A Novel Model of Pancreatic Cancer Dormancy Reveals Mechanistic Insights and a Dormancy Gene Signature with Human Relevance

Abstract

One Sentence Summary:A novel model of resectable pancreatic cancer reveals pancreatic cancer dormancy is characterized by significant cellular plasticity, heterogeneity and chromatin remodeling Abstract Latent recurrences following curative-intent pancreatic cancer surgery is a major clinical problem thought to be due to the reactivation of dormant tumor cells that disseminate before the primary tumor has been removed. How dormancy is established and ultimately reversed to drive recurrence is poorly understood. Here we introduce a novel model of pancreatic cancer dormancy that mimics early and latent survival outcomes of resected patients. Using single-cell transcriptomics we compared primary, dormant, and reactivated tumor cells and found the primary and reactivated tumor cell transcriptomes clustered together with and away from the dormant tumor cells. Using a chromatin accessibility assay we found dormancy exhibits large scale changes in chromatin remodeling. Dormant tumor cells express cancer stem cell markers that are lost upon reactivation and are chemotherapy resistant. We identified a dormancy gene signature and investigated this in patients undergoing surgery for localized PC by isolating cells from the primary tumor and liver disseminated tumor cells (DTCs) for single-cell transcriptomics.We found the signature correlated with DTCs indicating that these cells are dormant at the time of surgery. The signature also identified CCL5 as a novel dormancy marker in PC. Mechanisms of PC dormancy include upregulation of the transcriptional repressor Dec2 which drives quiescence, monoallelic suppression of the mutant KRAS allele by DNA methylation, and immunoregulation. We conclude that PC dormancy is a highly plastic and heterogeneous cellular state governed by tumor cell autonomous and non-autonomous mechanisms.

Targeting dormant tumor cells to prevent cancer recurrence

“…Surprisingly, dormant myeloma cells also showed enrichment for myeloid cell differentiation markers, which could be induced through the interaction with osteoblasts in the endosteal niche where dormant myeloma cells typically reside [16]. Another study using single‐cell mRNA sequencing in a model for pancreatic cancer dormancy identified yet another plethora of pathways required to maintain dormancy in pancreatic cancer‐derived liver metastasis, including liver‐specific signaling cascades involved in apolipoprotein expression and neurotropic receptor signaling [18]. Although these studies identified many factors that can be associated with the DCC state in their specific dormancy models, computational approaches and meta‐analyses combining multiple DCC biomarker studies will be essential to define unifying DCC signatures that are more generally applicable.…”

Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies

“…At the pathway level, the analysis identified as enriched in DTCs a cellular program of decreased proliferation, protein biosynthesis/expression, and cellular energy metabolic pathways, such as the TCA cycle, OXPHOS, and the PPP. Noteworthy, these results were further validated in human DTCs from patients undergoing surgery for localized pancreatic cancer [165]. Interestingly, the metastatic route may also influence the metabolic preferences of DTCs.…”

New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries

“…On the other hand, probiotic administration was able to reduce recurrence in a RCT of superficial bladder cancer patients ( 251 ). The role of gut microbiome in cancer recurrence and metastasis needs to be further investigated in epidemiological studies as well as through use of immunocompetent pre-clinical models ( 252 , 253 ). As technological breakthroughs make high throughput sequencing more efficient and accessible, we have started generating vast amounts of metadata through metagenomic, metabolomics, and even transcriptomic sequencing of the resident flora.…”