Targeting Oncogenic Wnt/β-Catenin Signaling in Adrenocortical Carcinoma Disrupts ECM Expression and Impairs Tumor Growth

Morgan K Penny; Antonio M Lerario; Kaitlin J Basham; Sahiti Chukkapalli; Dipika R Mohan; Chris LaPensee; Kimber Converso-Baran; Mark J Hoenerhoff; Laura Suárez-Fernández; Carmen González Del Rey; Thomas J Giordano; Ruolan Han; Erika A Newman; Gary D Hammer

doi:10.3390/cancers15143559

Targeting Oncogenic Wnt/β-Catenin Signaling in Adrenocortical Carcinoma Disrupts ECM Expression and Impairs Tumor Growth

Cancers (Basel). 2023 Jul 10;15(14):3559. doi: 10.3390/cancers15143559.

Authors

Morgan K Penny¹, Antonio M Lerario², Kaitlin J Basham², Sahiti Chukkapalli³, Dipika R Mohan^{1

4}, Chris LaPensee², Kimber Converso-Baran⁵, Mark J Hoenerhoff⁶, Laura Suárez-Fernández⁷, Carmen González Del Rey⁸, Thomas J Giordano^{2

9}, Ruolan Han¹⁰, Erika A Newman³, Gary D Hammer^{2

11}

Affiliations

¹ Doctoral Program in Cancer Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA.
³ Mott Solid Tumor Oncology Program, C.S. Mott Children's and Women's Hospital, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ UMH Frankel Cardiovascular Center Physiology and Phenotyping Core, Ann Arbor, MI 48109, USA.
⁶ In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁷ Department Head and Neck Oncology, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain.
⁸ Department of Pathology, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain.
⁹ Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
¹⁰ Iterion Therapeutics, Inc., Houston, TX 77021, USA.
¹¹ Endocrine Oncology Program, Rogel Cancer Center, University of Michigan Health System, Ann Arbor, MI 48109, USA.

Abstract

Adrenocortical carcinoma (ACC) is a rare but highly aggressive cancer with limited treatment options and poor survival for patients with advanced disease. An improved understanding of the transcriptional programs engaged in ACC will help direct rational, targeted therapies. Whereas activating mutations in Wnt/β-catenin signaling are frequently observed, the β-catenin-dependent transcriptional targets that promote tumor progression are poorly understood. To address this question, we analyzed ACC transcriptome data and identified a novel Wnt/β-catenin-associated signature in ACC enriched for the extracellular matrix (ECM) and predictive of poor survival. This suggested an oncogenic role for Wnt/β-catenin in regulating the ACC microenvironment. We further investigated the minor fibrillar collagen, collagen XI alpha 1 (COL11A1), and found that COL11A1 expression originates specifically from cancer cells and is strongly correlated with both Wnt/β-catenin activation and poor patient survival. Inhibition of constitutively active Wnt/β-catenin signaling in the human ACC cell line, NCI-H295R, significantly reduced the expression of COL11A1 and other ECM components and decreased cancer cell viability. To investigate the preclinical potential of Wnt/β-catenin inhibition in the adrenal microenvironment, we developed a minimally invasive orthotopic xenograft model of ACC and demonstrated that treatment with the newly developed Wnt/β-catenin:TBL1 inhibitor Tegavivint significantly reduced tumor growth. Together, our data support that the inhibition of aberrantly active Wnt/β-catenin disrupts transcriptional reprogramming of the microenvironment and reduces ACC growth and survival. Furthermore, this β-catenin-dependent oncogenic program can be therapeutically targeted with a newly developed Wnt/β-catenin inhibitor. These results show promise for the further clinical development of Wnt/β-catenin inhibitors in ACC and unveil a novel Wnt/β-catenin-regulated transcriptome.

Keywords: COL11A1; Wnt; Wnt/β-catenin; adrenal; adrenocortical carcinoma; collagen; extracellular matrix; targeted therapy; xenograft; β-catenin.

Abstract

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