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The impact of Wnt signaling on carcinogenesis of colorectal cancer is well-studied (reviewed in Polakis67). Loss of APC is the main driver of Wnt signaling in colorectal cancer and its important role was further highlighted by several recent studies. By genome editing of APC using the CRISPR/Cas9 technology, the carcinogenesis of CRC could be modeled ex vivo in human intestinal organoids.68, 69 Furthermore, studies of human CRC samples and tumors from mouse models revealed that different mutations of APC result in distinct levels of canonical Wnt pathway activity and are associated with characteristic tumor locations within the large intestine.70, 71 Using a mouse model with reversible knockdown of APC via shRNA, it was demonstrated that adenomas could regress to normal tissue if APC function is restored, underlining the importance of continuous Wnt signaling for tumor maintenance.72 Moreover, it was also shown that in spite of truncated APC, Wnt pathway activity can still be modulated by interference with Wnt secretion.73 Interestingly, a molecular classification of colorectal cancers based on expression and mutation data demonstrates that despite comparable frequencies of APC mutations between subtypes, Wnt target genes can be differentially expressed. Molecular subtypes with high expression levels of Wnt target genes were associated with better overall survival rate after relapse compared to subtypes with low expression levels of the respective genes.74
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Development of PDAC is mainly driven by oncogenic Ras signaling and the impact of Wnt signaling has not been fully understood. Unlike CRC, mutations of key Wnt pathway components are rare in PDAC (Figure 2), but nuclear localization of β-catenin is regularly found.81 Results from mouse models indicate that Wnt signaling can initiate tumor formation when activated at distinct tumor stages (reviewed in White et al.82). However, stabilized β-catenin can also inhibit reprogramming of acini into preneoplastic lesions in the presence of mutated KRAS,83 indicating a more complex role of Wnt signaling during tumor development. Recent studies show that PDAC relies on Wnt ligand stimulation, as PDAC cell lines carrying a mutation in RNF43 are particularly sensitive towards treatment with the Porcupine inhibitor LGK974.42 Furthermore, induction of the Wnt antagonist DKK1 as well as treatment with the anti-Fzd antibody OMP18R5 delays PDAC formation.84, 83 Autocrine Wnt7b was found to increase Wnt signaling in pancreatic cell lines and to promote anchorage-independent cell growth.85
In recent years, knowledge about the role of Wnt signaling in hematopoiesis and leukemia has increased.90 Normal hematopoietic stem cells (HSC) depend on a finely controlled level of Wnt signaling for long-term maintenance, whereas Wnt activity is substantially increased in most leukemias.91 Acute myelogenous leukemia (AML) is the most common type of acute leukemia in adults and characterized by frequent chromosomal translocations. In MLL-fusion positive AML mouse models, leukemia initiating cells (LIC) can arise from HSC as well as myeloid progenitor cells after progression through a pre-LIC state.92, 93 β-catenin appears to be essential for the progression of pre-LICs to the LIC state and for LIC self-renewal.94, 95 Frequent translocation products found in AML, such as AML1-ETO, MLL-AF9 and PML-RARα positively affect canonical Wnt signaling in patient samples and derived cell lines.93, 96, 97
The most common leukemia in childhood is acute lymphoblastic leukemia (ALL). The majority of LICs in T-cell ALL (T-ALL) harbor activating mutations of the Notch signal pathway (reviewed in Ferrando98). However, canonical Wnt signaling in HSC and thymocytes synergizes with PTEN loss and c-Myc amplification to generate a β-catenin dependent and Notch independent T-ALL subset in mouse studies and human T-ALL patients.99, 100 Besides the driving role of canonical Wnt signaling during tumorigenesis of specific T-ALL subsets, active β-catenin appears to play an important role during LIC self-renewal in a broader context. Giambra and colleagues showed that LICs in bulk NOTCH1 driven T-ALL mouse models are marked by high Wnt activity.101 Inactivation of β-catenin in these tumors eliminated LICs without affecting the short-term viability of the bulk tumor.
