Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes

Maurer, H. Carlo; Holmstrom, Sam R.; He, Jing; Laise, Pasquale; Su, Tao; Ahmed, Aqeel; Hibshoosh, Hanina; Chabot, John A.; Oberstein, Paul E.; Sepulveda, Antonia R.; Genkinger, Jeanine M.; Zhang, Jiapeng; Iuga, Alina; Bansal, Mukesh; Califano, Andrea; Olive, Kenneth P.

doi:10.1136/gutjnl-2018-317706

Cited by 166 publications

(262 citation statements)

References 26 publications

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“…Although prior studies have made correlations between epithelial and stromal transcriptomes in PDA (Maurer et al, 2019;Moffitt et al, 2015;Puleo et al, 2018), it remains unclear whether the evolution of these two compartments is dependent on one another.…”

Section: Discussionmentioning

confidence: 99%

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Somerville

Biffi

Daßler-Plenker

et al. 2019

Preprint

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AbstractA highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans-differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63-dependent manner. These non cell-autonomous effects occur, at least in part, through TP63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

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Section: Discussionmentioning

confidence: 99%

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Somerville

Biffi

Daßler-Plenker

et al. 2019

Preprint

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“…An important feature of squamous subtype tumors is that they display poorly differentiated histopathological features and an exceptionally poor prognosis (13,35,36,52,72,73).…”

Section: Discussionmentioning

confidence: 99%

ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer

Somerville

et al. 2019

Preprint

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ClassificationBIOLOGICAL SCIENCES: Cell Biology. KeywordsZBED2, IRF1, interferon, lineage plasticity, pancreatic ductal adenocarcinoma ABSTRACT Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease.Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of interferon-stimulated genes, which occurs through antagonism of Interferon Regulatory Factor 1 (IRF1)-mediated transcriptional activation at co-occupied promoter elements. Consequently, ZBED2 attenuates the transcriptional output and growth arrest phenotypes downstream of interferon signaling in multiple PDA cell line models. We also found that ZBED2 is preferentially expressed in the squamous molecular subtype of human PDA, in association with inferior patient survival outcomes. Consistent with this observation, we show that ZBED2 can repress the pancreatic progenitor transcriptional program, enhance motility, and promote invasion in PDA cells. Collectively, our findings suggest that high ZBED2 expression is acquired during PDA progression to suppress the interferon response pathway and to promote lineage plasticity in this disease.

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“…To infer the function of tuft cells in human pancreas disease, we evaluated tuft cell marker expression in RNA-seq data collected from human samples. To do this, we laser-capture dissected and sequenced the epithelium from 45 patients with precursor lesions (26 PanIN and 19 IPMN) and 197 patients with PDA (as described in (42). We then generated and overlaid a humanized version of our KC tuft cell signature on these data (KC Tuft single sample gene set enrichment analysis, ssGSEA) and found significantly higher expression in precursor lesions than cancer, consistent with tuft cell formation early in disease progression followed by loss later on (p<0.01, Figure 6A) (5).…”

Section: Pancreatic Tuft Cells In Human Disease Tuft Cells Are Alsomentioning

confidence: 99%

“…of human IPMN (n =19), PanIN (n = 26) and PDA (n = 197) were generated using laser capture microdissection with subsequent RNA sequencing as described previously (42,70). These samples have not been previously published (manuscript in preparation).…”

Section: Analysis Of Tuft Cell Gene Signatures In Human Pda Compartmmentioning

confidence: 99%

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

DelGiorno

Chung

et al. 2019

Preprint

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Despite numerous advances in our understanding of pancreatic ductal adenocarcinoma (PDA) genetics and biology, this disease is expected to become the second leading cause of cancer-related U.S. deaths within the next few years. Incomplete understanding of how it arises precludes development of early detection and interception strategies to improve therapeutic outcomes. Acinar to ductal metaplasia involving genesis of tuft cells is one early step in PDA formation, but their functional significance has remained obscure due to their rarity and a lack of methods and relevant animal models for their molecular and functional analysis. Here, we show that deletion of tuft cell master regulator Pou2f3 eliminates pancreatic tuft cells and increases fibrosis, alters immune cell activation, and accelerates disease progression. We demonstrate that tuft cell expression of the prostaglandin D 2 synthase Hpgds restrains pancreatic disease progression in early stages by inhibiting stromal activation. Analyses of human data sets are consistent with mouse studies. We propose that tuft cells and, by inference, the associated metaplastic lesions, play a protective role early in pancreatic tumorigenesis. Significance:We find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D 2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type. Introduction:Chemical or mechanical injury of the pancreas results in a cell state-switching event termed acinar to ductal metaplasia (ADM) where digestive enzyme producing acinar cells dedifferentiate into proliferative ductal-like cells to restore pancreas homeostasis. This process is perturbed during neoplastic progression, where, in mouse models, initiating Kras mutations prevent tissue healing and, instead, ADM is thought to progress to pancreatic intraepithelial neoplasia (PanIN) and then pancreatic ductal adenocarcinoma (PDA). This is an example of Dvorak's thesis, which states that cancer represents the ever-healing wound (1).The profound difference between the normal healing process and the perturbed response engendered by oncogene activation raises the important question of whether key cell types that result from ADM impact cancer progression. Here, we investigate the role of tuft cells as they appear in response to oncogeneinduced metaplasia in a number of cancers of human significance including lung, stomach, intestine, and pancreas (2-6).Tuft cells are solitary chemosensory cells found throughout the hollow organs of the respiratory and digestive tracts. They are readily identified by their striking morphological features, including long, blunt microvilli, deep actin rootlets, and an extensive tubulovesicular system in the supranuclear cytoplasm (7).Their expression of taste, neuronal, and inflammatory cell signaling factors is thought to enable monitoring of intraluminal homeostasis and to achieve loc...

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Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes

Cited by 166 publications

References 26 publications

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

ZBED2 is an antagonist of Interferon Regulatory Factor 1 and modulates cell identity in pancreatic cancer

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

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