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Frederick J, Virk RKA, Ye IC, Almassalha LM, Wodarcyk GM, VanDerway D, Gonzalez PC, Nap RJ, Agrawal V, Anthony NM, Carinato J, Li WS, Dunton CL, Medina KI, Kakkaramadam R, Jain S, Shahabi S, Ameer G, Szleifer IG, Backman V. Leveraging chromatin packing domains to target chemoevasion in vivo. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.14.623612. [PMID: 39605341 PMCID: PMC11601449 DOI: 10.1101/2024.11.14.623612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains (TADs). However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based mechanistic model that connects chromatin organization to cell fate decisions, specifically survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional efficiency through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. Using live-cell chromatin imaging, we conducted a compound screen that identified several TPRs which synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft (PDX) model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a novel framework for enhancing cancer therapies, with broad potential across multiple cancer types.
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Affiliation(s)
- Jane Frederick
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Ranya K A Virk
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - I Chae Ye
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Luay M Almassalha
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Department of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Greta M Wodarcyk
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - David VanDerway
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Paola Carrillo Gonzalez
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Rikkert J Nap
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Vasundhara Agrawal
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Nicholas M Anthony
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - John Carinato
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Wing Shun Li
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Cody L Dunton
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Karla I Medina
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Rivaan Kakkaramadam
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Surbhi Jain
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Shohreh Shahabi
- Department of Obstetrics and Gynecology, Prentice Women's Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Guillermo Ameer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Igal G Szleifer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
- Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
| | - Vadim Backman
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
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Sun J, Li F, Zhao Y, Zhao L, Qiao C, Li Z, Guo Q, Lu N. LZ-207, a Newly Synthesized Flavonoid, Induces Apoptosis and Suppresses Inflammation-Related Colon Cancer by Inhibiting the NF-κB Signaling Pathway. PLoS One 2015; 10:e0127282. [PMID: 26023926 PMCID: PMC4449173 DOI: 10.1371/journal.pone.0127282] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 04/13/2015] [Indexed: 12/19/2022] Open
Abstract
Flavonoids and flavonoid derivatives, which have significant biological and pharmacological activities, including antitumor and anti-inflammatory activities, have been widely used in human healthcare. To design a more effective flavonoid antitumor agent, we altered the flavonoid backbone with substitutions of piperazine and methoxy groups to synthesize a novel flavonoid derivative, LZ-207. The anticancer effect of LZ-207 against HCT116 colon cancer cells and the underlying mechanism of this effect were explored in this study. Specifically, LZ-207 exhibited inhibitory effects on growth and viability in several human colon cancer cell lines and induced apoptosis in HCT116 cells both in vitro and in vivo. LZ-207 treatment also suppressed the nuclear translocation of NF-κB and the phosphorylation of IκB and IKKα/β in a dose-dependent manner in both HCT116 cells and human acute monocytic leukemia THP-1 cells. Moreover, LZ-207 also reduced the secretion of the pro-inflammatory cytokine interleukin-6 (IL-6) in LPS-induced THP-1 cells, and this effect was confirmed at the transcriptional level. Furthermore, LZ-207 significantly inhibited HCT116 cell proliferation that was elicited by LPS-induced THP-1 cells in a co-culture system. These findings elucidated some potential molecular mechanisms for preventing inflammation-driven colon cancer using the newly synthesized flavonoid LZ-207 and suggested the possibility of further developing novel therapeutic agents derived from flavonoids.
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Affiliation(s)
- Jie Sun
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
| | - Fanni Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
| | - Yue Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
| | - Li Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
| | - Chen Qiao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
| | - Zhiyu Li
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People’s Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
- * E-mail: (QG); (NL)
| | - Na Lu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
- * E-mail: (QG); (NL)
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Green TL, Santos MF, Ejaeidi AA, Craft BS, Lewis RE, Cruse JM. Toll-like receptor (TLR) expression of immune system cells from metastatic breast cancer patients with circulating tumor cells. Exp Mol Pathol 2014; 97:44-8. [PMID: 24836676 DOI: 10.1016/j.yexmp.2014.05.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 05/07/2014] [Indexed: 12/12/2022]
Abstract
The risk posed by breast cancer represents a complex interaction among factors affecting tumor immunity of the host. Toll-like receptors (TLRs) are members of the innate immune system and generally function to attract host immune cells upon activation. However, the good intentions of TLRs are sometimes not transferred to positive long-term effects, due to their involvement in exacerbating inflammatory effects and even contributing to continued inflammation. Chronic inflammatory states are considered to favor an increased predisposition to cancer, with continuous activation of inflammatory cytokines and other hallmarks of inflammation exerting a deleterious effect. Circulating tumor cells (CTCs) are neoplastic cells present in the peripheral blood circulation that have been found to be an indicator of disease progression and long-term survival. In the present study, we examined the expression of TLRs on dendritic cells, which play a major role in eliciting anti-tumor immunity, in metastatic breast cancer patients with CTCs. Flow cytometric data showed significant differences between circulating tumor cell (CTC) positive patients and CTC negative patients in their expression of TLR2 by CD8 positive cytotoxic T cells and TLR2, TLR4, TLR3, and TLR8 by CD11c positive dendritic cells (p<0.05). Expression of TLR2, TLR4, and TLR8 was increased in CTC positive patients, whereas TLR3 expression was decreased in the dendritic cell population.
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Affiliation(s)
- Taryn L Green
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Mark F Santos
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Ahmed A Ejaeidi
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Barbara S Craft
- Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Robert E Lewis
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Julius M Cruse
- Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA
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