, where two cells merge to inherit each other’s genetic material.

The fusion of the sperm and egg is an essential process during sexual reproduction; however, both the sperm and egg are haploid cells, that is, they contain only half the genetic material that a differentiated cell contains. Normally, a human cell contains one set of twenty-three pairs, that is, forty-six chromosomes. The inheritance of more genetic material, in other words, a “DNA overload”, often causes genome instability or loss of reproductive capacity – for instance, Down’s Syndrome is caused by the inheritance of one extra chromosome in the human cell. Therefore, it is not surprising that human cells do not appear to undergo cell–cell fusion to obtain more genetic material from other human cells on a regular basis.

Cancer cells are notorious for their genome instability, shown to be essential for their survival, especially under therapeutic assault, but this genome instability merely indicates that their DNA gets messed up more rapidly; the majority of them still contain the same amount of genetic material as their normal counterparts. Nonetheless, there are extreme cases in which cancer cells display multiploidy – a phenomenon in which cells contain multiple sets of DNA.

Scientists have learned to trigger such phenomena in vitro, but it remains unknown why and how cancer cells accumulate the DNA in vivo.

Kyosuke Kagami of Kanazawa University, in conjunction with colleagues from several institutes in Japan, has now investigated the process in trophoblastic tumors, a very rare cancer stemming from placental trophoblasts. Placental trophoblasts are specialized cells that form the outer layer of the blastocyst that develops into the fetal side of the placenta, the organ allowing the fetus to connect with the mother to obtain oxygen and nutrients and remove waste.

Even though there are rare reports of microchimerism,[6] consensus was held that material exchange between mother and child is highly selective at the placenta, because unprohibited exchange can result in fetal fatality.

In contrast to the normal placental situation, Kagami and colleagues report that cancer cells from placental site trophoblastic tumors (PSTTs) can acquire uninherited maternal genes, and the results obtained from whole-genomic sequencing suggest that cell–cell fusion may have occurred. The PSTT cancer cells used the acquired maternal genes to produce the antibody immunoglobulin.

This finding explains the clinical observation of renal antibody accumulation, which is a complication among these patients. Importantly, because the observation was made in a cancer relapse patient after immunotherapy, it also raises the possibility that cancer cells may gain functional genetic material from surrounding cells.

This research has brought to light a new route of tumor adaptation through intercellular DNA transfer.

The work is still preliminary: the fusion event was not directly observed but indirectly deduced from the tumor’s genome. Additional studies using newly collected and archived PSTT samples will be needed to validate and extend the findings. Moreover, PSTTs are extremely rare and longitudinal sampling remains challenging: future advancements will rely on reliable model systems and novel technologies to track intercellular DNA transfer in vivo.

Key Reference: K. Kagami et al., Placental Site Trophoblastic Tumor Acquires Immune Functions by Incorporating Host Maternal Genes. Advanced Science (2026), DOI: 10.1002/advs.76071

Other References:

1. S. Fischer et al. Indication of horizontal DNA gene transfer by extracellular vesicles. PLoS ONE (2016). DOI: 10.1371/journal.pone.0163665
2. E.G. Maurais et al. Genome instability triggers intercellular DNA transfer between human cells. Cell (2026). DOI: 10.1016/j.cell.2026.04.041
3. I. Martin-Padura et al. Spontaneous cell fusion of acute leukemia cells and macrophages observed in cells with leukemic potential. Neoplasia (2012). DOI: 10.1593/neo.12736
4. J.L. Spees et al. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci USA (2006). DOI: 10.1073/pnas.0510511103
5. M. Waterhouse et al. Horizontal DNA transfer from donor to host cells as an alternative mechanism of epithelial chimerism after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant (2011). DOI: 10.1016/j.bbmt.2010.09.001
6. K.J. Chua et al. Identifying key questions and challenges in microchimerism biology. Adv Sci (2005). DOI: 10.1002/advs.202514969

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