<scp>GPCRs</scp> in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets

Sriram, Krishna; Salmerón, Cristina; Wiley, Shu Z.; Insel, Paul A.

doi:10.1111/bph.15028

Cited by 24 publications

(18 citation statements)

References 127 publications

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“…Since GPCRs can signal through the G12 family of small G proteins (Kurose, 2003), many studies have evaluated the contribution of Gα12 and Gα13 to physiologic and pathologic processes (Sriram et al, 2020;Syrovatkina and Huang, 2019;Tutunea-Fatan et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing interest in understanding the role of effectors downstream of GPCRs and determining whether these effectors could be potential therapeutic targets (Hauser et al, 2017). Since GPCRs can signal through the G12 family of small G proteins (Kurose, 2003), many studies have evaluated the contribution of Gα12 and Gα13 to physiologic and pathologic processes (Sriram et al, 2020; Syrovatkina and Huang, 2019; Tutunea-Fatan et al, 2020). These studies, which have been primarily performed in epithelial cancer cell lines, showed that Gα13 functions as a tumor promoter (Chow et al, 2016; Kelly et al, 2007; Kelly et al, 2006; Kozasa et al, 2011; Rasheed et al, 2018; Zhang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

Shields

Spaulding

Khalafalla

et al. 2021

Preprint

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Gα13 transduces signals from G protein-coupled receptors. Gα13 is pro-tumorigenic in epithelial cancer cell lines, which contrasts with its tumor-suppressive function in transgenic mouse models of lymphomas. Here we show that while loss of Gα13 in pancreatic cell lines decreases tumor growth in vivo, Gα13 loss in the Kras-driven (KC) mouse model of pancreatic tumor initiation does not affect tumor development or survival. Instead, Gα13 loss in the Kras/Tp53 (KPC) transgenic mouse model of advanced pancreatic cancer promotes well-differentiated tumors with increased tumor burden and reduced survival. Mechanistically, Gα13 loss in the KPC mouse model enhances E-cadherin-mediated cell-cell junctions and mTOR signaling. Importantly, human pancreatic cancers with low Gα13 expression exhibit increased E-cadherin protein expression and mTOR signaling. This work establishes a context-dependent role of Gα13 in pancreatic tumorigenesis, demonstrating a tumor-suppressive role in transgenic mouse models of advanced pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

Shields

Spaulding

Khalafalla

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…This is extremely beneficial in the study of GPCRs located at the plasma membrane as the receptors are typically not only at the cell membrane, but also at intracellular sites such as endosomes, endoplasmic reticulum, and the Golgi complex [38] and TIRF imaging minimizes their intracellular visualisation. Next, we aimed to demonstrate the applicability of qPAINT analysis to quantitatively P2Y 2 receptors were labelled with a primary antibody which we validated using the immortalised human pancreatic stellate cell line PS-1 as it expresses traces amounts of the protein of interest (see Figure S2 for negative control results) [19,39]. For DNA-PAINT imaging, the anti-P2Y 2 receptor antibody was chemically coupled to an optimised docking strand sequence design to increase imaging speed.…”

Section: Super-resolution Imaging Of P2y 2 Receptors In Aspc-1 Cells Using Dna-paintmentioning

confidence: 99%

Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization

et al. 2021

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G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of analysis employed. Here, we use a quantitative single molecule super-resolution imaging technique named qPAINT to quantify complex formation within an example GPCR. qPAINT, based upon DNA-PAINT, takes advantage of the binding kinetics between fluorescently labelled DNA imager strands to complementary DNA docking strands coupled to protein targeting antibodies to quantify the protein copy number in nanoscale dimensions. We demonstrate qPAINT analysis via a novel pipeline to study the oligomerization of the purinergic receptor Y2 (P2Y2), a rhodopsin-like GPCR, highly expressed in the pancreatic cancer cell line AsPC-1, under control, agonistic and antagonistic conditions. Results reveal that whilst the density of P2Y2 receptors remained unchanged, antagonistic conditions displayed reduced percentage of oligomers, and smaller numbers of receptors in complexes. Yet, the oligomeric state of the receptors was not affected by agonist treatment, in line with previous reports. Understanding P2Y2 oligomerization under agonistic and antagonistic conditions will contribute to unravelling P2Y2 mechanistic action and therapeutic targeting.

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“…Functional aspects of GPCR have been established in cancers, including pancreatic cancer, both in the cells of cancer and tumor microenvironment. A wide variety of GPCRs are expressed by pancreatic adenocarcinoma tumor cells [ 145 ]. As the GPCRs are the largest drug target family, about 34% of all drugs approved by the Food and Drug Administration (FDA) targeted 108 members of GPCR [ 146 ].…”

Section: Role Of G Protein-coupled Receptor In Pancreatic Cancermentioning

confidence: 99%

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

et al. 2021

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One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine′s action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.

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

Cited by 24 publications

References 127 publications

Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

Gα13 loss promotes tumor progression in the KPC transgenic mouse model of advanced pancreatic cancer

Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

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