Kanazawa University Research: Scanning nanoprobe microscope reveals the hidden flexibility of cancer cells

KANAZAWA, Japan, Oct. 28, 2025 /PRNewswire/ -- Researchers at the Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, report in ACS Applied Nano Materials a new method to precisely measure nuclear elasticity—the stiffness or softness of the cell nucleus—in living cells. By employing a technique called Nanoendoscopy-AFM (NE-AFM), which inserts a nanoneedle probe directly into cells, the team revealed how cancer cell nuclei stiffen or soften depending on chromatin structure and environmental conditions.

The findings provide fundamental insights into how the physical properties of cancer cell nuclei change during disease progression, highlighting their potential as biomarkers for diagnosis and treatment evaluation.

Changes in nuclear mechanics are a hallmark of cancer and can indicate malignant transformation. Traditionally, nuclear elasticity has been studied using atomic force microscopy (AFM) probes pressing on the cell membrane or by aspirating isolated nuclei. Both methods suffer from limitations: they are influenced by surrounding cellular structures or fail to capture intact nuclear states. The new NE-AFM method developed by Takehiko Ichikawa and colleagues at Kanazawa University overcomes these barriers by inserting a nanoneedle probe directly into living cells thousands of times without causing severe damage, allowing nanoscale mapping of nuclear elasticity.

The researchers found that human lung cancer cells (PC9) showed significantly increased nuclear elasticity under serum-free conditions. This stiffening correlated with increased trimethylation of histone H4 at lysine 20 (H4K20me3), a marker of chromatin compaction. Treatment with transforming growth factor beta (TGF-β), which induces epithelial–mesenchymal transition (EMT), caused nuclear softening and reduced H4K20me3 levels. The study shows that nuclear elasticity changes are driven primarily by chromatin compaction states, not by alterations in nuclear lamins. Brain-metastatic derivatives of PC9 cells (PC9-BrM) exhibited similar nuclear elasticity trends, suggesting that chromatin regulation of nuclear mechanics plays a role in their invasive behavior.

The team employed Nanoendoscopy-AFM, a technique combining atomic force microscopy with nanoneedle probes fabricated by electron beam deposition. The probes, only ~160 nm in diameter, were inserted repeatedly into living cells to record thousands of force–distance curves across nuclear surfaces. From these measurements, the researchers created three-dimensional elasticity maps of intact nuclei in human lung cancer cells. Unlike traditional AFM methods, NE-AFM distinguishes cell membrane elasticity from nuclear elasticity and avoids interference from cytoskeletal structures. Immunoblotting experiments were also performed to correlate elasticity changes with histone modifications and nuclear protein levels.

"Our work shows that nuclear elasticity is not just a physical property but a reflection of underlying chromatin states," says Ichikawa. "With Nanoendoscopy-AFM, we now have a powerful tool to directly probe the nucleus of living cancer cells. This opens the door to new diagnostic approaches and to a better understanding of how mechanical forces shape cancer progression."

The research demonstrates that nuclear elasticity can act as a measurable biomarker of cancer progression. The NE-AFM method provides an unprecedented ability to probe intact nuclear mechanics and could become a tool for early cancer diagnosis and prognosis, studying chromatin regulation during metastasis, and exploring the mechanics of other organelles such as mitochondria.

Fig. 1 Nanomechanical measurement of a living cell nucleus by Nanoendoscopy-AFM.

https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Figure-1_ACS-Applied-Nano-Materials_Oct.-2025.png

(a) A scanning electron microscope (SEM) image of the nanoneedle probe used for the measurements. (b) Elasticity map of a 1 µm × 1 µm area on the nuclear surface, showing the change in elasticity before (Control) and after treatment with TGF-β. (c) Schematic illustration of the measurement, where the nanoneedle probe is inserted into a living cell to directly indent the nucleus and measure its elasticity. (d) A typical force-distance curve showing the force increase corresponding to the indentation of the cell membrane and the nuclear envelope.

Adapted from ACS Appl. Nano Mater., 2025. (DOI: 10.1021/acsanm.5c03044). Licensed under CC-BY 4.0.

Glossary

• Scanning nanoprobe microscope: A nanotechnology-based tool that can probe inside living cells with ultra-fine precision.
• Nuclear elasticity: How stiff or soft a cell nucleus is, linked to chromatin structure and disease state.
• Chromatin compaction: The way DNA and proteins are tightly or loosely packed, affecting gene activity and nuclear mechanics.
• Histone H4K20me3: A chemical modification of histone proteins associated with compact, inactive DNA.

Reference
Takehiko Ichikawa, Yohei Kono, Makiko Kudo, Takeshi Shimi, Naoyuki Miyashita, Tomohiro Maesaka, Kojiro Ishibashi, Kundan Sivashanmugan, Takeshi Yoshida, Keisuke Miyazawa, Rikinari Hanayama, Eishu Hirata, Kazuki Miyata, Hiroshi Kimura, and Takeshi Fukuma.
"Probing Nanomechanics by Direct Indentation Using Nanoendoscopy-AFM Reveals the Nuclear Elasticity Transition in Cancer Cells." ACS Applied Nano Materials (2025).

DOI: 10.1021/acsanm.5c03044

URL: https://pubs.acs.org/doi/10.1021/acsanm.5c03044

Funding
This work was supported by the World Premier International Research Center Initiative (WPI), MEXT, Japan, JSPS KAKENHI (20H00345, 21H05251, 22H01954, 23K05763), and other national research programs. Additional support came from the Mitani Foundation, Takeda Science Foundation, Shimadzu Science Foundation, and Nakatani Foundation.

Contact:
Kimie Nishimura (Ms)
Project Planning and Outreach, NanoLSI Administration Office
Nano Life Science Institute, Kanazawa University
Kakuma-machi, Kanazawa 920-1192, Japan
Email: [email protected]

About Nano Life Science Institute (WPI-NanoLSI), Kanazawa University

Understanding nanoscale mechanisms of life phenomena by exploring "uncharted nano-realms".

Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale.

https://nanolsi.kanazawa-u.ac.jp/en/

About the World Premier International Research Center Initiative (WPI)

The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).

See the latest research news from the centers at the WPI News Portal:

https://www.eurekalert.org/newsportal/WPI

Main WPI program site: www.jsps.go.jp/english/e-toplevel

About Kanazawa University

Founded in 1862 in Ishikawa Prefecture, Kanazawa University is one of Japan's leading comprehensive national universities with a history spanning more than 160 years. With campuses at Kakuma and Takaramachi–Tsuruma, the university upholds its guiding principle of being "a research university dedicated to education, while opening its doors to both local and global society."

Internationally recognized for its research institutes, including the Nano Life Science Institute (WPI-NanoLSI) and the Cancer Research Institute, Kanazawa University promotes interdisciplinary research and global collaboration, driving progress in health, sustainability, and culture.

http://www.kanazawa-u.ac.jp/en/

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