Dedifferentiation-mediated stem cell niche maintenance in early-stage ductal carcinoma in situ progression: insights from a multiscale modeling study

• Type of Material: Article
• Authors: Joseph D Butner, Houston Methodist Research Institute; Prashant Dogra, Houston Methodist Research Institute; Caroline Chung, The University of Texas MD Anderson Cancer Center; Javier Ruiz-Ramirez, Houston Methodist Research Institute; Sara Nizzero, Houston Methodist Research Institute; Marija Plodinec, University of Basel; Xiaoxian Li, Emory University; Ping-Ying Pan, Houston Methodist Research Institute; Shu-hsia Chen, Weill Cornell Medicine, New York; Vittorio Cristini, Houston Methodist Research Institute; Bulent Ozpolat, The University of Texas MD Anderson Cancer Center; George A Calin, The University of Texas MD Anderson Cancer Center; Zhihui Wang, Houston Methodist Research Institute
• Language: English
• Date: 2022-05-21
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41419-022-04939-x
• Title of Journal or Parent Work: CELL DEATH & DISEASE
• Volume: 13
• Issue: 5
• Start Page: 485
• End Page: 485
• Grant/Funding Information: This research has been supported in part by the National Science Foundation Grant DMS-1930583 (VC, ZW), the National Institutes of Health (NIH) Grants 1R01CA253865 (VC, BO, ZW), 1U01CA196403 (VC, ZW), 1U01CA213759 (VC, BO, ZW), 1R01CA226537 (VC, ZW), 1R01CA222007 (VC, BO, GAC, ZW), and U54CA210181 (SHC, VC, ZW).; Work in GAC’s laboratory is also supported by NCI grant 1R01 CA182905-01, NIGMS grant 1R01GM122775-01, DoD Idea Award W81XWH-21-1-0030, a Team DOD grant in Gastric Cancer W81XWH-21-1-0715, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a CLL Global Research Foundation 2019 grant, a CLL Global Research Foundation 2020 grant, the G. Harold & Leila Y. Mathers Foundation, two grants from Torrey Coast Foundation, an Institutional Research Grant and Development Grant associated with the Brain SPORE 2P50CA127001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: PLASTICITY; Cell Biology; CANCER; Science & Technology; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Pathology

Abstract

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is sensitive to perturbations in several key mechanisms that are instrumental to early disease development. Our studies reveal that long-term maintenance of multipotent stem-like cell niches within the tumor are dependent on cell dedifferentiation plasticity, and that disease progression will become arrested due to dilution of the multipotent stem-like population in the absence of dedifferentiation. We have identified dedifferentiation rates necessary to maintain biologically relevant multipotent cell populations, and also explored quantitative relationships between dedifferentiation rates and disease progression rates, which may potentially help to optimize the efficacy of emerging anti-cancer stem cell therapeutics.