A Tumor–Brain Endocrine Axis That Drives Ovarian Cancer Metastasis

Our research is driven by the idea that ovarian cancer is not only a disease of tumor cells, but also a disease that can affect and be shaped by the whole body, including the brain. We aim to understand how ovarian tumors spread and communicate with distant organs, including the brain. Although ovarian cancer cells rarely metastasize to the brain, our work suggests that a tumor–brain axis may promote metastatic progression. The Lotus Award will allow us to investigate this bold and largely unexplored area of ovarian cancer research: the tumor–brain connection. Our ultimate goal is to translate these discoveries into new therapeutic strategies that prevent recurrence and extend survival for patients with ovarian cancer.

"To the ovarian cancer community: your struggles, persistence, courage, and hope inspire our work every single day. We are committed to understanding how ovarian cancer spreads and resists therapy. Our team studies how ovarian tumors communicate with the brain and how this communication impacts the whole body. Our goal is to translate these insights into new strategies to prevent recurrence and improve outcomes for patients living with this disease."

Ovarian cancer remains one of the deadliest malignancies due to early dissemination and frequent relapse. While metastasis typically occurs within the abdomen and lungs, brain involvement is rare, leading to the assumption that the brain plays little role in ovarian cancer progression. Our research challenges this paradigm by revealing a previously unrecognized tumor-brain communication axis that actively drives metastatic disease.

We discovered that ovarian cancer communicates with the brain even without spreading there. Tumor-derived signals circulate to the brain and activate an stress-hormone system normally engaged during acute physiological challenges. This system releases cortisol, a hormone that should rise briefly and return to baseline. In patients with ovarian cancer, however, cortisol levels remain persistently elevated, and higher cortisol levels are associated with faster disease progression and worse survival.

Using ovarian cancer mouse models, we identified corticotropin-releasing hormone (CRH)–producing neurons in the brain as key mediators of this dysregulation. Tumor-derived signals activate these neurons, sustaining stress-hormone signaling and promoting metastasis. We further discovered that a subset of ovarian tumors produces CRH, activating cortisol-independent pathways that promote metastatic progression. Importantly, pharmacological inhibition of CRH signaling suppresses metastasis in vivo.

This project will define how ovarian cancer induces CRH expression in the brain and elucidate the mechanisms by which tumor-derived CRH promotes metastasis. By targeting this pathway with brain-penetrant CRH receptor antagonists already in clinical testing for depression, our work opens the door to new therapeutic strategies aimed at preventing relapse and improving long-term survival for women with ovarian cancer.

Swarnali Acharyya is an Associate Professor in the Department of Pathology and Cell Biology and the Institute for Cancer Genetics at Columbia University. Her laboratory studies metastasis as a systemic process, focusing on mechanisms that drive metastatic progression and systemic metabolic dysfunction, including cachexia. She completed postdoctoral training at Memorial Sloan Kettering Cancer Center with Dr. Joan Massagué. Her postdoctoral work on blocking CXCL1/2 chemokines to overcome chemoresistance and metastasis was published in Cell and is now in Phase 2 clinical trials at MSKCC. Dr. Acharyya joined Columbia University as a tenure-track Assistant Professor in 2014 and was promoted to Associate Professor with tenure in 2023.

Her laboratory investigates two major areas of metastasis biology. First, her group studies the programs that drive metastasis and resistance to targeted therapies. Her recent work on brain metastasis has been recognized by the Schaefer Research Scholar Award, Irma T. Hirschl/Monique Weill-Caulier Trust Scholar Award, American Lung Association Discovery Award, and James Dougherty Award from the Lung Cancer Research Foundation. Second, her group studies the systemic effects of metastasis, particularly cancer cachexia. Her laboratory was the first to demonstrate how metastatic cancer cells distantly reprogram muscle through deregulation of the zinc transporter ZIP14. This work, published in Nature Medicine, was recognized by the Pershing Square Sohn Prize and opened a new research direction for treating cancer cachexia. Through research efforts in both areas, Dr. Acharyya aims to develop durable therapies that improve outcomes and quality of life for metastatic cancer patients.