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24Oct 2014

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How stromal cells influence therapy resistance in breast cancer

Stromal cells can communicate with breast cancer cells and influence the way they respond to chemotherapy or radiation treatment. Mirjam Boelens from the Netherlands Cancer Institute has figured out how this communication can take place and which genetic pathways are involved. These findings were published on October 23 in the journal Cell.

"We are starting to realize that we should not just look at cancer cells, but also the cells that are surrounding them", says Mirjam Boelens. In the past few years, Boelens worked as a KWF-fellow in the laboratory of Andy Minn in the Abramson Family Cancer Research Institute at the University of Pennsylvania. There, she worked on the communication between stromal fibroblasts -  the cells of the connective tissue that surrounds organs - and breast cancer cells. There were already some indications that these stromal cells can influence therapy sensitivity of breast tumors. Boelens tried to figure out the mechanisms behind this. It turns out that stromal cells communicate with breast cancer cells using exosomes, small vesicles containing (in this case) pieces of RNA. These tiny bits of RNA can activate genetic pathways in breast cancer cells that make them therapy resistant.

"The fact that these cells use exosomes to communicate and activate resistance pathways is something quite new", says Boelens. "This offers new possibilities for developing drugs that can sensitize therapy resistant tumors." Boelens and her colleagues showed that the activated pathways in the breast cancer cells are the ones involving the genes STAT1 and NOTCH3. They also showed that these pathways can predict therapy resistance in primary human breast cancer. And when the researchers inhibited the NOTCH signaling pathway in mice, the breast cancer cells in these mice regained sensitivity against radiation therapy.

A very interesting next step would be to see whether activation of the resistance pathways in the tumor cells can be prevented by blocking the communication between the stromal cells and the cancer cells. That's what Boelens is currently working on as a postdoc in the research group of Jos Jonkers at the Netherlands Cancer Institute (NKI). She is now studying the role of the exosomes in a mouse model that spontaneously develops breast cancer. She wants to track the exosomes in this natural situation, and try to target them to see whether this could help prevent the tumor becoming therapy resistant.

All work thus far has been done with so-called triple negative breast cancer cells. Another line of research Boelens is currently focusing on, is to determine the role of the stromal cells in other types of breast cancer, among which invasive lobular carcinoma.

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