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Abstract Papillary thyroid cancer (PTC) is the most common cancer in young women and is increasing 3% annually in incidence. While PTC is often slow-growing and surgically resectable, recurrence years to decades later occurs in 20% of patients (now only in their 40s/50s), decreasing survival by ~60%. The identification of prognostic biomarkers and actionable therapeutic targets for high-risk PTC is critically important and an unmet need. RNASeq analysis of our repository of PTC and matched normal tissues identified collagen 26A1 (COL26A1) as significantly upregulated in patients with extrathyroidal extension (ETE), lymph node metastasis, and multifocal tumors, indicative of high-risk for recurrence. Correspondingly, survival curves of The Cancer Genome Atlas (TCGA) demonstrated increased COL26A1 expression decreases survival probability by 25% (p=0. 0086) and correlated with MACIS score (q=0. 001), differentiation score (q=0. 025), tumor stage (q=0. 025), and ETE (p=0. 0038). COL26A1 expression was increased in PTC cell lines K1 (3-fold) and TPC1 (5-fold) compared to “normal” thyroid epithelial cells, NThy-ori-3-1. CRISPR knockdown of COL26A1 repressed RNA (50%) and protein (70%) expression. COL26A1 repression decreased known cancer-promoting activities of collagens, including proliferation (30%), clonogenicity (33%), anchorage-independent growth (37%), cell motility (43%), Matrigel invasion (30%), in situ gelatin degradation (70%), and migration (33%). Cell-to-cell adhesion and cell-matrix adhesion also decreased (36% and 25%, respectively). This coincided with reduced anoikis resistance (31%), increased MMP expression (50%), and reductions in mesenchymal markers (30%) and increases in epithelial markers (3-fold). Evidence that COL26A1 is a secreted protein was validated by conditioned media isolations whereby expression was decreased in knockdowns compared to control cells (70%). Preliminary data indicate the control cells’ conditioned media can restore the aggressive phenotypes, including cell motility (51%). Qiagen Ingenuity Pathway Analysis (IPA) elucidated the potential role of androgen receptor (AR) in linking COL26A1 with PTC, coinciding with the known effects of sex hormones on collagen expression and organization, and the sex disparity in PTC. Preliminary data indicate that physiologic levels of androgen decrease COL26A1 RNA (46%) and protein (45%) expression in K1 cells expressing the androgen receptor. Thus, COL26A1 may serve as a prognostic marker and actionable target for small molecule inhibitors in high-risk PTC. Citation Format: Michelle Carnazza, Danielle Quaranto, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Humayun K. Islam, Julie S. Di Martino, Raj K. Tiwari, Jan Geliebter. Collagen COL26A1 correlates with poor papillary thyroid cancer prognosis and in vitro characteristics of metastasis indicating a potential role as a biomarker or therapeutic target abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5663.
Carnazza et al. (Fri,) studied this question.