CYR61/CCN1 expression in resected pancreatic ductal adenocarcinoma: A retrospective pilot study of the interaction between the tumors and their surrounding microenvironment

Abou-Kheir, Wassim; Mukherji, Deborah; Hadadeh, Ola; Saleh, Eman S.; Bahmad, Hisham F.; Kanso, Mariam; Khalifeh, Mohamad; Shamseddine, Ali; Tamraz, Sally; Jaafar, Rola; Dagher, Christelle; Khalifeh, Ibrahim; Faraj, Walid

doi:10.1016/j.heliyon.2020.e03842

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…Furthermore, the clinically important issue of desmoplasia in cancer appears to center around CCN proteins. CCN1 was highly expressed in PDAC tissues relative to other organ specific tumor tissues while moderate and overexpression of CCN1 was associated with dysplastic PanIN grade 3 tissues (Abou‐Kheir et al 2020). Thus it needs to be determined if CCN1 might be modulating the interaction between pancreatic tumors, the surrounding microenvironment and the precursors.…”

Section: Pancreatic Cancermentioning

confidence: 99%

The CCN axis in cancer development and progression

Yeger

Perbal²

2021

J. Cell Commun. Signal.

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Since the authors first reviewed this subject in 2016 significant progress has been documented in the CCN field with advances made in the understanding of how members of the CCN family of proteins, CCN1‐6, contribute to the pathogenesis and progression, positive and negative, of a larger variety of cancers. As termed matricellular proteins, and more recently the connective communication network, it has become clearer that members of the CCN family interact complexly with other proteins in the extracellular microenvironment, membrane signaling proteins, and can also operate intracellularly at the transcriptional level. In this review we expand on this earlier information providing new detailed information and insights that appropriate a much greater involvement and importance of their role in multiple aspects of cancer. Despite all the new information many more questions have been raised and intriguing results generated that warrant greater investigation. In order to permit the reader to smoothly integrate the new information we discuss all relevant CCN members in the context of cancer subtypes. We have harmonized the nomenclature with CCN numbering for easier comparisons. Finally, we summarize what new has been learned and provide a perspective on how our knowledge about CCN1‐6 is being used to drive new initiatives on cancer therapeutics.

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Section: Pancreatic Cancermentioning

confidence: 99%

The CCN axis in cancer development and progression

Yeger

Perbal²

2021

J. Cell Commun. Signal.

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“…Six of these genes were also bound by PDX1 in the adult islet in both mouse and human (bold gene in Figure 5F). These ductal specific genes are known to be involved in mitochondrial function ( ATP1B1 and ATP1A1 ), related to pancreatic cancer progression ( ACTN4, TPM1 , CYR61, CLDN3 ) (31, 32). In parallel, only 4 genes ( MEIS2, ISL1, PAX6, and SCGN ) were expressed in embryonic beta cells and bound by PDX1 in pancreas development in both mouse and human, which play important roles in pancreas development (33–37).…”

Section: Resultsmentioning

confidence: 99%

PDX1 directs a core developmentally and evolutionarily conserved gene program in the pancreatic islet

Yang

Raum

Kim

et al. 2021

Preprint

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Pancreatic and duodenal homeobox 1 (PDX1) is crucial for pancreas organogenesis, yet the dynamic changes in PDX1 targets in mouse or human pancreas development have not been examined. We integrated the PDX1 cistrome with cell lineage-specific gene expression in both mouse and human developing pancreas. We identified a core set of developmentally and evolutionarily conserved PDX1 bound genes that reveal the broad multifaceted role of PDX1 in pancreas development. Despite the well-known, dramatic changes in PDX1 function and expression, we showed that PDX1 binding is largely stable from embryonic pancreas to adult islet. This may point towards a dual role of PDX1, activating or repressing the expression of its targets at different ages, dependent on other functionally-congruent or directly-interacting partners. Our work also suggests that PDX1 functions not only in initiating pancreas differentiation, but also as a potential keepsake of the progenitor program in the adult beta cells.

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“…Here, the mRNA expression and protein abundance of c-Myc and CYR-61 were reduced in PANC-1 xenografts of ( R , S ′)-MNF-treated mice relative to vehicle-treated controls along with significant reduction in YAP protein in the treated tumors. The effect on CYR61 expression is of interest as increased CYR61 expression is associated with PDAC aggressiveness, drug resistance, and tumor-microenvironment interactions 75 – 77 .…”

Section: Discussionmentioning

confidence: 99%

Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist

Wnorowski

Dudzik

Bernier

et al. 2022

Sci Rep

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Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S′)-4′-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased β2-adrenergic receptor (β2-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β2-AR in (R,S′)-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S′)-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S′)-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased β2-AR/Gαs/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S′)-MNF administration significantly reduced PANC-1 tumor growth and circulating l-lactate concentrations. Global metabolic profiling of (R,S′)-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S′)-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards β-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased β2-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.

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CYR61/CCN1 expression in resected pancreatic ductal adenocarcinoma: A retrospective pilot study of the interaction between the tumors and their surrounding microenvironment

Cited by 4 publications

References 28 publications

The CCN axis in cancer development and progression

The CCN axis in cancer development and progression

PDX1 directs a core developmentally and evolutionarily conserved gene program in the pancreatic islet

Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist

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