Protein folding chaperonin as biological indicator for cancer progression and metastasis

Abstract Protein folding complexes are a vital link between the expression of tumor-promoting oncogenes and oncogenic cancer behavior known as the hallmarks of cancer. Of these, the eukaryotic type II chaperonin, Chaperonin-Containing TCP-1 (CCT or TRiC) folds many of the oncoproteins (e.g., KRAS, MYC, CDKs, STAT3, etc.) that drive cancer growth and invasion. CCT is a complex machine composed of eight subunits, each encoded by a unique gene (cct1-8), which folds proteins in an ATP-dependent fashion within an inner chamber. Previous work in breast cancer revealed that the CCT2 subunit was highly expressed in breast tumor tissues and correlated with advanced breast cancer stage, metastasis, and decreased patient survival. To determine the pattern of CCT2 expression across multiple cancers in comparison to normal tissues, we interrogated the UCSC Xena database to compare cohorts, GTEx (normal tissues), TCGA (adult cancerous and normal tissues), and TARGET (pediatric cancerous and normal tissues). Tumor specimens from adult TCGA expressed significantly higher levels of CCT2 than GTEx, and pediatric TARGET samples had significantly higher expression levels of CCT2 than TCGA and normal samples. Histological detection of CCT2 in multiple cancer tissues was increased (e.g., pediatric cancers and sarcomas being among the highest) compared to cancer-adjacent tissues or normal tissues and supported the bioinformatics data. Manipulating CCT2 levels in individual breast, neuroblastoma, and prostate cancer cells revealed the strategic importance of this chaperonin subunit in supporting the metastatic cancer phenotype. Exogenous expression of CCT2 promoted uncontrolled and anchorage-independent growth and migration of cancer cells, which was reversed upon depletion of the subunit, causing cancer cell death. Moreover, conditioned media from cancer cells exogenously expressing CCT2 also drove the migration and growth of cancer cells. Exosomes isolated from this media contained high levels of CCT2 mRNA, further demonstrating the metastasis-promoting potential of this chaperonin subunit. The feasibility of using CCT2 as a biomarker to detect cancer progression was confirmed using antibodies to detect CCT2 in the identification of circulating tumor cells using the CellSearch System. These results provide validation to further develop the use of CCT2 as a diagnostic marker for cancer progression and metastasis and as a promising therapeutic target for new drug development. Citation Format: Annette R. Khaled, James Velazquez, Lam Truong, Colten Frank, Carolyn Dang, Amanda Cox, Heba Ghozlan, Eunkyung Lee, Amr S. Khaled, Priya K. Gopalan. Protein folding chaperonin as biological indicator for cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2463.