Wnt signaling is activated in over 50% of breast cancer patients and linked to reduced overall survival.129 The role of canonical Wnt signaling in triple negative breast cancer development and progression has been studied intensively.130, 131, 132 However, high levels of nuclear β-catenin were also found in other breast cancer subtypes.133 Only a small fraction of tumors harbor somatic mutations of key pathway regulators such as β-catenin130 (Figure 2), but canonical Wnt ligands and receptors are often overexpressed in breast cancers134, 135, 136 whereas secreted antagonists are silenced.137 In mice, MMTV-Wnt induced tumors are dependent on continuous Wnt signaling,138 which leads to progenitor-like signatures in tumor cells.139 Overexpression of R-spondin2 alone was shown to initiate mammary tumors in mouse models.140
Recently, exosomes were found to be potential mechanism by which tumors prime their metastatic niche.167 Exosomes are small vesicles secreted by cells and function in intercellular communication. It was shown that they can be vehicles for the transport of active Wnt ligands28 or incorporate β-catenin.168 Exosomes secreted from fibroblast in the tumor microenvironment can enhance motility and protrusive activity of breast cancer cells via the Wnt/PCP pathway.169 Co-injection of breast cancer cells with fibroblast in orthotopic mouse models was shown to promote metastasis. Mechanistically, this results from a tethering of Wnt11 to fibroblast-derived exosomes.169 Another route by which distant metastasis is proposed to spread is via circulating tumor cells (CTCs).170 Single-cell RNA sequencing of CTCs was performed for prostate and pancreatic cancer and both studies identified a role for Wnt signaling. In CTCs of pancreatic cancer, Wnt2 expression increased anchorage-independent sphere formation and their metastatic propensity.171 In another study, the non-canonical Wnt signaling pathway was found to be upregulated in CTCs of prostate cancer cells that are resistant to androgen receptor inhibition.172 Taken together, there is increasing evidence that both canonical and non-canonical Wnt signaling can support tumor metastasis in a highly tissue-specific manner.
Besides the intracellular perturbation of Wnt secretion, an array of drugs targeting extracellular Wnt ligands and their receptors are under development. OMP-54F28 is a fusion protein consisting of a Fzd8 and a human IgG1 Fc domain. This decoy receptor for Wnt ligands reduces the size of tumor xenografts and overall tumor initiating cell number in mouse models of hepatocellular carcinoma and ovarian cancer.186 Currently, the substance is undergoing three phase 1b trials in liver, ovarian and pancreatic cancer in combination with established therapeutics. Furthermore, a phase I clinical trial testing the safety of OMP131R10, a RSPO3-binding antibody, has been initiated in June 2015 for patients with solid tumors and metastasized colorectal cancer.
In addition to approaches targeting Wnt secretion and ligands, an inhibitor of the downstream Wnt pathway is currently undergoing clinical trials. PRI-724 and the closely related compound ICG-001 specifically target the complex formation of β-catenin and CBP while enhancing the formation of β-catenin/p300 complexes in ALL cells.192 Treatment with PRI-724 therefore inhibits the self-renewing downstream effects of β-catenin-CBP activity and leads to reduction of tumor burden.193 Following promising results from phase I trials,194 a new phase II trial of PRI-724 in combination with bevacizumab therapy in metastatic colorectal carcinoma patients is planned.195 Tankyrase inhibitors such as XAV939, which stabilize Axin by blocking its PARsylation, have shown promising results as Wnt inhibitors.196 Subsequently, additional compounds targeting this enzyme have been developed.197 However, no tankyrase inhibitor is currently undergoing clinical testing, which may be linked to their toxicity in preclinical models.198
Mary Jean leaves to cherish her memories: five sons, Alvin Tarleton (Bobbie), Teverris Dotson (Willena), and Mark Dotson of Vicksburg, Mississippi, Billy Dotson (Audrey) and Lorenzo Dotson (Linda) of Memphis, Tennessee; one daughter, Marilyn Mitchell (Mike) of Vicksburg, Mississippi; two sisters, Helen McComb (Willie) and Edna Tarleton of Port Gibson, Mississippi one brother, Earnest Tarleton (Linda) of Port Gibson, Mississippi; fifteen grandchildren; five great grandchildren; and a host of nieces, nephews, cousins and friends.
Shirlena Cook Lambert was born on August 27, 1963 to Maggie Dell Cook and the late Huey Mace in Vicksburg, Ms. God and his infinite wisdom reached out his hand and called Shirlena to rest on Monday, October 25, 2021 at St. Dominic Hospital in Jackson, MS. She was preceded in death by her grandmother Cleo Honey Eatmon and Grandfather Robert Eatmon, father Huey Mace and brothers William Cook, Walter Cook, and Walter Pittman.
Shirlena confessed Christ at an early age at Belmont Missionary Baptist Church in Utica, MS, where she was an active member of the choir; she enjoyed singing with many other church choirs as well as singing with her family. She attended the Hinds County Schools District and graduated from Utica High School in
Shirlena realized she had a passion for teaching at very young age and strived for excellence in the field of Education throughout her lifetime. She obtained her B.S degree in Education from Jackson State University and shortly after, a Master's degree in Education from William Carey College in Hattiesburg, MS. Later in her professional career, she obtained her Specialist Degree in Education from Argosy University -Atlanta, GA where she also completed her doctoral course work in Educational Leadership. Shirlena served as a professional educator in both the Jackson Public Schools and Hattiesburg Public Schools districts in Mississippi. She also continued her career as an educator in the Cobb and Douglas County Public Schools districts in Georgia. She was a proud member of Phi Beta Sorority, Incorporated. Shirlena was a beloved wife and a wonderful mother of her children. 350c69d7ab