Institute of Musculoskeletal Medicine (IMM)

Project description:

Breast cancer bone metastases frequently lead to a debilitating and incurable condition associated with poor prognosis. Patients with advanced metastatic disease often develop cancer cachexia, a multifactorial syndrome characterized by progressive skeletal muscle wasting, resulting in a severe functional impairment and increased mortality.

Our preliminary data demonstrate that breast cancer bone metastasis promotes intramuscular fat accumulation and muscle atrophy, contributing to the progressive decline in muscle function. We hypothesize that this skeletal muscle degeneration results from cancer-driven dysregulation of fibro-adipogenic progenitors (FAPs), a population of muscle-resident stromal cells. Furthermore, we have identified a previously unrecognized role of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in FAPs, mediating their pro-adipogenic and pro-atrophic phenotype within the cancer-associated muscle environment.

We propose that STAT3 activation in FAPs enhances their proliferation and survival, reprograms their lineage commitment toward adipogenesis, and alters their secretory profile, thereby promoting muscle atrophy. To test this hypothesis, we will combine complementary in vitro approaches with mouse models of breast cancer bone metastasis to I) characterize the role of the STAT3 pathway in bone metastases-induced FAP expansion and adipocyte differentiation; II) investigate the role of the STAT3 pathway in FAP-mediated myotube atrophy; and III) evaluate the therapeutic potential of targeting STAT3 to mitigate bone metastasis-induced muscle atrophy and intramuscular fat accumulation.

This project is both original and innovative, addressing an unexplored mechanism of muscle degeneration in the context of bone metastases. We anticipate that our findings will elucidate the STAT3-dependent regulation of FAPs and its impact on myofiber protein turnover, thereby providing a mechanistic rationale for targeting the STAT3 pathway as a therapeutic strategy. Moreover, the identification of novel FAP-derived mediators may open new avenues for the treatment of bone metastases-associated muscle loss and weakness.