Chukkapalli, S. | Search bioRxiv

bioRxiv2024

Structural enrichment attenuates colitis-associated colon cancer

Colorectal cancer (CRC) is a major public health concern and disproportionately impacts racial/ethnic minority populations in the US. Animal models are helpful in examining human health disparities because many stress-induced human health conditions can be recapitulated using mouse models. Azoxymethane (AOM)/ dextran sodium sulfate (DSS) treatment can be used to model colitis-associated cancers. While colitis-associated cancers account for only 2% of colon cancers, the AOM/DSS model is useful for examining links between inflammation, immunity, and colon cancer. Mice were housed in enriched and impoverished environments for 1-month prior to behavioral testing. Following behavioral testing the mice were subjected to the AOM/DSS model. While our analysis revealed no significant behavioral variances between the impoverished and enriched housing conditions, we found significant effects in tumorigenesis. Enriched mice had fewer tumors and smaller tumor volumes compared to impoverished mice. African Americans are at higher risk for early onset colorectal cancers in part due to social economic status. Furthermore, housing conditions and environment may reflect social economic status. Research aimed at understanding links between social economic status and colorectal cancer progression is important for eliminating disparities in health outcomes.

cancer biology↗

bioRxiv2022

Targeting oncogenic Wnt/β-catenin signaling in adrenocortical carcinoma disrupts ECM expression and impairs tumor growth.

Adrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer with limited treatment options and poor survival for patients with advanced disease. Improved understanding of transcriptional programs engaged in ACC will help direct rational, targeted therapies. While activating mutations in Wnt/{beta}-catenin signaling are frequently observed, the {beta}-catenin-dependent transcriptional targets that promote tumor progression are poorly understood. To address this question, we used independent component analysis and identified a novel Wnt/{beta}-catenin-associated signature in ACC predictive of poor survival. This signature was enriched for the extracellular matrix (ECM), suggesting a potential role for Wnt/{beta}-catenin in regulating the ACC microenvironment. We further investigated the minor fibrillar collagen, collagen XI alpha 1 (COL11A1), and found that COL11A1 expression strongly correlated with both Wnt/{beta}-catenin activation and poor patient survival. Inhibition of constitutively active Wnt/{beta}-catenin signaling in the human ACC cell line, NCI-H295R, significantly reduced expression of COL11A1 and other ECM components, and decreased viability of cancer cells in vitro. To investigate the preclinical potential of Wnt/{beta}-catenin inhibition in vivo, we developed and characterized a novel orthotopic xenograft model utilizing minimally invasive techniques. Treatment with the newly developed Wnt/{beta}-catenin:TBL1 inhibitor Tegavivint significantly reduced tumor growth in this preclinical model. Together, our data supports that inhibition of aberrantly active Wnt/{beta}-catenin disrupts transcriptional reprogramming of the microenvironment and reduces ACC growth and survival. Furthermore, this {beta}-catenin-dependent oncogenic program can be therapeutically targeted with a newly developed Wnt/{beta}-catenin inhibitor. These results show promise for further clinical development of Wnt/{beta}-catenin inhibitors in ACC and unveil a novel Wnt/{beta}-catenin-regulated transcriptome. Simple SummaryAdrenocortical carcinoma (ACC) is a rare, often deadly cancer arising from the adrenal gland. Mortality associated with ACC remains unchanged over the last several decades. The rarity of ACC, an incomplete understanding of its molecular basis, and limited availability of pre-clinical models have hampered the development of new effective therapies. The present work aims to address these gaps with a focus on the Wnt/{beta}-catenin cell signaling pathway, which is aberrantly activated in ~40% of ACC tumors. We discover a novel ECM program activated in ACC that is associated with Wnt/{beta}-catenin and poor survival. Wnt/{beta}-catenin inhibition disrupts expression of ECM genes and induces loss of cancer cell viability. To extend these findings, we develop a rapid orthotopic mouse model of ACC and demonstrate that disruption of the Wnt/{beta}-catenin axis with novel small molecule inhibitor Tegavivint is a potential effective therapeutic strategy to reduce ACC tumor burden in vivo.

cancer biology↗