How a Receptor Boosts WNT Signals in Pancreatic Cancer

In this new study, researchers revealed a novel role for LGR6 in enhancing WNT signals in pancreatic cancer. 

Pancreatic cancer is one of the deadliest forms of cancer, with a very low survival rate and limited treatment options. Understanding the molecular mechanisms that drive the development and progression of this disease is crucial for finding new ways to prevent and treat it. One of the key players in pancreatic cancer is the WNT signaling pathway, which regulates many aspects of cell growth, differentiation and survival. WNT signaling is often dysregulated in pancreatic cancer, leading to uncontrolled cell proliferation, invasion and resistance to therapy.

“The canonical WNT pathway is reportedly an essential protagonist in organ development as well as oncogenesis in multiple cancers.”

How does WNT signaling become so powerful in pancreatic cancer cells? In a new study, researchers Jing Wang, Dominik T. Koch, Felix O. Hofmann, Daniel Härtwig, Iris Beirith, Klaus Peter Janssen, Alexandr V. Bazhin, Hanno Niess, Jens Werner, Bernhard W. Renz, and Matthias Ilmer from Ludwig-Maximilians-University, University of Science and Technology of China, Technical University of Munich, and German Cancer Consortium revealed a novel role for a receptor called LGR6 in enhancing WNT signals in this disease. Their research paper was published on September 27, 2023, in Aging’s Volume 15, Issue 20, entitled, “WNT enhancing signals in pancreatic cancer are transmitted by LGR6.”

The Study

LGR6 is a member of the leucine-rich repeat-containing G-protein-coupled receptor (LGR) family, which can bind to proteins called R-spondins (RSPOs). RSPOs are known to potentiate WNT signaling by preventing the degradation of WNT receptors and co-receptors on the cell surface. The authors of this study note that LGR5 has previously been described as a WNT target gene as well as a marker of cancer stem cells. In this study, the team aimed to determine whether its homologue LGR6 incorporates similar functional aspects in pancreatic ductal adenocarcinoma (PDAC).

“In this work, we aimed to decipher the functions of LGR6 in WNT signaling of PDAC, apart from its assumed assignment as a receptor to RSPO. Taken into account the connections between WNT signaling and EMT, we further hypothesized a likely interplay of LGR6 and EMT.”

The researchers found that LGR6 is differentially expressed in various pancreatic cancer cell lines, depending on their phenotype and WNT activation status. Cell lines that have a more epithelial-like appearance and are more sensitive to WNT signals tend to express higher levels of LGR6 than cell lines that have a more mesenchymal-like appearance and are less responsive to WNT signals. Moreover, the researchers showed that adding RSPOs to the culture medium increased LGR6 expression in the epithelial-like cell lines, suggesting that there is a positive feedback loop between LGR6 and WNT signaling.

To investigate the functional role of LGR6 in pancreatic cancer, the researchers used small interfering RNAs (siRNAs) to knock down its expression in two epithelial-like cell lines. They found that reducing LGR6 levels decreased the activation of WNT signaling, as measured by the expression of WNT target genes and the accumulation of β-catenin, a key mediator of WNT signals. It is important to note that β-catenin is also a key mediator of epithelial–mesenchymal transition (EMT) — a process by which epithelial cells disconnect from each other and transdifferentiate into mesenchymal cells. Furthermore, the researchers observed that knocking down LGR6 impaired the ability of PDAC cells to form colonies in soft agar, a measure of their tumorigenic potential. It also reduced their capacity to form spheres in suspension, a measure of their stemness or self-renewal ability.

“Taken together, we present new evidence in PDAC that LGR6 might be a novel WNT target gene in this tumor. LGR6 seems to be involved in EMT and cancer stemness.”


This study sheds new light on the molecular mechanisms that modulate WNT signaling in pancreatic cancer and reveals a novel role for LGR6 as a WNT enhancer. Their results suggest that LGR6 is an important regulator of WNT signaling and stemness in pancreatic cancer cells, especially those with an epithelial phenotype. The authors propose that LGR6 may act as a switch that amplifies WNT signals in response to RSPOs, thereby enhancing the malignant properties of pancreatic cancer cells. They also speculate that LGR6 may have potential value for treatment stratification of pancreatic cancer patients, as its expression may indicate the responsiveness of tumors to therapies targeting WNT signaling.

“This knowledge could be applicable for detection and treatment of special subsets of pancreatic cancer cells. Further research is still needed to dissect the exact mechanisms under physiological as well as pathological conditions of benign and cancerous pancreatic cells.”

Click here to read the full study published in Aging.

