Close to the Bone: SKCC Investigators Uncover Link between Mitochondrial Metabolism and Chondrosarcoma

The research sheds light on a key cellular change that contributes to the malignancy of a common form of bone cancer, and which might aid in the development of biomarkers and therapeutic approaches to detect and treat this form of cancer.

PHILADELPHIA -- New research from the Sidney Kimmel Cancer Center – Jefferson Health (SKCC) sheds light on a key cellular change that contributes to the malignancy of a common form of bone cancer, and which might aid in the development of biomarkers and therapeutic approaches to detect and treat this form of cancer.

The new study, which was conducted by SKCC investigators Atrayee Basu-Mallick, MD, Clinical Assistant Professor of Medical Oncology and Director of SKCC’s Multidisciplinary Bone and Sarcoma Center; Ubaldo Martinez-Outschoorn, MD, Associate Professor of Medical Oncology and Co-leader of SKCC’s Translational Cellular Oncology Research Program; and Megan Roche, a graduate student in Martinez-Outschoorn’s laboratory, was recently published in the journal BBA Molecular Basis of Disease.

The team of researchers, which also included Wei Jiang, MD, PhD, a sarcoma pathologist at SKCC; John Abraham, MD, of Fox Chase Cancer Center; and Judith Bovée of Leiden University in the Netherlands, focused their attention on the role of a mitochondrial membrane protein termed TOMM20 in a form of bone cancer known as chondrosarcoma.

Chondrosarcoma is the second most common primary bone malignancy, accounting for one-fourth of all primary bone sarcomas, and unfortunately it is resistant to both radiation and chemotherapy treatments. This bone cancer generally occurs in adults. Because mutations in mitochondrial enzymes are common in this disease, the investigators examined the expression of a number of mitochondrial proteins in chondrosarcoma, looking especially for those whose expression increased significantly in high-grade sarcomas that represent the most advanced, aggressive stage of this cancer. From among the proteins tested, they discovered that TOMM20 expression is noticeably elevated in high-grade chondrosarcoma, prompting them to conduct further studies to determine the role of TOMM20 in cancer progression.

“We followed up our initial findings and went on to show that TOMM20 over-expression promotes cancer aggressiveness by driving tumor growth, invasiveness, resistance to apoptosis, and resistance to chemotherapy,” Basu-Mallick explained. “Uncovering this link to chemotherapy resistance is clinically important, because the main option for patients is surgery to remove the sarcoma. Surgical excision of the tumor has some serious downsides, and furthermore the prognosis for patients with metastatic or inoperable chondrosarcoma is quite poor due to the current lack of effective chemotherapies.”

How does TOMM20 enhance the aggressiveness of chondrosarcomas?

The investigators looked more closely at the mitochondrial metabolism of the tumor cells, and found that a number of cellular pathways and processes associated with cell proliferation are upregulated in chondrosarcomas with high expression levels of TOMM20. In addition, they discovered that these chondrosarcomas exhibit higher levels of metabolite uptake and increased rates of oxygen consumption, consistent with increased energy generation by mitochondria, which are often likened to the “batteries” of the cell.

“The increased expression of TOMM20 seems to push the cancer cells into metabolic over-drive, where they ramp up their cell growth pathways, consume oxygen, and utilize energy sources such as glucose and lactate more efficiently, and thus are refractory to widely used cancer treatments such as chemotherapy agents,” Roche said.

Further studies are planned to investigate the cellular consequences of elevated TOMM20 expression in chondrosarcoma cells, focusing on the complex metabolic pathways that operate within the cells. The research findings also have important implications for clinical aspects of chondrosarcoma treatment. For instance, TOMM20 expression levels can be monitored in a patient’s tumor and used as a molecular biomarker to more precisely evaluate the stage and aggressiveness of the tumor, thereby providing important diagnostic and prognostic information. Furthermore, a more detailed understanding of the biochemical role of TOMM20 in tumor progression raises the long-term prospect of targeting TOMM20 as a potential therapy to treat or delay the progression of chondrosarcoma, thus giving hope to patients suffering from this aggressive bone cancer who currently have few treatment options.

“The areas of mitochondrial biology, metabolism, and the bone tumor microenvironment are research strengths within the SKCC,” said Andrew E. Aplin, PhD, Enterprise Associate Director for Basic Science at SKCC and Kalbach-Newton Professor in Cancer Research. “This translational and collaborative study may also inform ongoing investigations in other cancer types that arise in or metastasize to the bone.

By Mark Fortini

Article reference: Megan E. Roche, Zhao Lin, Diana Whitaker-Menezes, Tingting Zhan, Karoly Szuhai, Judith VMG Bovee, John A. Abraham, Wei Jiang, Ubaldo Martinez-Outschoorn, Atrayee Basu-Mallick, “Translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20) facilitates cancer aggressiveness and therapeutic resistance in chondrosarcoma,” Biochim Biophys Acta Mol Basis Dis, DOI: 10.1016/j.bbadis.2020.165962.