Fat tissue could explain triple negative breast cancer spread - and point to treatments, find CDI scientists

Triple-negative breast cancer (TNBC) is aggressive and hard to treat. But the role of fat tissue in how the cancer spreads may help point toward new understanding and treatments, according to a new paper from scientists at the Hackensack Meridian Center for Discovery and Innovation (CDI) and colleagues at Georgetown University’s Lombardi Comprehensive Cancer Center.

The scientists have now demonstrated that the fat tissue can be hijacked by tumor cells to launch itself to spread further inside the body using adipomes, which are miniscule extracellular vesicles released by fat tissues, spreading outward from the breast and outward to other organs. 

This discovery may provide a new strategy for preventing disease progression at much earlier stages than currently possible. The findings appear in npj Breast Cancer, a Nature Portfolio journal, published by senior author Jyothi Nagajyothi, Ph.D., a member of the Center for Discovery and Innovation (CDI) and Georgetown Lombardi, and lead author Hariprasad Thangavel, Ph.D., a member of Nagajyothi’s research team. The study was conducted in collaboration with Georgetown Lombardi’s Robert Glazer, Ph.D., professor of oncology at Georgetown University, and other investigators from the research team. 

“The findings of this study establish adipomes as potent and previously unrecognized regulators of the metastatic cascade in TNBC,” write the authors. 

“This work challenges the traditional view of tumor-adjacent adipocytes as passive lipid reservoirs, and reveals instead their active and dynamic role as key orchestrator of the mammary TME (tumor microenvironment),” they add. 

What has previously been known is that the “metastatic cascade” begins with cancer cells invading the stroma which is the supportive tissue and blood vessels in the breast, enabled by invadopodia, which are kind of like tentacles of proteins protruding from the plasma membrane which degrade the body’s defense and pave the way for cancer's spread. That process has been well observed by scientists.

Nagajyothi’s team has now probed into the earlier phases getting to that process, focusing especially on those adipomes, which are kind of like cellular messengers which kick off the cancer growth cycle. Using human clinical samples acquired from the Hackensack Meridian Health (HMH) Network Biorepository and preclinical models, they scrutinized each step of the process. To do this, the team pioneered a first-of-its kind purification technique capable of isolating pure adipomes from intact tissues, blood, and other bodily fluids - a major technical hurdle that had previously blocked progress in the field. This unique method is so distinct that it is currently the subject of a pending U.S. patent application (US Patent App. 19/233,485) filed by Hackensack Meridian Health. Both Nagajyothi and Thangavel are named as inventors.

The adipomes deliver a specific ‘lipid code’ that reprograms the cancer cells, activating stress-response signaling, boosting protein synthesis, and upregulating key processes including mitochondrial signaling and translational machinery between cells. All of this comes together to foster the invadopodia in TNBC. 

But there could be future therapies interrupting this process in turn - possibly turning the tide against this tough tumor type, the scientists write. 

“Together, these findings establish adipocyte-derived adipomes as potent regulators of TNBC investigation and metastasis and reveal a previously unrecognized tumor-adipocyte signaling axis that may present new opportunities for therapeutic targeting,” they conclude.

Nagajyothi and her laboratory have long focused on adipose (fat) tissues and their role in diseases such as Chagas cardiomyopathy, pulmonary tuberculosis, COVID and post-COVID cardiomyopathy, as well as non-infectious diseases, such as type 2 diabetes, lean diabetes, in addition to cancers (breast cancer and metastasis and multiple myeloma).