The Forbeck Forum on Cellular Quiescence and Tumor Dormancy was held from November 14 to 17 at the Hilton Denver Inverness, 200 Inverness Drive West in Englewood, CO.

The conference started with introductions and a kick-off definition-of-terminology session in which each participant provided their definitions of key terms including quiescence, G0 and dormancy, leading to a lively discussion.

Each invited participant had 45 minutes and each Forbeck Scholar had 30 minutes for Forbeck Scholars to lead a group discussion related to the conference theme. Thes sessions encouraged lively discussion in a think tank style.  At the end of the meeting, in the final session, participants reflected on some of the key take-home points from the meeting.

The presentations focused on quiescence, senescence and dormancy. In session I on the human cell cycle, Sabrina Spencer, Ph.D. discussed her laboratories’ findings on key determinants of reversible versus irreversible cell cycle arrest and measuring the depth of quiescence, as well as time lapse microscopy tools for the response of melanoma cells to BRAF inhibitor treatment.  Alexis Barr, Ph.D. described her laboratory’s research combining quantitative, single-cell, timelapse imaging of genetically engineered cell lines with screening, proteomics and bioinformatics analysis to patient data to understand how quiescent cells retain proliferative potential. She described her efforts to benefit cancer patients by pushing dormant cells to senescence, preventing dormant cells from entering the cell cycle, or killing dormant cells with therapies.

Jeanette Cook, Ph.D. described her lab’s research developing a fluorescent reporter that provides information on how long it has been since a cell divided. She also described a new pathway for suppression of DNA replication competence in early quiescence. Guang Yao, Ph.D. shared his laboratory’s research investigating the relationship between quiescence and senescence. His findings show that cells can transition from quiescence to senescence without a need to proliferate, and the transition is regulated by the RB-E2F-CDK network. He argued that there is a continuum of states from cellular quiescence to senescence with mTOR and lysosomal function playing a major role as a regulator of a cell’s position in the continuum.

Session 2 focused on quiescence in model systems and organisms. Andrew Dillin, Ph.D. discussed his lab’s findings from a forward genetic screen in C. elegans that revealed the importance of lysosome damage as a mode for a failure to re-enter the cell cycle in the absence of the unfolded protein response. Dan Gottschling, Ph.D. described studies in yeast that revealed trajectories for aging that highlight the importance of mitochondria and interorganelle communication in the aging process. Mo Motamedi, Ph.D. described his laboratory’s research investigating how fission yeast adapt to changes in available nutrients by entering a quiescent state and the role of heterochromatin factors in quiescence-induced transcriptional silencing. Benjamin Roche, Ph.D. discussed the results of his laboratory’s studies of the genes that are essential specifically in nondividing cells that including proteins involved in transcription, RNA interference, RNA export and metabolic genes.

Session 3 on quiescence, senescence and aging included Darren Baker, Ph.D. discussing senescent cells in organisms, the impact on mice of eliminating senescent cells, and the potential of senolytics for cancer patients. Hilary Coller, Ph.D. discussed molecular mechanisms that contribute to the hallmarks of quiescence and a pathway involving chromatin remodeling that contributes to gene expression changes with quiescence. Scholar Paulina Podszywalow-Bartnicka discussed the role of leukemia stem cells in leukemia relapse after treatment of Bcr-Abl activity by Imatinib. She presented her newest data showing that Imatinib causes increased transcriptional readthrough leading to the generation of transcripts containing sequences transcribed from downstream of the gene, a process that can impact the decision to quiesce or differentiate. Simon Buczacki, Ph.D., FRCS, presented his lab’s research using gene-edited colon organoids that shows that a cell’s phenotype can be determined by the order in which somatic mutations are introduced. Epigenetic alterations in chromatin structure were found to restrict cellular plasticity following acquisition of additional driver mutations.

In Section 4, Jose Javier Bravo-Cordero reported on his group’s investigation of the biology of dormant cancer cells and their influence on the tissue microenvironment. He discussed his group’s application of high-resolution imaging technologies to unravel the important role of the extracellular matrix in regulating the dynamics of dormant tumor cells and their niches. James Alvarez, Ph.D., discussed his laboratory’s research on metabolic reprogramming that occurs as cancer cells become dormant and strategies to target metabolic pathways to enforce quiescence or kill the dormant cells. Scholar Lucia Borriello, Ph.D. discussed her research investigating whether therapies such as paclitaxel that target primary tumors in alter the composition of the tumor microenvironment to trigger the awakening of dormant disseminated tumor cells directly and via recruited neutrophils. Cyrus Ghajar, Ph.D. discussed his laboratory’s research establishing in vivo models for tumor dormancy. Finally, Lewis Chodosh, M.D., Ph.D. reported on his laboratory’s mouse model for human breast cancer that recapitulates key features of human cancer progression including metastasis, residual disease, dormancy, and recurrence. He also presented on the tools that his laboratory is developing to enable the detection and characterization of disseminated tumor cells in patients as a biomarker for recurrence risk and as a pharmacodynamic marker to monitor the effect of therapies against this population.

The forum provided an opportunity for extensive and engaged discussion. The participants learned about emerging models, resources and novel concepts in the field of cellular quiescence, senescence and tumor dormancy.

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