Senescent stromal cells drive chemotherapy-induced peripheral neuropathy

Chemotherapy has extended survival for cancer patients across the cancer landscape. Unfortunately, chemotherapy is not benign as it induces a broad range of side effects that can significantly impact a cancer survivor’s quality of life. One such side effect is chemotherapy induced peripheral neuropathy (CIPN), affecting up to 90% of patients receiving taxanes, with 30% experiencing lifelong symptoms. Permanent symptoms can include tactile or thermal allodynia (pain), numbness, and dysesthesia (tingling) in the hands and feet, making everyday tasks a struggle. Current treatments, such as cryotherapy, offer only temporary and limited relief. Because chemotherapy induces robust senescence, we asked if senescence contributed to CIPN. Our genetic and pharmacologic studies revealed that senescence not only drives CIPN but also hinders axonal repair post-chemotherapy. Here we will ask how senescence drives CIPN by, 1) elucidating the impact of senescence on axonal loss in CIPN and 2) identifying senescent cells and determining how they contribute to CIPN. Preliminary data suggest that senescent nonneuronal cells in the peripheral nervous system (PNS) are key players in CIPN, likely through the secretion of p38MAPK-MK2 dependent senescence associated secretory phenotype (SASP) factors that activate neuronal SARM1 and impede the formation of reparative Schwann cells. We will use innovative genetic mouse models and in vitro assays to study the role senescent cells play and elucidate their mechanisms of action in CIPN. Our work promises not only a deeper understanding of CIPN’s molecular drivers but also potential new avenues for relieving the suffering of millions of cancer survivors.