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To Persist Through Chemotherapy, Cancer Cells Turn To Cannibalism

Some cancer cells survive chemotherapy by devouring their neighboring tumor cells, research from Tulane University suggests[1]. This act of cannibalism may give these cancer cells the energy required to stay alive and begin tumor relapse after the treatment is completed.

“Understanding the properties of these senescent cancer cells that allow their survival after chemotherapy treatment is extremely important,”

says Crystal A. Tonnessen-Murray, a postdoctoral research fellow in James G. Jackson’s laboratory at the Tulane University School of Medicine.

Cancer Cell Senescence

Chemotherapy drugs such as doxorubicin kill cancer cells by damaging their DNA, but cells that survive initial treatment can soon give rise to relapsed tumors. This is a particular problem in breast cancers that retain a normal copy of a gene called TP53[2].

Instead of dying in response to chemotherapy-induced DNA damage, these cancer cells generally just stop proliferating and enter a dormant but metabolically active state known as senescence.

In addition to surviving chemotherapy, these senescent cancer cells produce large amounts of inflammatory molecules and other factors that can promote the tumor’s regrowth. Chemotherapy-treated breast cancer patients with normal TP53 genes are therefore prone to relapse and have poor survival rates.

In this study, Tonnessen-Murray and colleagues discovered that, following exposure to doxorubicin or other chemotherapy drugs, breast cancer cells that become senescent frequently engulf neighboring cancer cells. The researchers observed this surprising behavior not only in cancer cells grown in the lab, but also in tumors growing in mice.

Lung and bone cancer cells are also capable of engulfing their neighbors after becoming senescent, the researchers discovered.

Staying Alive

Tonnessen-Murray and colleagues found that senescent cancer cells activate a group of genes that are normally active in white blood cells that engulf invading microbes or cellular debris. After “eating” their neighbors, senescent cancer cells digested them by delivering them to lysosomes, acidic cellular structures that are also highly active in senescent cells.

Importantly, the researchers determined that this process helps senescent cancer cells stay alive. Senescent cancer cells that engulfed a neighboring cell survived in culture for longer than senescent cancer cells that didn’t.

doxorubicin-treated mouse mammary tumors 1
Cell-in-cell structures are observed in doxorubicin-treated mouse mammary tumors and breast cancer cell lines.
Credit: Tonnessen-Murray, et al.

The researchers suspect that consuming their neighbors may provide senescent cancer cells with the energy and materials they need to survive and produce the factors that drive tumor relapse.

“Inhibiting this process may provide new therapeutic opportunities, because we know that it is the breast cancer patients with tumors that undergo TP53-mediated senescence in response to chemotherapy that have poor response and poor survival rates,”

Jackson says.

The study was supported by the U.S. Department of Defense Breast Cancer Research Program.

[1] Crystal A. Tonnessen-Murray, Wesley D. Frey, Sonia G. Rao, Ashkan Shahbandi, Nathan A. Ungerleider, Joy O. Olayiwola, Lucas B. Murray,
Benjamin T. Vinson, Douglas B. Chrisey, Christopher J. Lord, and James G. Jackson. Chemotherapy-induced senescent cancer cells engulf
other cells to enhance their survival. Journal of Cell Biology 2019 DOI: 10.1083/jcb.201904051

[2] Chen, M.B., Y.Q. Zhu, J.Y. Xu, L.Q. Wang, C.Y. Liu, Z.Y. Ji, and P.H. Lu. 2012. Value of TP53 status for predicting response to neoadjuvant chemotherapy in breast cancer: a meta-analysis. PLoS One. 7:e39655. https://doi.org/10.1371/journal.pone.0039655