Cell Cycle, Cancer and Aging

CellCycle280-220Cell division requires faithful duplication of the genome as chromatin, and subsequent partitioning of chromosomes into progeny cells at mitosis. Cell cycle progression is stringently regulated and mechanisms that ensure the fidelity of this process are often deregulated in cancer. Normal cells are growth factor dependent and commit to initiate DNA replication at the G1/S phase transition. This growth-factor dependent control of the cell cycle is abrogated in cancer cells. Our studies have established that pluripotent stem cells have an abbreviated cell cycle due to a reduced G1 phase.

All dividing cells must package newly replicated DNA into chromatin during S phase, which necessitates the coordinated expression of multiple histone genes that encode the core nucleosomal proteins. Because transcription of histone genes is tightly coupled with the onset of DNA replication at the G1/S phase transition, we have pioneered the use of histone H4 genes as a paradigm for cell cycle control of transcription. These studies have resulted in the definition of a new cell cycle regulatory signaling pathway (Cyclin E-CDK2-NPAT-HiNFP axis). This pathway converges on subnuclear structures referred to as Histone Locus Bodies that contain histone gene clusters and the regulatory machinery for transcribing and processing of histone mRNAs (see Nuclear Structure and Function). We are examining cell cycle control in vivo during the earliest stages of embryonic development from the zygote to the blastocyst using conditional null mouse models lacking critical gene regulators. Recent findings from our laboratory have identified modifications in the higher-order organization of histone genes during breast cancer initiation and progression. In utilizing chromosome conformation capture and multispectral imaging strategies we are mechanistically characterizing modifications in genome structure and function that are functionally associate with cancer-compromised cell cycle control and regulation of proliferation. 

Beyond defining basic mechanisms of cell cycle control in cancer cells and pluripotent embryonic stem cells, we are also addressing broader physiological processes linked to cancer and regenerative medicine. For example, tumor progression and cancer metastasis are examined in immune-deficient mouse models and organoid cultures (see Musculoskeletal Biology and Pathology). Moreover, we are examining mechanisms of stem cell self-renewal and expansion of lineage-committed cells as it relates to regenerative medicine and aging (see Stem Cells and Regenerative Medicine). Recent initiatives are advancing understanding of the distinction between ductal carcinoma in situ breast tumors that will remain indolent and those that will progress and metastasize.  

Landmark Papers

Ghule PN, Boyd JR, Kabala F, Fritz AJ, Bouffard NA, Gao C, Bright K, Macfarlane J, Seward DJ, Pegoraro G, Misteli T, Lian JB, Frietze S, Stein JL, van Wijnen AJ, Stein GS. Spatiotemporal higher-order chromatin landscape of human histone gene clusters at histone locus bodies during the cell cycle in breast cancer progression. Gene. 2023 Jul 1;872:147441. doi: 10.1016/j.gene.2023.147441. Epub 2023 Apr 23. Erratum in: Gene. 2023 May 11;873:147469. PMID: 37094694; PMCID: PMC10370284.

Messier TL, Boyd JR, Gordon J, Tye CE, Page NA, Zaidi SK, Komm BS, Frietze S, Stein JL, Lian JB, Stein GS. Epigenetic and transcriptome responsiveness to ER modulation by tissue selective estrogen complexes in breast epithelial and breast cancer cells. 2022. Paper submitted.

Mohammed El Dika, Andrew J. Fritz1 , Rabail H. Toor , Princess D. Rodriguez , Stephen J. Foley , Rahim Ullah , Daijing Nie , Bodhisattwa Banerjee, Dorcas Lohese, Kirsten M. Tracy , Karen C. Glass, Seth Frietze, Prachi N. Ghule , Jessica L. Heath, Anthony N. Imbalzano, Andre van Wijnen , Jonathan Gordon, Jane B. Lian, Janet L. Stein, Gary S. Stein. Epigenetic-mediated regulation of gene expression for biological control and cancer: fidelity of mechanisms governing the cell cycle, Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine. Switzerland: Springer Nature. 2022. In print.

Nachmanson D, Officer A, Mori H, Gordon J, Evans MF, Steward J, Yao H, O'Keefe T, Hasteh F, Stein GS, Jepsen K, Weaver DL, Hirst GL, Sprague BL, Esserman LJ, Borowsky AD, Stein JL, Harismendy O. The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ. NPJ Breast Cancer. 2022 Jan 13;8(1):6. doi: 10.1038/s41523-021-00365-y. PMID: 35027560; PMCID: PMC8758681.

Fertal SA, Zaidi SK, Stein JL, Stein GS, Heath JL. CXCR4 Mediates Enhanced Cell Migration in CALM-AF10 Leukemia. Front Oncol. 2022 Jan 5;11:708915. doi: 10.3389/fonc.2021.708915. PMID: 35070954; PMCID: PMC8767107. https://doi.org/10.3389/fonc.2021.708915

Nirala NK, Li Q, Ghule PN, Chen HJ, Li R, Zhu LJ, Wang R, Rice NP, Mao J, Stein JL, Stein GS, van Wijnen AJ, Ip YT. Hinfp is a guardian of the somatic genome by repressing transposable elements. Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2100839118. doi: 10.1073/pnas.2100839118. PMID: 34620709; PMCID: PMC8521681.

