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MASTL regulates EGFR signaling to impact pancreatic cancer progression.

ABSTRACT: Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown. Based on a comprehensive investigation involving PC patient samples, murine models of PC progression (Kras;PdxCre-KC and Kras;p53;PdxCre-KPC), and loss and gain of function studies, we report a previously undescribed critical role of MASTL in promoting cancer malignancy and therapy resistance. Mechanistically, MASTL promotes PC by modulating the epidermal growth factor receptor protein stability and, thereupon, kinase signaling. We further demonstrate that combinatorial therapy targeting MASTL promotes the efficacy of the cell-killing effects of Gemcitabine using both genetic and pharmacological inhibitions. Taken together, this study identifies a key role of MASTL in promoting PC progression and its utility as a novel target in promoting sensitivity to the anti-PC therapies.

SUBMITTER: Fatima I

PROVIDER: S-EPMC8817225 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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MASTL regulates EGFR signaling to impact pancreatic cancer progression.

Fatima Iram I Barman Susmita S Uppada JayaPrakash J Chauhan Shailender S Rauth Sanchita S Rachagani Satyanarayana S Ponnusamy Moorthy Palanimuthu MP Smith Lynette L Talmon Geoffrey G Singh Amar B AB Batra Surinder K SK Dhawan Punita P

Oncogene 20210730 38

Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role ...[more]

PMID: 34331012

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Project description:BackgroundChemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.MethodsWe utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.ResultsHere, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.ConclusionOverall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.

Project description:Pancreatic cancer is one of the cancers with the poorest prognosis, with a 5-year survival rate of approximately 5-10%. Thus, it is urgent to identify molecular targets for the treatment of pancreatic cancer. Using serial transplantations in a mouse pancreatic orthotopic inoculation model, we previously produced highly malignant pancreatic cancer sublines with increased tumor-forming abilities in vivo. Here, we used these sublines to screen molecular targets for the treatment of pancreatic cancer. Among the genes with increased expression levels in the sublines, we focused on those encoding cell surface receptors that may be involved in the interactions between cancer cells and the tumor microenvironment. Based on our previous RNA-sequence analysis, we found increased expression levels of neurotensin (NTS) receptor 1 (NTSR1) in highly malignant pancreatic cancer sublines. Furthermore, re-analysis of clinical databases revealed that the expression level of NTSR1 was increased in advanced pancreatic cancer and that high NTSR1 levels were correlated with a poor prognosis. Overexpression of NTSR1 in human pancreatic cancer cells Panc-1 and SUIT-2 accelerated their tumorigenic and metastatic abilities in vivo. In addition, RNA-sequence analysis showed that MAPK and NF-κB signaling pathways were activated upon NTS stimulation in highly malignant cancer sublines and also revealed many new target genes for NTS in pancreatic cancer cells. NTS stimulation increased the expression of MMP-9 and other pro-inflammatory cytokines and chemokines in pancreatic cancer cells. Moreover, the treatment with SR48692, a selective NTSR1 antagonist, suppressed the activation of the MAPK and NF-κB signaling pathways and induction of target genes in pancreatic cancer cells in vitro, while the administration of SR48692 attenuated the tumorigenicity of pancreatic cancer cells in vivo. These findings suggest that NTSR1 may be a prognostic marker and a molecular target for pancreatic cancer treatment.

Project description:PurposeTriple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is associated with high invasiveness, high metastatic occurrence and poor prognosis. Protein tyrosine kinase 7 (PTK7) plays an important role in multiple cancers. However, the role of PTK7 in TNBC has not been well addressed. This study was performed to evaluate the role of PTK7 in the progression of TNBC.MethodsCorrelation of PTK7 expression with clinicopathological parameters was assessed using tissue microarray immunohistochemistry (IHC) staining in 280 patients with breast cancer. PTK7 expression in TNBC (MDA-MB-468, MDA-MB-436 and MDA-MB-231) and non-TNBC (MCF7 and SK-BR-3) breast cancer cell lines were examined using immunoblotting assay. PTK7 correlated genes in invasive breast carcinoma were analyzed using cBioPortal breast cancer datasets including 1,904 patients. PTK7 overexpressed or knockdown TNBC cell lines (MDA-MB-468 and MDA-MB-436) were used to analyze the potential roles of PTK7 in TNBC metastasis and tumor progression. A TNBC tumor bearing mouse model was established to further analyze the role of PTK7 in TNBC tumorigenicity in vivo.ResultsPTK7 is highly expressed in breast cancer and correlates with worse prognosis and associates with tumor metastasis and progression in TNBC. Co-expression analysis and gain- or loss-of-function of PTK7 in TNBC cell lines revealed that PTK7 participates in EGFR/Akt signaling regulation and associated with extracellular matrix organization and migration genes in breast cancer, including COL1A1, FN1, WNT5B, MMP11, MMP14 and SDC1. Gain- or loss-of-function experiments of PTK7 suggested that PTK7 promotes proliferation and migration in TNBC cell lines. PTK7 knockdown MDA-MB-468 cell bearing mouse model further demonstrated that PTK7-deficiency inhibits TNBC tumor progression in vivo.ConclusionThis study identified PTK7 as a potential marker of worse prognosis in TNBC and revealed PTK7 promotes TNBC metastasis and progression via EGFR/Akt signaling pathway.

Project description:BackgroundRegenerating family member 3A (REG3A) is involved in the development of multiple malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). However, any role of REG3A in PDAC remains controversial due to its unclear tissue localization or direct receptors, and complex downstream signal transductions.MethodsMorphological analysis and public multi-omics data retrieval were was utilized to elucidate the tissue localization of REG3A in PDAC. To ascertain the pro-oncogenic role of secreted REG3A, experiments were conducted using in vitro PDAC cell lines and in vivo tumor formation assays in nude mice. A battery of investigative techniques, including RNA sequencing, phospho-kinase arrays, western blot analyses, in silico docking simulations, gene truncation strategies, and co-immunoprecipitation, were employed to delve into the downstream signaling transduction pathways induced by REG3A.ResultsIn this study, we confirmed an association between increased serum levels of REG3A and poor prognosis in patients with PDAC. Morphological staining and bioinformatic analysis showed that REG3A was mainly expressed in peritumoral acinar cells that were spatially close to tumor region, while it was almost negative in PDAC tumor cells. Peritumoral REG3A expression levels, but not tumoral REG3A, were highly correlated with PDAC progression. Further in vitro experiments including RNA sequencing and molecular biological assays revealed that secreted REG3A could directly bind to the epidermal growth factor receptor (EGFR), an important pro-oncogene involved in cellular proliferation, and subsequently activate the downstream mitogen-activated protein kinase (MAPK) signals to promote PDAC tumor cell growth.ConclusionTaken together, our data indicated that increased expression of REG3A in peritumoral acinar cells acts as a specific event to indicate PDAC progression, and verified EGFR as a possible target of REG3A, providing mechanistic insights into the role of REG3A, the diagnostic method and therapeutic strategy of PDAC.

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MASTL regulates EGFR signaling to impact pancreatic cancer progression.

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MASTL regulates EGFR signaling to impact pancreatic cancer progression.

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