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TP53 Restoration Sensitizes Pancreatic Cancer to Multiple Drugs

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Patients over the age of 50 years old who have been diagnosed with pancreatic cancer have a poorer rate of survival compared to younger patients. This means that pancreatic cancer is a disease associated with aging. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC) and it is frequently diagnosed in its later stages. PDAC is often refractive to chemotherapies and develops resistance to inhibitors and other drugs. Therefore, there is a critical need for researchers to discover novel strategies to overcome drug resistance in PDAC cells.

One potential strategy is to focus on a key gene known for its involvement in many cell processes, including drug resistance and metabolism: TP53. The TP53 gene is often mutated or deleted in cancer cells, which can lead to drug resistance and cancer metastasis. In PDACS, this tumor suppressor gene has been shown to be mutated in 50–75% of patients.

“Many genes have been implicated in PDAC including KRAS, TP53, CDKN2A, SMAD4 and PDGFβR [3, 8, 9, 1822].”

In a new study, researchers—from Brody School of Medicine at East Carolina University, Università di Bologna, University of Parma, and University of Wroclaw—further elucidated TP53’s role in drug resistance in PDAC cells. On April 27, 2022, their research paper was published in Aging (Aging-US) on the cover of Volume 14, Issue 8, and entitled, “Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties.”

The Study

In these in vitro studies, the researchers cultured two different PDAC cell lines. One cell line had a gain of function (GOF) TP53 mutation (MIA-PaCa-2) and the other had a loss of TP53 (PANC-28). Both PDAC cell lines also have activating mutations in the KRAS gene. Next, the team introduced either wild-type TP53 (WT-TP53) or a control vector into both PDAC cell lines. Effects from this experiment were analyzed using 26 clinically approved agents.

The chemotherapeutic drugs included: Docetaxel, 5-fluorouracil (5-FU), gemcitabine, Aclacinomycin, Doxorubicin, and Cisplatin. The signal transduction inhibitors included: ARS-1620, PD0325901, LY294002, Pifithrin-μ, 6-bromoindirubin-30-oxime (BIO), SB415286, CHIR99021, Rapamycin, AG1498, Gilteritinib, Sorafenib, OTX008, Tiplaxtinin, Verapamil, and Vismodegib. The natural products included: Cyclopamine, Parthenolide2, Isoliquiritin2, Genistein2, and Daidzein2. The researchers also illustrated the effects of WT-TP53 and mutant TP53 on PDAC cell metabolism with metformin and rapamycin.

“An overview of the effects of WT and mutant TP53 on metabolic properties, together with the effects of metformin and rapamycin, and drugs used to inhibit pancreatic cancer growth, is presented in Figure 16.”

Figure 16. Influences of mutant and WT-TP53 on mitochondrial activity and glucose metabolism and effects of rapamycin and metformin. The effects of WT and mutant TP53 on key enzymes important in glycolysis and how they can influence metabolism and PDAC tumor growth. In our studies, we have examined the effect of GOF mutant TP53 and in some cases WT TP53. In addition, sites of interaction of the type 2 diabetes drug metformin and the immunosuppressive drug rapamycin and their effects on AMPK and mTORC1 are indicated. TP53 can induce mitochondrial apoptosis pathway by regulating the expression of PUMA and other proteins.

The Results

The researchers found that, in the presence of chemotherapeutic drugs, PDAC clonogenicity was decreased by the restoration of WT-TP53. Overall, the restoration of WT-TP53 in PDAC cells increased sensitivity/decreased resistance to various chemotherapeutic drugs, inhibitors and natural products. WT-TP53 also influenced  PDAC cell metabolic properties, including their metabolism. The authors also noted that the activity of mTORC1 (target of rapamycin), which is important in cellular growth and metabolism, can be affected by mutant TP53. They found that GOF mutated TP53 may render PDAC cells more resistant to rapamycin.

“Rapamycin and metformin can interfere with some of the important pathways in the mitochondria, some of which are regulated by TP53 [9698].”


Overall, these results suggest that WT-TP53 can play a key role in PDAC cell sensitivity to multiple drugs used to treat pancreatic cancer. Further studies are needed to better understand the mechanisms underlying the effects of TP53 on drug resistance and metabolism in PDAC cells, as well as its clinical implications.

“Regardless of which of the above processes contributes more to the reduction of mitochondrial metabolism in comparison with the same cells that only express GOF TP53, together the observed changes suggest restoration of WT-TP3 activity confers increased sensitization to various drugs and therapeutic molecules, natural products as well as nutraceuticals.”

Click here to read the full research paper published by Aging (Aging-US).

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Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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