Update on Biology and Genomics of Adrenocortical Carcinomas: Rationale for Emerging Therapies

Abstract

The adrenal glands are paired endocrine organs that produce steroid hormones and catecholamines required for life. Adrenocortical carcinoma (ACC) is a rare and often fatal cancer of the peripheral domain of the gland, the adrenal cortex. Recent research in adrenal development, homeostasis, and disease have refined our understanding of the cellular and molecular programs controlling cortical growth and renewal, uncovering crucial clues into how physiologic programs are hijacked in early and late stages of malignant neoplasia. Alongside these studies, genome-wide approaches to examine adrenocortical tumors have transformed our understanding of ACC biology, and revealed that ACC is comprised of distinct molecular subtypes associated with favorable, intermediate, and dismal clinical outcomes. The homogeneous transcriptional and epigenetic programs prevailing each ACC subtype suggest likely susceptibility to any of a plethora of existing and novel targeted agents, with the caveat that therapeutic response may ultimately be limited by cancer cell plasticity. Despite enormous biomedical research advances in the last decade, the only potentially curative therapy for ACC to date is primary surgical resection, and up to 75% of patients will develop metastatic disease refractory to standard-of-care adjuvant mitotane and cytotoxic chemotherapy. A comprehensive, integrated and current bench-to-bedside understanding of our field's investigations into adrenocortical physiology and neoplasia is crucial to developing novel clinical tools and approaches to equip the one-in-a-million patient fighting this devastating disease.

β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

“…Classically, Wnt pathway activation culminates in β-catenin co-activation of TCF/LEF-driven transcription and expression of programs that facilitate stem cell and tissue maintenance (11). This is also true in the adrenal cortex, the tissue of origin of ACC, where cell type specification is established by integration of paracrine and endocrine cues (12). All adrenocortical cells express master transcription factor SF1 (NR5A1).…”

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

“…Classically, Wnt pathway activation culminates in β-catenin co-activation of TCF/LEF-driven transcription and expression of programs that facilitate stem cell maintenance (Nusse and Clevers, 2017). This is also true in the adrenal cortex, the tissue of origin of ACC, where cell type specification is established by integration of paracrine and endocrine cues (Lerario et al, 2022). All adrenocortical cells express master transcription factor SF1 (NR5A1).…”

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution

“…Our understanding of ACC pathogenesis has increased considerably over the past decade following in-depth characterisations of the molecular processes involved in development, homeostasis and disease of the adult adrenal gland [2,3,14,15,19–21,27,28]. In the present study, we contribute to this emerging field by providing a cellular transcriptome atlas of ACC at single-nuclei resolution that complements existing data and reveals a mixture of cell types present within the malignant adrenal cortex.…”