Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D2

DelGiorno, Kathleen E.; Chung, Chi Yeh; Vavinskaya, Vera; Maurer, H. Carlo; Novak, Sammy Weiser; Lytle, Nikki K.; Ma, Zhibo; Giraddi, Rajshekhar R.; Wang, Dezhen; Fang, Linjing; Naeem, Razia; Andrade, Leonardo R.; Ali, Wahida H.; Tseng, Hubert; Tsui, Crystal; Gubbala, Vikas B.; Ridinger-Saison, Maya; Ohmoto, Makoto; Erikson, Galina; O’Connor, Carolyn; Shokhirev, Maxim N.; Hah, Nasun; Urade, Yoshihiro; Matsumoto, Ichiro; Kaech, Susan M.; Singh, Pankaj K.; Manor, Uri; Olive, Kenneth P.; Wahl, Geoffrey M.

doi:10.1053/j.gastro.2020.07.037

Cited by 48 publications

(59 citation statements)

References 61 publications

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“…A scRNA-seq study of intestinal epithelium previously demonstrated that tuft cells can be categorized as either neuronal or inflammatory-like based on marker expression 42 . We were unable to identify these subpopulations in our recently published scRNA-seq analysis of Kras G12D -induced tuft cells, but our study contained relatively few cells 6,8 . Further, tuft cells in our previous study were isolated by FACS for Siglecf+EpCAM+ expression and may have only represented a portion of the total tuft cell population.…”

Section: Capture Of Transcriptomic Changes Associated With Tuft Cell Developmentmentioning

confidence: 76%

“…Previously, we have shown that tuft cells form in response to oncogenic Kras G12D -induced ADM in the pancreas 7 . Despite the paucity of tuft cells in this disease state, abrogation by genetic ablation of master regulator transcription factor Pou2f3 results in acceleration of tumorigenesis, demonstrating that rare cell types can significantly impact disease progression 8 . Identifying the mechanisms of tuft cell injury mitigation and resolution in pancreatitis will provide the opportunity to co-opt or target these processes for patient benefit.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently shown that ADM results in the transdifferentiation of acinar cells to tuft cells, which are rare chemosensory cells typically absent from the normal mouse pancreas 6 . Using a combination of lowinput RNA sequencing strategies, super resolution microscopy, and genetically engineered mouse models (GEMMs), we demonstrated that tuft cells inhibit pancreatic tumorigenesis by modulating tissue stroma [6][7][8] . These data demonstrate that rare ADM-derived cell types have the potential to significantly impact disease progression.…”

Section: Introductionmentioning

confidence: 99%

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Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Lytle

Chen

et al. 2021

Preprint

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BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from genetically wild type ADM, the associated transcriptional changes, and to identify markers of disease progression. METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate upon injury. Transcripts of over 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Single-cell trajectories were generated. Data were compared to gastric metaplasia and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population (Muc6+, Tff2+) resembling gastric pyloric, gland-base cells. Lineage trajectories suggest that this pyloric metaplasia is an intermediate cell identity between acinar cells and the generation of metaplastic tuft and enteroendocrine cells (EECs). 3-D electron microscopy demonstrates that all identified lineages populate ADM lesions. EECs exhibit substantial heterogeneity, including emergence of enterochromaffin (5-HT+) and delta (SST+) cells. Human pancreatitis shows a similar pyloric metaplasia phenotype and a conserved transcriptional program. CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo pyloric metaplasia to mucinous progenitor-like populations, some of which can then seed disparate tuft cell and EEC lineages. EEC subtypes are diverse with the potential to direct disease progression. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases. Keywords: plasticity, pancreatitis, paligenosis, SPEM, Tuft cells, Enteroendocrine cells

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Section: Capture Of Transcriptomic Changes Associated With Tuft Cell Developmentmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Lytle

Chen

et al. 2021

Preprint

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“…POU2F3-positive tuft-like cells have also been identified in pancreatic neoplasia, where they restrain tumorigenesis (DelGiorno et al, 2020). Interestingly, hyperactivation of MAPK signaling (via TGF- mediated activation of EGFR) is observed in Menetrier's disease, a hypertrophic gastropathy characterized by hyperproliferation of isthmus progenitors and the preferential differentiation of these progenitors into surface mucous cells at the expense of parietal and chief cells (Fiske et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Zewdu

Mehrabad

Ingram

et al. 2021

eLife

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Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.

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“…Another recently published study, by DelGiorno et al, 4 used genetic means to completely ablate tuft cells from mouse pancreas. They also found that loss of tuft cells promoted progression to PDAC.…”

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confidence: 99%

Repurposing Tuft Cells to Suppress Pancreatic Cancer

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2021

Cellular and Molecular Gastroenterology and Hepatology

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Tuft Cells Inhibit Pancreatic Tumorigenesis in Mice by Producing Prostaglandin D2

Cited by 48 publications

References 61 publications

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma

Repurposing Tuft Cells to Suppress Pancreatic Cancer

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