Collier Lab
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Under the direction of Christopher Collier, MD, assistant professor of Orthopaedic Surgery at the Indiana University School of Medicine, the Collier Lab -- more broadly referred to as the Indiana Orthopaedic Oncology Lab -- is dedicated to understanding the intersection of Orthopaedics and Cancer. Its mission consists of:
Advancing the Science of Musculoskeletal Oncology: The Collier Lab strives to ask thoughtful questions pertaining to the musculoskeletal oncology patient, ranging from the origins of sarcoma to the development of epigenetic therapies for osteosarcoma to understanding the significance of oligometastatic disease to bone.
Remembering Those Who Benefit Most from Our Daily Work: The lab's researchers know that at the core of what we do is a commitment to our patients, both current and future, to remember why our work matters to their daily lives.
Advancing the Science of Musculoskeletal Oncology: The Collier Lab strives to ask thoughtful questions pertaining to the musculoskeletal oncology patient, ranging from the origins of sarcoma to the development of epigenetic therapies for osteosarcoma to understanding the significance of oligometastatic disease to bone.
Remembering Those Who Benefit Most from Our Daily Work: The lab's researchers know that at the core of what we do is a commitment to our patients, both current and future, to remember why our work matters to their daily lives.
Fostering an Environment of Collaboration: The lab's aim to provide a meeting place for medical professionals, scientists, and students of all levels - across multiple disciplines - to combine expertise, develop new ideas, and advance the field, together.
Supporting the Development of Young Scientists: The Collier Lab recognizes the role that academic labs play in developing the scientists of tomorrow. We commit to providing an exciting and fun environment that delivers mentorship, teaching, laboratory skills, and resources to emerging scientists.
Ethical Conduct of Research: The lab values the scientific process and acknowledge that it depends on the highest ethical and moral standards. We embrace honesty, curiosity, constructive criticism, peer-review, and above all, we carry a mutual respect for one another and our colleagues.
Active Research
Cachexia, a multifactorial syndrome characterized by progressive loss of muscle mass, is experienced by 80% of patients with advanced cancer and responsible for 20 to 40% of cancer-related deaths. Metastatic bone disease (MBD), which occurs when cancer spreads from the primary site to bone, is a leading cause of cancer-related morbidity and is present in 30% of patients with metastatic disease at cancer diagnosis. Direct links between cachexia and metastatic bone disease are emerging, with evidence of IL-6, TNF-a, and TGF-b-mediated crosstalk between tumor, muscle, and bone that culminates in muscle weakness and wasting. Therefore, there is a critical need to elucidate mechanisms of cachexia-related muscle and bone dysfunction in the setting of metastatic bone disease.
The laboratory is developing novel models of metastatic renal cell carcinoma (RCC) to bone to study its effects on normal muscle and bone. RCC is of particular interest because it frequently metastasizes to bone and 40% of patients with the disease develop cachexia. This intermediate risk, compared to other cancer types, offers an opportunity to study histologically similar tumors along a spectrum of cachectic potential. The lab's long-term goal is to develop surgical and medical therapies targeting cachexia-related muscle and bone dysfunction.
Epigenetic deregulation is an emerging hallmark of cancer that enables tumor cells to escape surveillance by tumor suppressors and ultimately progress. The structure of the epigenome consists of covalent modifications of chromatin components, including acetylation by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs). Targeting these enzymes with inhibitors to restore epigenetic homeostasis has been explored for many cancers. Osteosarcoma, an aggressive bone malignancy that primarily affects children and young adults, is notable for widespread genetic and epigenetic instability. For example, recent whole-genome sequencing suggests that osteosarcomas are driven by a relatively small number of mutations compared to adult tumors – frequently in genes encoding epigenetic regulators – while copy number alterations and structural variants predominate. Epigenetics may also be critical in osteosarcoma metastases, which are accompanied by a shift in the cancer epigenome despite minor changes in the mutational landscape. For these reasons, the emergence of epigenomic therapies has been met with great enthusiasm by those studying osteosarcoma, owing to the relatively limited activity of other newer agents and the significant epigenetic dysregulation observed in osteosarcoma tumors.
In collaboration with the laboratory of Ed Greenfield, PhD, at the Indiana University School of Medicine, the Collier Lab recently developed a three-dimensional in vitro osteosarcoma drug-screening platform that provides highly-uniform sarcospheres to mimic micrometastatic disease. Sarcospheres generated from three highly-metastatic human cell lines were then used to screen the NCI panel of 114 FDA-approved oncology drugs. Two of the fifteen most effective drugs were the HDAC inhibitors romidepsin and vorinostat, which were the only two epigenetic therapies included in the panel. After further characterization in normal cell lines and in combination with standard-of-care MAP (methotrexate, doxorubicin, and cisplatin) chemotherapy, romidepsin emerged as the most promising drug evaluated. These findings are consistent with the growing interest in epigenetic therapies for the treatment of osteosarcoma and suggest the need for further preclinical evaluation of the agents to optimize their success in scarcely available clinical trials.
