PROGRAM | Mechanical Engineering

By: Murtaza Wasi Chair: Liyun Wang

ABSTRACT

One in eight women in the United States will develop breast cancer during her lifetime.
For patients diagnosed at early stages, the five-year survival rate is as high as 99%. However, the survival rate is drastically reduced when breast cancer metastasizes to distant organs such as bones. Metastatic breast cancer disrupts bone homeostasis, leading to osteolytic lesions and increased fracture risk. Standard cancer treatments like chemotherapy often result in further bone loss due to their adverse skeletal effects. In contrast, exercise has emerged as a safe intervention for cancer patients, improving the overall health and mental wellness as well as the survival for breast cancer patients. Given that the average age of breast cancer diagnosis is 62 years old, and that bone’s responses to exercise diminish with aging, additional interventions are needed to maintain the patients’ skeletal health by countering the effects from aging, breast cancers, and cancer treatments. An exciting novel target comes from the newly discovered mechanosensitive Piezo1 ion channels, which are shown to be essential for loading-induced bone formation and counter age-associated bone loss. In particular, the specific Piezo1 agonist, Yoda1, presents a potential adjunct therapy alongside exercise.
This research aims to investigate whether Yoda1-augmented loading can mitigate bone loss associated with aging, metastatic breast cancer, and chemotherapy. To accomplish this goal, I have performed several preclinical studies and included three of them in this thesis. The first study was to evaluate the effects of Yoda1 and moderate tibial loading, alone or combined, on healthy aged mice and mice undergoing chemotherapy treatment. I then investigated how Yoda1-augmented tibial loading affected skeletal integrity in aged mice bearing metastatic breast cancers. Finally, I present the data from a recently completed experiment, in which the effects of Yoda1 treatment were evaluated in aged mice bearing breast cancer and undergoing chemotherapy treatment. These studies have been designed to challenge the skeleton system increasingly with aging, cancer therapy, and cancer metastasis.
Findings from these tailored studies provide valuable insights into potential therapeutic strategies of mitigating bone loss afflicting breast cancer patients and survivors. The first study confirmed a decline of bone structure with aging, attributed to increased bone resorption exceeding bone formation. Although tibial loading (peak load 4.5 N, 4 Hz, 300 cycles/day, 5 days/week, 4 weeks) alone showed no effect on the cortex, Yoda1 (2.5/5 mg/kg) with and without tibial loading effectively counteracted the aging effect on the skeleton by promoting cortical bone formation. Doxorubicin (DOX) administration (2.5/5 mg/kg) tipped the scales further in favor of resorption and resulted in a dose-dependent decline in bone properties, particularly evident in various cortical regions. Yoda1 and tibial loading combined, but not individually applied showed site-dependent benefits in mice receiving DOX. Cellular analysis revealed doxorubicin-induced acute osteocyte apoptosis and decline in osteoblast activity which was partially restored upon Yoda1 treatment. In the second study, the benefits of bone formation was again observed in the Yoda1-treated aged mice. Although the mice bearing breast cancer Py8119 and treated with Yoda1 alone showed more severe osteolytic lesions from increased osteoclast activities and tumor proliferation and apoptosis markers, the combination of Yoda1 with tibial loading in fact mitigated the loss of cortical bone in sites both near and away from the tumor, due to relatively lower osteoclastic bone resorption. Preliminary findings for the last study confirmed the dominated effects of DOX on bone resorption as in the first study, and the efficacy of Yoda1 and loading combination in maintaining bone properties to the pre-treatment levels by promoting bone formation.
Taken together, this thesis provides the experimental data supporting the skeletal benefits of Yoda1-augmented tibial loading using aged mice bearing metastatic breast cancer and undergoing chemotherapy. However, the mixed outcome of Yoda1 on tumor proliferation is a major concern and calls for further studies and deeper mechanistic understanding of Piezo1-based interventions on cancer bone metastasis. Nevertheless, the findings from this thesis shed light on the potential pros and cons of this novel therapy in enhancing the skeletal health for elderly breast cancer patients.

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