3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer PMID: 40847193

ADC Targets in Oncology

2026-04-10

3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer

Commun Biol. 2025 Aug 22;8(1):1261. doi: 10.1038/s42003-025-08699-0.

Sarah J Harmych ¹ ² , Thomas P Hasaka ³ , Chelsie K Sievers ¹ , Seung Woo Kang ² ⁴ ⁵ , Marisol A Ramirez ⁶ ⁷ , Vivian Truong Jones ¹ ⁸ , Zhiguo Zhao ⁶ , Oleg Kovtun ⁹ , Claudia C Wahoski ¹ ¹⁰ , Qi Liu ⁶ ⁷ , Ken S Lau ² ⁴ ⁵ ¹¹ ¹² , Robert J Coffey ¹ ⁴ , Joshua A Bauer ³ ¹² ¹³ , Bhuminder Singh ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
2. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
3. Vanderbilt Institute of Chemical Biology, High-Throughput Screening Facility, Vanderbilt University, Nashville, TN, USA.
4. Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
5. Center for Computational Systems Biology, Vanderbilt University, Nashville, TN, USA.
6. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
7. Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
8. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
9. Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
10. Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.
11. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
12. Vanderbilt-Cancer Ingram Center, Vanderbilt University Medical Center, Nashville, TN, USA.
13. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
14. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
15. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA. [email protected].
16. Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
17. Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA. [email protected].
18. Vanderbilt-Cancer Ingram Center, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].

Abstract

Loss of polarity is a hallmark of Cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype impacts prognosis and therapy outcomes, particularly in colorectal Cancer (CRC). However, the mechanisms and drugs that impact EMT-related morphological changes are understudied, due to the complete failure of typical live/dead 2D high-throughput screens to capture morphology or the lack of robustness of 3D screens. We designed a high-throughput screen using 3D type I Collagen cultures of CRC cells to assess morphological changes in colonies and identified several FDA-approved drugs that re-epithelialize CRC colonies. One of these drugs, azithromycin, increased colony circularity, enhanced E-cadherin membrane localization and ZO-1 localization to tight junctions, caused transcriptomic changes consistent with downregulation of EMT, and elevated sensitivity to the chemotherapeutic, irinotecan. A retrospective analysis of patient data demonstrated that the use of azithromycin in patients undergoing treatment for CRC with irinotecan had improved the 5 year survival compared to the chemotherapy alone. These results highlight the importance of morphological screens to identify novel drug candidates and synergistic mechanisms.