| Autor: |
Mallin MM; Johns Hopkins Medicine, Baltimore, MD, United States., Rolle LTA; Johns Hopkins Medicine, Baltimore, MD, United States., Schmidt MJ; University of Southern California, Los Angeles, CA, United States., Priyadarsini Nair S; Johns Hopkins Medicine, Baltimore, MD, United States., Zurita AJ; The University of Texas MD Anderson Cancer Center, Houston, Tx, United States., Kuhn P; University of Southern California, Los Angeles, CA, United States., Hicks J; University of Southern California, Los Angeles, CA, United States., Pienta KJ; Johns Hopkins Medicine, Baltimore, MD, United States., Amend SR; Johns Hopkins University, Baltimore, MD, United States. |
| Abstrakt: |
Our research aims to understand the adaptive, ergo potentially metastatic, responses of prostate cancer to changing microenvironments. Emerging evidence implicates a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study revealed that PACC presence in patient prostate tumors at the time of radical prostatectomy was predictive of future metastasis. To test for a causative relationship between PACC state biology and metastasis in prostate cancer, we leveraged a novel method designed for flow-cytometric detection of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) from animal models. This approach provides both quantitative and qualitative information about the number and PACC-status of recovered CTCs and DTCs. Specifically, we applied this approach to analysis of subcutaneous, caudal artery, and intracardiac murine models. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. Furthermore, in vivo colonization assays proved PACC populations can regain proliferative capacity at metastatic sites. Additional in vitro analyses revealed a PACC-specific partial Epithelial-to-Mesenchymal-Transition phenotype and a pro-metastatic secretory profile, together providing preliminary evidence of pro-metastatic mechanisms specific to the PACC state. Implications: Considering that many anti-cancer agents induce the PACC state, our data positions the increased metastatic competency of PACC state cells as an important unforeseen ramification of neoadjuvant regimens, which may help explain clinical correlations between chemotherapy and metastatic progression. |
