Tracking the progression of prostate cancer cells metastasis

Significance 

Among men, prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths. Since the disease is clinically identified only when large tumors comprising hundreds of millions of cancer cells are present, studies in animal models applying sensitive whole-organ imaging and tissue analysis methods are needed to understand prostate cancer initiation and early progression, including early metastatic spread to distant tissues.

Cold Spring Harbor Laboratory (CSHL) Associate Professor Pavel Osten and Professor Lloyd Trotman have developed a new way to study the life history of prostate cancer in mice. The pair combined their expertise in whole-organ imaging and prostate cancer to track how prostate cancer cells grow into tumors and spread to other organs. Their method allows scientists to study the behavior and properties of prostate cancer, for the first time, in a setting that accurately mimics the disease in real life. The study was published in Cell Reports

The authors described a novel approach to the study of cancer in animal models, one that combines single-cell resolution imaging of entire organs by STPT, computational quantification of putative cancer cell distribution across the imaged organs, and immunostaining of thick tissue sections generated during STPT imaging to validate and further characterize the combination of molecular and morphological pathology. They demonstrated these methods in the study of prostate cancer in a fluorescent version of the RapidCaP model, a genetically engineered mouse (GEM) model for native metastatic prostate cancer, which is based on a focal deletion of Pten and Trp53 genes by lentivirus-based delivery of Cre recombinase directly into the prostate gland.

The STPT-based approach to imaging the different stages of prostate cancer in the RapidCaP model uniquely combines automated high-resolution whole-organ imaging and analysis of prostate cancer initiation, progression, and metastasis at cellular resolution with traditional IF analysis of cytoskeletal protein markers to further examine cellular features of prostate cancer cells in the prostate and other metastatic tissues.

The researchers were able to track the progression of prostate cancer cells from their birth up to 20 days later, when they started spreading within the organ. Later, these fugitive cells started migrating to the liver and, unexpectedly, the brain.

The scientists hope this versatile new method will help tackle unexplored questions about the early steps of cancer’s growth and escape into other organs, wherever it starts.

About the author

Pavel Osten’s lab works on identification and analysis of brain regions, neural circuits, and connectivity pathways that are disrupted in genetic mouse models of autism and schizophrenia. Osten hypothesizes that (1) systematic comparison of multiple genetic mouse models will allow determination of overlaps in pathology—neural circuit endophenotypes—responsible for the manifestation of neuropsychiatric disorders and (2) neural circuit-based classification of autism and schizophrenia will provide key circuit targets for detailed mechanistic studies and therapeutic development. Osten and colleagues have developed the first systematic approach to the study of neural circuits in mouse models of psychiatric diseases, based on a pipeline of anatomical and functional methods for analysis of mouse brain circuits. An important part of this pipeline is high-throughput microscopy for whole-mouse brain imaging, called serial two-photon (STP) tomography. This year, they used this method to describe the first whole-brain activation map representing social behavior in normal mice. They are currently focusing on using this approach to study brain activation changes in two mouse models of autism: the 16p11.2 df/+ mouse model, which shows an increased propensity to seizures and hyperactivity, and the CNTNAP2 knockout mouse model, which shows abnormal social behavior.

Reference

Julian Taranda, Grinu Mathew, Kaitlin Watrud, Nour El-Amine, Matthew F. Lee, Corey Elowsky, Anastasiia Bludova, Sintia Escobar Avelar, Dawid G. Nowak, Tse-Luen Wee, John E. Wilkinson, Lloyd C. Trotman, Pavel Osten. Combined whole-organ imaging at single-cell resolution and immunohistochemical analysis of prostate cancer and its liver and brain metastasesCell Reports, 2021; 37 (7): 110027 DOI: 10.1016/j.celrep.2021.110027

Go To Cell Reports

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