New discovery reveals crucial link between cholesterol and breast cancer progression

Cancer Center at Illinois (CCIL) Program Leader Erik Nelson's lab made an important discovery about the relationship between cholesterol and breast cancer progression with crucial implications for breast cancer therapeutics.

Breast cancer is the second leading cause of cancer-related death for American women, and more than 90% of breast cancer deaths are caused by metastatic spread of the disease. While breast cancer therapies have improved significantly in recent years, scientists do not yet understand the totality of molecular mechanisms involved in breast cancer progression and treatment resistance.

With previous knowledge in hand about an association between cholesterol and poor breast cancer outcomes, Nelson's team identified-with preclinical animal models-a cholesterol metabolite called hydroxycholesterol (27HC) that suppresses the ability of the immune system to attack cancer. They showed that 27HC worked on neutrophils-a type of immune cell-and stimulated the secretion of extracellular vesicles (EVs). However, they were not certain whether 27HC changed the communication between immune cells and cancer cells.

In their latest study, Nelson's team made a significant breakthrough: a line of communication used by neutrophil-EVs stimulates breast cancer progression. The findings are detailed in a paper in the journal Cancer Letters. Additional research collaborators from the CCIL include members Jefferson Chan and Wawrzyniec Dobrucki.

In our study, we described one of the axes used by neutrophil-EVs to stimulate breast cancer progression. 27HC 'tells' neutrophils what to put into EVs before sending them out. These customized neutrophil-EVs communicate with cancer cells themselves and instruct them to change their 'makeup.' The cancer cells then change to become more 'stem-like,' allowing them to become resistant to standard chemotherapies as well as spread (metastasize) to other organs."

Natalia Krawczynska, first author

Of the research results, Nelson said, "We show that EVs from neutrophils instruct cancer cells to engage in pathways making them resistant to chemotherapies. That means, if we can disrupt this process, we can offer a solution to patients with current metastatic disease-making their current medications work better."

Future research direction

Based on these findings, the team will now start working on developing new treatment strategies focused on disrupting this communication in the early stages of breast cancer, with the goal of decreasing the occurrence of breast cancer metastasis.

"Given that technology allows us to diagnose breast cancer at early stages, finding a way to prevent metastatic cancer before it clinically appears-by stopping the communication of neutrophil-EVs with cancer cells-might help stop the spread of cancer cells and metastatic disease," added Krawczynska.

Nelson's lab will now evaluate how they can modulate this communication to boost current breast cancer treatment strategies. This will involve intense basic science research and pre-clinical studies to evaluate the efficacy of various existing compounds. In addition-given the relatively new field of EVs-they plan to collaborate with chemists to screen and develop new compounds with the potential to alter EV communication with cancer cells.

Additionally, the lab will evaluate different cues from diets, drugs, or human biology that might also alter this neutrophil-EVs communication in cancer. "We want to investigate how neutrophil-EVs impact other cells directly, or via a 'telephone game' mechanism within the tumor microenvironment, influencing cancer progression," said Krawczynska.

This comprehensive investigation will leverage interdisciplinary expertise of biologists like Nelson, engineers, chemists, and computational biologists. Thankfully, the CCIL is ideally situated at the nexus of these research strengths.

From here, Nelson's lab plans to establish collaborations with clinicians and patients to start investigating whether monitoring of EVs in the blood could predict metastatic recurrence in breast cancer patients. This project has potential to open a new way for early preventative strategies, ultimately improving cancer patients' outcomes.

"Our work provides fundamental insight into how immune cells talk with cancer cells, and how that can be hijacked by a cholesterol metabolite," said Nelson of this study's significance. "This discovery offers hope, because we found that when the 'message' is eliminated, the cancer cells can revert to being more stationary and sensitive to medications, and thereby more effective," said Nelson.