Fritz AJ, Hong D, Boyd J, Kost J, Finstaad KH, Fitzgerald MP, Hanna S, Abuarqoub AH, Malik M, Bushweller J, Tye C, Ghule P, Gordon J, Frietze S, Zaidi SK, Lian JB, Stein JL, Stein GS. RUNX1 and RUNX2 transcription factors function in opposing roles to regulate breast cancer stem cells. J Cell Physiol. 2020 Oct;235(10):7261-7272. doi: 10.1002/jcp.29625. Epub 2020 Mar 17. PMID: 32180230; PMCID: PMC7415511.

Heath JL, Cohn GM, Zaidi SK, Stein GS. The role of cell adhesion in hematopoiesis and leukemogenesis. J Cell Physiol. 2019 Nov;234(11):19189-19198. doi: 10.1002/jcp.28636. Epub 2019 Apr 13. PMID: 30980400.

Fritz AJ, Gillis NE, Gerrard DL, Rodriguez PD, Hong D, Rose JT, Ghule PN, Bolf EL, Gordon JA, Tye CE, Boyd JR, Tracy KM, Nickerson JA, van Wijnen AJ, Imbalzano AN, Heath JL, Frietze SE, Zaidi SK, Carr FE, Lian JB, Stein JL, Stein GS. Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer. Genes Chromosomes Cancer. 2019 Jul;58(7):484-499. doi: 10.1002/gcc.22731. Epub 2019 Mar 15. PMID: 30873710; PMCID: PMC6549233.

Hong D, Fritz AJ, Gordon JA, Tye CE, Boyd JR, Tracy KM, Frietze SE, Carr FE, Nickerson JA, Van Wijnen AJ, Imbalzano AN, Zaidi SK, Lian JB, Stein JL, Stein GS. RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol. 2019 Jun;234(6):8597-8609. doi: 10.1002/jcp.27841. Epub 2018 Dec 4. PMID: 30515788; PMCID: PMC6395522.

Carver GE, Locknar SA, Weaver DL, Stein JL, Stein GS. Real-time detection of breast cancer at the cellular level. J Cell Physiol. 2019 May;234(5):5413-5419. doi: 10.1002/jcp.27451. Epub 2018 Oct 26. PMID: 30362286; PMCID: PMC6344234.

Zaidi SK, Nickerson JA, Imbalzano AN, Lian JB, Stein JL, Stein GS. Mitotic Gene Bookmarking: An Epigenetic Program to Maintain Normal and Cancer Phenotypes. Mol Cancer Res. 2018 Nov;16(11):1617-1624. doi: 10.1158/1541-7786.MCR-18-0415. Epub 2018 Jul 12. PMID: 30002192; PMCID: PMC6214712.

Hong D, Fritz AJ, Zaidi SK, van Wijnen AJ, Nickerson JA, Imbalzano AN, Lian JB, Stein JL, Stein GS. Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. J Cell Physiol. 2018 Dec;233(12):9136-9144. doi: 10.1002/jcp.26847. Epub 2018 Jul 3. PMID: 29968906; PMCID: PMC6185773.

Ghule PN, Seward DJ, Fritz AJ, Boyd JR, van Wijnen AJ, Lian JB, Stein JL, Stein GS. Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S-phase transition. J Cell Physiol. 2018 Oct;233(10):6406-6413. doi: 10.1002/jcp.26741. Epub 2018 May 10. PMID: 29744889; PMCID: PMC6043376.

Zaidi SK, Frietze SE, Gordon JA, Heath JL, Messier T, Hong D, Boyd JR, Kang M, Imbalzano AN, Lian JB, Stein JL, Stein GS. Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer. Mol Cell Biol. 2017 Nov 13;37(23):e00352-17. doi: 10.1128/MCB.00352-17. PMID: 28923849; PMCID: PMC5686582.

Balatti V, Nigita G, Veneziano D, Drusco A, Stein GS, Messier TL, Farina NH, Lian JB, Tomasello L, Liu CG, Palamarchuk A, Hart JR, Bell C, Carosi M, Pescarmona E, Perracchio L, Diodoro M, Russo A, Antenucci A, Visca P, Ciardi A, Harris CC, Vogt PK, Pekarsky Y, Croce CM. tsRNA signatures in cancer. Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):8071-8076. doi: 10.1073/pnas.1706908114. Epub 2017 Jul 10. PMID: 28696308; PMCID: PMC5544330.

Wu Q, Lian JB, Stein JL, Stein GS, Nickerson JA, Imbalzano AN. The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics. 2017 Jun;9(6):919-931. doi: 10.2217/epi-2017-0034. Epub 2017 May 19. PMID: 28521512; PMCID: PMC5705788.

Reagan MR, Lian JB, Rosen CJ, Stein GS. A perspective on malignancy in the marrow. J Cell Physiol. 2017 Dec;232(12):3218-3220. doi: 10.1002/jcp.25860. Epub 2017 May 16. PMID: 28206683; PMCID: PMC5559340.

VanOudenhove JJ, Grandy RA, Ghule PN, Lian JB, Stein JL, Zaidi SK, Stein GS. Unique Regulatory Mechanisms for the Human Embryonic Stem Cell Cycle. J Cell Physiol. 2017 Jun;232(6):1254-1257. doi: 10.1002/jcp.25567. Epub 2017 Jan 31. PMID: 27532275; PMCID: PMC5315681.