Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways

Abstract

Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM+/CD45− cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention.

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

“…Culture of PCa cells with NE demonstrated a decrease in expression of both p27 and p21 (Figure 3A–C). Previous reports have demonstrated that an increased ratio of p-ERK 1/2 to p-p38 MAPK is associated with re-activation from dormancy in prostate and other cancers (7,9,31). Thus, we also evaluated p-ERK and p-p38 levels following exposure to NE (Figure 3D–E).…”

The Different Routes to Metastasis via Hypoxia-Regulated Programs

“…Hypoxia activates an unfolded protein response (UPR) that results in the attenuation of translation initiation and the induction of cell cycle arrest genes [4,109,110]. Intriguingly, the UPR was found in dormant cancer cells in experimental models [111] and transcripts for speci c UPR genes were also found to be upregulated in dormant DTCs isolated from BM of prostate cancer patients [112]. These genes could also be turned on in DTCs in the target organ by the fact that they carry a signature epigenetically imprinted in the primary tumors (i.e., the DTCs carry a remodeled chromatin in response to hypoxia in the primary site) [7,113].…”

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

“…The culprits for the recurrent disease are the small number of residual cells that are disseminated from the primary tumor prior to treatment (4). Even patients with asymptomatic disease or no evidence of primary disease progression are known to often harbor cancer cells at distant organs such as bone, and they can be isolated from the bone marrow aspirate (5). These cells include quiescent cancer stem cells (CSCs) 2 and may reacquire clonogenic growth in a favorable environment and cause recurrent disease, which is evident in 20 -50% of patients who were treated for localized primary disease (6).…”