Abstract
Entosis is a type of regulated cell death that promotes cancer cell competition. Though several studies have revealed the molecular mechanisms that govern entosis, the clinical and genetic correlates of entosis in human tumors is less well understood. Here we reviewed entotic cell-in-cell (CIC) patterns in a large single institution sequencing cohort (MSK IMPACT clinical sequencing cohort) of more than 1600 human pancreatic ductal adenocarcinoma (PDAC) samples to identify the genetic and clinical correlates of this cellular feature. After case selection, 516 conventional PDACs and 21 ASCs entered this study and ~45,000 HPFs (median 80 HPFs per sample) were reviewed; 549 entotic-CICs were detected through our cohort. We observed that entotic-CIC occurred more frequently in liver metastasis compared with primary in PDAC. Moreover, poorly differentiated adenocarcinoma or adenosquamous carcinoma had more entotic-CIC than well or moderately differentiated adenocarcinoma. With respect to genetic features TP53 mutations, KRAS amplification, and MYC amplification were significantly associated with entosis in PDAC tissues. From a clinical standpoint entotic CICs were independently associated with a poor prognosis by multivariate Cox regression analysis when considering all cases or primary PDACs specifically. These results provide a contextual basis for understanding entosis in PDAC, a highly aggressive cancer for which molecular insights are needed to improve survival.
Highlights
Entosis is a type of regulated cell death that originates from actomyosin-dependent cell-in-cell (CIC) internalization and Supplementary information The online version of this article contains supplementary material, which is available to authorized users.is executed by lysosomes [1]
Entosis was first discovered as a nonapoptotic cell death process in 2007 [2], and thought to have an advantage for cancer cell survival by promoting cell competition through direct cell–cell interactions unlike other forms of cell death including ferroptosis that occurs at the level of individual cells [3]
In pancreatic ductal adenocarcinoma (PDAC), we have recently shown that mutant TP53 status and/or metabolic related gene expression changes are positively correlated with formation of entotic CIC [10]
Summary
In pancreatic ductal adenocarcinoma (PDAC), we have recently shown that mutant TP53 status and/or metabolic related gene expression changes are positively correlated with formation of entotic CIC [10]. The extent to which entosis correlates with metastatic propensity remains unknown, as does the extent to which genes other than TP53 contribute to this phenotypic change. For this reason, we investigated the CIC pattern in PDAC using a large single institution cohort of both primary and metastasis samples for which targeted sequencing data of more than 400 genes are available
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