Molecular landscape of colorectal cancers harboring R-spondin fusions.

3588 Background: Gene fusions involving R-spondin ( RSPO) family members have been shown to drive Wnt-dependent tumor initiation in colorectal cancer (CRC). Therapies targeting Wnt pathway are being actively investigated for tumors harboring RSPO2/3 fusions. Here we set out to characterize the molecular features of CRC with and without RSPO fusions to gain insight into potential rationale combination therapy strategies. Methods: Tumor DNA sequencing of 592 genes (NextSeq, Illumina), RNA sequencing of 53 gene fusions (ArcherDx FusionPlex) and immunohistochemistry for PD-L1 on tumor cells (SP142) were tested on CRC tumors at Caris Life Sciences, Phoenix, AZ. Molecular profiles of RSPO2/3 positive (pos) were compared with negative (neg) tumors, Fisher-Exact was used for comparative analysis. Results: A total of 1356 CRC samples were analyzed. RSPO3 and RSPO2 fusions were detected in 42 (3.1%) and 4 (0.3%) samples, respectively, including 5 fusion events not previously reported (e.g., IFNGR1-RSPO3). A female predominance was seen in RSPO fusion pos vs. neg tumors (71.7% vs 45.0%, p < 0.001); no association with age or tumor sidedness was seen. RSPO2/3 fusions were mutually exclusive of MSI-high (0 vs. 5%), ERBB2 alterations (0 vs. 1% mutation, 4% amplification) and other Wnt pathway activation drivers including APC (2 vs. 75%), CTNNB1 (0 vs. 1.4%) and RNF43 (0 vs. 5.3%) mutations. Significantly higher BRAF (26 vs. 7%), RAF1 (4.5 vs. 0.4%) and SMAD4 (30 vs. 11%) mutation rates were seen in RSPO pos vs. neg tumors (p < 0.05). A universal co-activation of MAPK pathway ( KRAS, NRAS or BRAF) was seen with RSPO fusions. There was a significantly elevated PD-L1 expression in RSPO3 pos tumors (14%) compared to RSPO neg (6%, p = 0.04) and APC-mutated (5%, p = 0.02) tumors that are MSS. Conclusions: This is the largest series of CRC cases harboring an RSPO rearrangement reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO fusions in CRC and suggested potential combinatorial approach to target Wnt/MAPK pathway. The immune modulatory effects specific to RSPO2/3 fusion revealed by PD-L1 expression suggest co-targeting Wnt pathway with PD1/PDL1 inhibitors in RSPO pos tumors.

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Wnt Pathway Activation in Long Term Remnant Rat Model

BioMed Research International ◽

10.1155/2014/324713 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

E. Banon-Maneus ◽

J. Rovira ◽

M. J. Ramirez-Bajo ◽

D. Moya-Rull ◽

N. Hierro-Garcia ◽

...

Keyword(s):

Kidney Disease ◽

Wnt Pathway ◽

Target Genes ◽

Nuclear Translocation ◽

Mrna Level ◽

Pathway Activation ◽

Renal Ablation ◽

End Stage ◽

Insight Into

Progression of chronic kidney disease (CKD) is characterized by deposition of extracellular matrix. This is an irreversible process that leads to tubulointerstitial fibrosis and finally loss of kidney function. Wnt/β-catenin pathway was reported to be aberrantly activated in the progressive damage associated with chronic organ failure. Extensive renal ablation is an experimental model widely used to gain insight into the mechanisms responsible for the development of CKD, but it was not evaluated for Wnt/β-catenin pathway. This study aimed to elucidate if the rat 5/6 renal mass reduction model (RMR) is a good model for the Wnt/β-catenin activation and possible next modulation. RMR model was evaluated at 12 and 18 weeks after the surgery, when CKD is close to end-stage kidney disease demonstrated by molecular and histological studies. Wnt pathway components were analyzed at mRNA and protein level. Our results demonstrate that Wnt pathway is active by increase ofβ-catenin at mRNA level and nuclear translocation in tubular epithelium as well as some target genes. These results validate the RMR model for future modulation of Wnt pathway, starting at shorter time after the surgery.

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Faculty Opinions recommendation of Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1157767.618990 ◽

2009 ◽

Author(s):

Martin Fernandez-Zapico

Keyword(s):

Pancreatic Cancer ◽

Wnt Pathway ◽

Beta Catenin ◽

Pathway Activation ◽

Oncogenic Function

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Faculty Opinions recommendation of Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725301255.793502912 ◽

2015 ◽

Author(s):

Alex Toker ◽

Kristin Brown

Keyword(s):

Feedback Loop ◽

Mapk Pathway ◽

Human Cancer ◽

Pathway Activation

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Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

npj Precision Oncology ◽

10.1038/s41698-021-00187-y ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Robert L. Hollis ◽

Barbara Stanley ◽

John P. Thomson ◽

Michael Churchman ◽

Ian Croy ◽

...

Keyword(s):

High Risk ◽

Ovarian Carcinoma ◽

Expression Patterns ◽

Parp Inhibitors ◽

Receptor Expression ◽

Cancer Type ◽

Sequencing Data ◽

Molecular Features ◽

Endometrioid Ovarian Carcinoma ◽

Molecular Landscape

AbstractEndometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

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Requirement of Ras/MAPK pathway activation by transforming growth factor β for transforming growth factor β1 production in a Smad-dependent pathway.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)88877-2 ◽

2000 ◽

Vol 275 (45) ◽

pp. 35656

Author(s):

Jianbo Yue ◽

Kathleen M. Mulder

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Mapk Pathway ◽

Transforming Growth Factor Β ◽

Transforming Growth Factor Β1 ◽

Pathway Activation ◽

Dependent Pathway

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Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Leukemia ◽

10.1038/s41375-021-01278-2 ◽

2021 ◽

Author(s):

Sarah A. Carratt ◽

Theodore P. Braun ◽

Cody Coblentz ◽

Zachary Schonrock ◽

Rowan Callahan ◽

...

Keyword(s):

Mapk Pathway ◽

Pathway Activation

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trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway

Scientific Reports ◽

10.1038/s41598-021-89506-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yusuke Hirata ◽

Miki Takahashi ◽

Yuto Yamada ◽

Ryosuke Matsui ◽

Aya Inoue ◽

...

Keyword(s):

Fatty Acids ◽

Mapk Pathway ◽

Regulatory Protein ◽

Strand Break ◽

Mitogen Activated Protein Kinase ◽

Ros Generation ◽

Apoptotic Pathway ◽

Interstrand Crosslinks ◽

Pathway Activation ◽

Dna Interstrand Crosslinks

Abstracttrans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

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