Metastatic breast cancer, also called stage 4 breast cancer, is when cancer cells spread from the breast to other parts of the body, such as the bones, lungs, liver, or brain. It is the most advanced stage of breast cancer and can be more challenging to treat. (Credit: Anna Tarazevich from Pexels)
ANN ARBOR, Mich. — Imagine a cancer that can play the ultimate game of hide and seek, lying dormant in your body for years before suddenly springing back to life. For roughly 40% of estrogen receptor-positive breast cancer patients, this is a terrifying reality.
New research from the University of Michigan and the University of California-San Diego has uncovered a startling mechanism behind how these “sleeper” cancer cells manage to survive and eventually return, potentially paving the way for new strategies that prevent the disease.
Most people assume that successful cancer treatment means the disease is completely gone. In estrogen receptor-positive breast cancer, however, things aren’t that simple. These crafty cancer cells can lurk in bone marrow for years — sometimes even decades — before resurging with a vengeance.
When these cells return, they’re not just a repeat performance. They can transform into an aggressive bone cancer that causes devastating complications like bone fractures and dangerous calcium imbalances. In some cases, they spread to other organs, creating a recurrent disease that currently has no cure.
The research, published in the Journal of Clinical Investigation, reveals a fascinating survival strategy that sounds like something out of a molecular espionage thriller. Cancer cells don’t fight alone — they form an alliance with mesenchymal stem cells in the bone marrow, essentially “borrowing” molecules to become stronger and more resistant.
“The cancer cells physically borrow molecules—proteins, messenger RNA—directly from the mesenchymal stem cells,” explains Dr. Gary Luker, senior author of the study, in a media release. “Essentially the mesenchymal stem cells act as very generous neighbors in donating things that make the cancer cells more aggressive and drug resistant.”
Through meticulous laboratory experiments, researchers discovered a key protein called GIV (or Girdin) that plays a crucial role in this survival mechanism. GIV makes these cancer cells particularly resistant to estrogen-targeted therapies like Tamoxifen, essentially giving them a “get out of jail free” card when confronted with treatment.
“These cancer cells ‘borrow’ essential proteins from stem cells in the bone marrow through cellular tunnels—much like smuggling,” explains study author Dr. Pradipta Ghosh.
This research isn’t just academic — it offers hope. By understanding how these cancer cells survive and become drug-resistant, scientists might develop targeted approaches to prevent cancer recurrence.
The potential implications are profound: imagine a future treatment that could seal these cellular “tunnels” or neutralize the proteins cancer cells smuggle, potentially stopping breast cancer from returning years after initial remission.
While more research is still necessary, this study represents a significant step forward in understanding one of cancer’s most insidious behaviors — its ability to wait, adapt, and return when least expected.
Paper Summary
Methodology
The researchers investigated how breast cancer cells interact with bone marrow stromal cells. They used co-culture models where breast cancer cells (MCF7 or T47D) were grown directly with mesenchymal stromal cells (MSCs) to simulate the bone marrow environment. The study employed RNA sequencing and proteomics to analyze gene and protein changes.
For comparison, they also grew cancer cells in conditioned media from MSCs (without direct contact). They isolated the cancer cells after culture and identified molecules transferred from MSCs or produced by the cancer cells due to direct interaction. These findings were further refined using 3D culture systems to ensure physiological relevance.
Key Results
The study revealed that direct contact between breast cancer cells and MSCs triggered significant changes. Cancer cells “borrowed” key molecules like the protein GIV (encoded by the CCDC88A gene) from MSCs, enhancing their aggressiveness. This borrowing occurred through tiny cell-to-cell tunnels called tunneling nanotubes. The transferred molecules helped cancer cells resist therapies and spread.
Researchers identified 39 unique genes activated in this process, which correlated with poor outcomes in breast cancer patients. By artificially increasing GIV levels in breast cancer cells, the researchers confirmed its role in promoting drug resistance and metastasis.
Study Limitations
Using conditioned media for comparisons might not fully replicate the effects of non-contact interactions in vivo. The study did not evaluate all the molecules potentially transferred back to MSCs from cancer cells. The experiments used immunodeficient mice, which lack an intact immune system, limiting insights into immune-related processes. Short-term co-culture setups might not capture the full extent of long-term interactions in the bone marrow niche.
Discussion & Takeaways
The study highlights how direct interaction with MSCs reprograms breast cancer cells, aiding their survival and metastasis. A key finding is the role of GIV in fostering drug resistance and early dissemination of cancer cells. This protein, absent in certain breast cancer cells, is borrowed from MSCs and integrates into cancer signaling pathways. These insights pave the way for targeting such intercellular exchanges to develop therapies that could disrupt cancer cell communication and halt disease progression.
Funding & Disclosures
The research was supported by grants from the National Institutes of Health, the W.M. Keck Foundation, and other organizations like the Padres Pedal the Cause. The authors disclosed that one of them received materials from a pharmaceutical company but stated no competing financial interests affecting the study.
