Abstract 5286: Matrix metalloproteinase 14 in associated with poor survival in adrenocortical carcinoma
Authors: Popova Liudmila V. , Mardis Elaine , Miller Katherine , Dedhia Priya H. 
Published: June 2023

Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal cortex. Five-year survival in Stage IV disease is 6%. Surgical resection is the mainstay of treatment; however, most patients present with unresectable disease or experience tumor recurrence after surgery. No targeted therapies are available for treatment of ACC. Thus, there is a critical need to understand molecular mechanisms driving advanced ACC. Matrix metalloproteinases (MMPs) have been associated with worse prognosis in other human cancers. Although pan-inhibition had limited clinical success, recent studies suggest select inhibition may improve patient outcomes. Here, we use The Cancer Genome Atlas (TCGA) and single nuclei RNA sequencing data (snRNAseq) to evaluate the expression of MMPs in ACC. RNA sequencing data from 77 ACC patients in TCGA was downloaded from UCSC Treehouse Public Data Tumor Compendium v11. Using the Kaplan-Meier estimator, survival was compared between the highest and lowest quartile of RNA expression for each MMP in R v.4.1. For snRNAseq, normal adrenal and adrenal adenoma samples were collected from a patient diagnosed with adrenal hypercortisolism. Seven primary and metastatic ACC samples were collected from patients diagnosed with ACC at time of surgical resection and included one primary tumor-metastasis pair. Single nuclei were isolated from frozen samples. Sequencing libraries were generated and sequenced on the Illumina NovaSeq 6000. Data were preprocessed using the 10x Genomics CellRanger software suite. Downstream analysis was performed using Seurat v.4 for R. ACC specimens in TCGA expressed all 24 MMPs with MMP14 demonstrating the highest expression. MMP14 expression was associated with significantly worse survival with a hazard ratio of 3.6 (95% CI 1.2 - 11.1). In addition, increased MMP14 expression was associated with higher AJCC tumor stage (p &lt; 0.05). snRNAseq analysis of our ACC primary and metastatic samples identified 7 adrenal cortex clusters and one cluster each - fibroblasts, macrophages, infiltrating lymphocytes, endothelial, and adrenal medulla cells. Two cell clusters were present in primary and metastatic samples but not benign adrenal samples and were characterized by high KI67 expression or high ribosomal content. MMP14 expression was significantly higher in metastatic versus primary tumors in 2 adrenal cortex clusters with 3.6 and 2 fold increased expression, respectively (p &lt; 0.05); and one of these clusters was defined by a 15-fold increase in expression of ZNRF3, which is involved in activation of the Wnt pathway. These data suggest that MMP14 expression is associated with worse survival and may be associated with metastatic progression. Further studies are needed to confirm whether simultaneous targeting of Wnt pathway and MMP14 may result in decreased metastatic progression.

Citation Format: Liudmila V. Popova, Elaine Mardis, Katherine Miller, Priya H. Dedhia. Matrix metalloproteinase 14 in associated with poor survival in adrenocortical carcinoma. [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 5286.