A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma

Lytle, Nikki K.; Ferguson, L. Paige; Rajbhandari, Nirakar; Gilroy, Kathryn; Fox, Raymond; Deshpande, Anagha; Schürch, Christian M.; Hamilton, Michael; Robertson, Neil; Lin, Wei; Noel, Pawan; Wartenberg, Martin; Zlobec, Inti; Eichmann, Micha David; Galván, José A.; Karamitopoulou, Evanthia; Gilderman, Tami; Esparza, Lourdes Adriana; Shima, Yutaka; Spahn, Philipp N.; French, Randall; Lewis, Nathan E.; Fisch, Kathleen M.; Šášik, Roman; Rosenthal, Sara Brin; Kritzik, Marcie; Hoff, Daniel D. Von; Han, Haiyong; Ideker, Trey; Lowy, Andrew M.; Adams, Peter D.; Reya, Tannishtha

doi:10.1016/j.cell.2019.03.010

Cited by 119 publications

(129 citation statements)

References 70 publications

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“…These cancer stem cells (CSC) have the ability to give rise to the heterogeneous cell population found within the primary tumor and are considered to be the metastasis-initiating tumor cells [209][210][211]. Multiple studies implicate the SHH pathway as a driver of CSC maintenance in cancers of the brain [191], breast [212,213], colon [214], lung [173,215], ovary [216], pancreas [217], prostate [218], as well as multiple myeloma [219] and chronic myelogenous leukemia [220,221]. GLI1 proteins regulate the expression of the pluripotency factors Nanog, octamer binding transcription factor 4 (OCT4), SOX2, WNT-2, CD44, and Kruppel-like factor 4 (KLF4) [148,165,167,168].…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Hedgehog Signaling and Truncated GLI1 in Cancer

Doheny

Manore

Wong

et al. 2020

Cells

110

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The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.

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Section: Cancer Stem Cellsmentioning

confidence: 99%

Hedgehog Signaling and Truncated GLI1 in Cancer

Doheny

Manore

Wong

et al. 2020

Cells

110

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“…Current single‐cell RNA‐seq analysis of pancreatic adenocarcinoma tumours (e.g. Elyada et al, 2019; Lytle et al, 2019) yields limited data for GPCRs: they are often not detected consistently, as a result of their low expression and the current state of single‐cell sequencing technology. With improved cell isolation protocols that can yield larger numbers of individual cell types and access to primary tissue, methods such as fluorescent‐activated cell sorting (FACS) may aid in separating immune cell populations for study of their function and GPCR expression.…”

Section: Discussion and Perspectivementioning

confidence: 99%

“…With improved cell isolation protocols that can yield larger numbers of individual cell types and access to primary tissue, methods such as fluorescent‐activated cell sorting (FACS) may aid in separating immune cell populations for study of their function and GPCR expression. Such an approach with pancreatic adenocarcinoma tumours from mice has provided novel information regarding CAFs and cancer stem cells (Elyada et al, 2019; Lytle et al, 2019). In particular, since immune‐oncology therapeutic approaches for pancreatic adenocarcinoma have not been successful (Upadhrasta & Zheng, 2019), such efforts in tumour immune cells might reveal GPCRs that could be useful targets for such approaches.…”

Section: Discussion and Perspectivementioning

confidence: 99%

GPCRs in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets

Sriram

Salmerón

Wiley

et al. 2020

British J Pharmacology

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Pancreatic cancer has one of the highest mortality rates (5‐year survival ~9%) among cancers. Pancreatic adenocarcinoma (PAAD) is the most common (>80%) and the most lethal type of pancreatic cancer. A need exists for new approaches to treat pancreatic adenocarcinoma. GPCRs, the largest family of cell‐surface receptors and drug targets, account for ~35% of approved drugs. Recent studies have revealed roles for GPCRs in PAAD cells and cells in the tumour micro‐environment. This review assesses current information regarding GPCRs in PAAD by summarizing omics data for GPCRs expression in PAAD. The PAAD “GPCRome” includes GPCRs with approved agents, thereby offering potential for their repurposing/repositioning. We then reviewed the evidence for functional roles of specific GPCRs in PAAD. We also highlight gaps in understanding the contribution of GPCRs to PAAD biology and identify several GPCRs that may be novel therapeutic targets for future work in search of GPCR‐targeted drugs to treat PAAD tumours.

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“…There are several studies indicating the tumor-promoting roles of regulatory T-cells. The prevalence of Tregs was increased in the peripheral blood, as well as in the tumor microenvironment, of patients with pancreatic cancer—a finding not only limited to the phase of disease progression, but also as early as in premalignant lesions [ 167 , 168 ]. Accordingly, Tregs are detectable in precursor lesions in intraductal papillary mucinous neoplasm (IPMNs) and with disease progression, there is a marked increase in the Treg/CD8+ T cell ratio [ 169 ].…”

Section: The Role Of Adaptive T Cells In Pdacmentioning

confidence: 99%

The Immune Microenvironment in Pancreatic Cancer

Huber

Brehm

Gress³

et al. 2020

IJMS

146

161

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The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

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A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma

Cited by 119 publications

References 70 publications

Hedgehog Signaling and Truncated GLI1 in Cancer

Hedgehog Signaling and Truncated GLI1 in Cancer

GPCRs in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets

The Immune Microenvironment in Pancreatic Cancer

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