Therapeutic targeting of polyploid giant cancer cells (PGCCs) and the cGAS/STING/Interferon pathway in Rhabdomyosarcoma
Rhabdomyosarcoma is a childhood muscle cancer that is difficult to cure once it returns after treatment. Our research uncovered a surprising reason why some cancer cells survive therapy. We discovered that treatment causes some tumor cells to become very large and carry extra DNA - these are called polyploid giant cancer cells (PGCCs). Rather than being evolutionary dead-ends that do not contribute to tumor growth, PGCCs actively send signals that convert nearby tumor cells into a therapy-resistant, stem-like state. These PGCCs remain in tumors for weeks after treatment and likely help the cancer grow back after therapy. Our work suggests that PGCCs arise when fast-growing tumor cells are damaged by chemotherapy or radiation and fail to divide properly. These PGCCs then switch on an alarm-like pathway, called cGAS-STING, which triggers release of interferon-ß, a molecule that reprograms neighboring cells to become resistant. Blocking this pathway with clinically-available drugs made tumors more sensitive to standard treatment – identifying possible new approaches to kill relapse and refractory rhabdomyosarcoma. Our project will map where PGCCs appear in patient samples, uncover how they influence other cells, and test clinically used drugs that block PGCC signaling using human tumors grown in zebrafish and mouse models. This work could lead to new therapies that prevent relapse by stopping PGCCs from creating treatment-resistant cancer cells.
Project Goals
Fusion-negative rhabdomyosarcoma (FN-RMS) is a childhood muscle cancer that is difficult to treat once it returns after therapy. Our research aims to understand why some cancer cells survive treatment and how to stop them. We have discovered that FN-RMS contain different kinds of cells, including a therapy-resistant cell that grows only after stress. Recently, we also identified a new and unusual cell type - polyploid giant cancer cells (PGCCs) - which are very large, contain extra DNA, and appear only after treatment. These PGGCs seem to play an important role in helping the cancer survive and grow after treatment, but their exact function is unknown. Our findings suggest that PGCCs form when fast-growing cancer cells fail to divide properly after damage from chemotherapy or radiation. Once formed, PGCCs activate a molecular “alarm system” that sends signals to nearby cells, encouraging them to become therapy-resistant. Our research will focus on three goals: first, to learn how PGCCs form and where they appear in patient tumors after treatment; second, to understand how they influence other cells to become therapy resistant; and third, to find medicines that can stop these cells from helping cancers regrow. By uncovering how PGCCs help cancer survive, this work could lead to new treatments that prevent relapse and improve survival for children with FN-RMS. Because PGCCs are found in many cancers, these discoveries are expected to benefit patients with other tumor types.
