Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes

Ai, Jiaoyu; Wörmann, Sonja M.; Görgülü, Kıvanç; Vallespinós, Mireia; Zagorac, Sladjana; Alcalá, Sonia; Wu, Nan; Kabacaoğlu, Derya; Berninger, Alexandra; Navarro, Diego; Kaya-Aksoy, Ezgi; Ruess, Dietrich Alexander; Ciecielski, Katrin J.; Kowalska, Marlena; Demir, Ihsan Ekin; Ceyhan, Güralp O.; Heid, Irina; Braren, Rickmer; Robinson‐Rechavi, Marc; Schreiner, Sabrina; Hofmann, Samuel; Kutschke, Maria; Jastroch, Martin; Slotta‐Huspenina, Julia; Muckenhuber, Alexander; Schlitter, Anna Melissa; Schmid, Roland M.; Steiger, Katja; Diakopoulos, Kalliope N.; Lesina, Marina; Sáinz, Bruno; Algül, Hana

doi:10.1053/j.gastro.2021.03.051

Cited by 11 publications

(13 citation statements)

References 40 publications

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“…1D), as well as a stemness signature previously described in PDAC (Fig. 1E) [22] . On the other hand, besides pathways related to ALK downstream signaling such as K-Ras or JAK/STAT, ALK HIGH samples also showed enrichment of an ALK overexpression (OE) gene signature described in breast cancer cells [23] (Fig.…”

Section: Alk Receptor Expression and Activation Are Linked To Stemnes...supporting

confidence: 70%

“…The signatures for stemness and ALK overexpression (OE) were previously described in Ai et al . [22] and Mazzeschi et al . [23] , respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The GSEA module of the GenePattern suite from the Broad Institute was used with 1000 permutations and FDR < 25% was considered statistically significant. The signatures for stemness and ALK overexpression (OE) were previously described in Ai et al [22] and Mazzeschi et al [23] , respectively. ALK mutational status was assessed using the webserver cBioPortal (Pancreas UTSW, Pancreas TCGA PanCan 2018, Pancreas TCGA, Pancreas ICGC and Pancreas QCMG 2016 project datasets; https://www.cbioportal.org) [24] .…”

Section: Bioinformatic Analysesmentioning

confidence: 99%

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ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

Parejo-Alonso

Royo-García

Espiau-Romera

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling drives tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased CSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients.

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Section: Alk Receptor Expression and Activation Are Linked To Stemnes...supporting

confidence: 70%

“…The signatures for stemness and ALK overexpression (OE) were previously described in Ai et al . [22] and Mazzeschi et al . [23] , respectively.…”

Section: Methodsmentioning

confidence: 99%

Section: Bioinformatic Analysesmentioning

confidence: 99%

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ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

Parejo-Alonso

Royo-García

Espiau-Romera

et al. 2022

Preprint

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“…Maximal tumor burden (10% of body weight) and maximal tumor size allowed by the ethics committee was not exceeded. No statistical methods were used to pre-determine sample sizes for in vivo experiments, but our sample sizes are similar to those reported in previous publications (30).…”

Section: Mouse Modelsmentioning

confidence: 93%

“…Primary lung tumor cells, and organoid cell lines were processed for immunoblotting according to a previously described protocol (30). Antibodies are listed in Supplementary Table S12.…”

Section: Immunoblotting Analysismentioning

confidence: 99%

Programmable in vivo CRISPR activation elucidates the oncogenic and immunosuppressive role of MYC in lung adenocarcinoma

Thege

Rupani

Bharati

et al. 2021

Preprint

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Conventional genetically engineered mouse models (GEMMs) are time consuming, laborious and offer limited spatio-temporal control. Here, we describe the development of a streamlined platform for in vivo gene activation using CRISPR activation (CRISPRa) technology. Unlike conventional GEMMs, our model system allows for flexible, sustained and timed activation of one or more target genes using single or pooled lentiviral guides. Using Myc and Yap1 as model oncogenes, we demonstrate gene activation in primary pancreatic organoid cultures in vitro and enhanced tumorigenic potential in Myc-activated organoids when transplanted orthotopically. By implementing our model as an autochthonous lung cancer model, we show that transduction-mediated Myc activation leads to accelerated tumor progression and significantly reduced overall survival relative to non-targeted tumor controls. Furthermore, we found that Myc-activation led to the acquisition of an immune suppressive cold tumor microenvironment. Through cross-species validation of our results using publicly available RNA/DNA-seq data sets, we were able to link MYC to a previously described, immunosuppressive transcriptomic subtype in patient tumors, thus identifying a patient cohort that may benefit from combined MYC/immune-targeted therapies. Overall, our work demonstrates how CRISPRa can be used for rapid functional validation of putative oncogenes and may allow for the identification and evaluation of potential metastatic and oncogenic drivers through competitive screening.

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Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

Parejo-Alonso¹,

Royo-García²,

Espiau-Romera³

et al. 2023

Biomedicine & Pharmacotherapy

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Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes

Cited by 11 publications

References 40 publications

ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

ALK signaling drives tumorigenicity and chemoresistance of pancreatic ductal adenocarcinoma cells

Programmable in vivo CRISPR activation elucidates the oncogenic and immunosuppressive role of MYC in lung adenocarcinoma

Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

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