In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1594-1594
Abstract:
The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. We performed single-cell transcriptomic analysis of a time-course experiment on the prostate organoid following Trp53 and Rb1 deletion. Critical to this study, we developed SEACells, a method that enumerates distinct, highly granular cell states, allowing for robust transcriptomic quantification. Leveraging the SEACell platform, we developed several graph-based computational approaches based on Markov absorption, diffusion maps, and attributed stochastic block models to quantify dynamic changes in plasticity. These quantitative models independently confirmed rapid collapse of cell-type fidelity in the form of a mixed luminal-basal phenotype following tumor suppressor gene deletion. These methods compute metrics for plasticity that we correlated to candidate driver gene programs. Among the strongest plasticity correlates, Jak-Stat and Fgfr signaling stood out as gene programs activated early in the time-course prior to any corresponding morphological changes. We further developed a regression-based approach to nominate ligand-receptor interactions that activate downstream Jak-Stat signaling, which identified Fgf-Fgfr interactions that were functionally validated with growth factor addition and pharmacological inhibition. Most strikingly, genetic or pharmacologic inhibition of Jak1/2 in combination with Fgfr blockade not only reversed the plastic state and restored organoids to their wild-type morphology, but also re-sensitized drug-resistant cells to antiandrogen therapy in models with residual AR expression. We additionally confirm early activation of Jak/Stat transcriptional programs in an Rb1/Trp53/Pten-deleted genetically engineered mouse model undergoing substantial cell-type diversification under plasticity in the context of the tumor microenvironment. Collectively, we show that lineage plasticity initiates quickly as a largely cell-autonomous process that is further increased in the in vivo setting, and through newly developed computational approaches, we identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors. Citation Format: Joseph M. Chan, Wouter R. Karthaus, Manu Setty, Jillian R. Love, Samir Zaidi, Jimmy Zhao, Zi-ning Choo, Sitara Persad, Justin LaClair, Kayla E. Lawrence, Ojasvi Chaudhary, Ignas Masilionis, Linas Mazutis, Ronan Chaligne, Dana Pe'er, Charles Sawyers. Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1594.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2022-1594
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
