LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer
Abstract Background Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood. Methods LAMC2 transcriptional l...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02516-w |
| _version_ | 1811335071006720000 |
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| author | Donatella Delle Cave Silvia Buonaiuto Bruno Sainz Marco Fantuz Maria Mangini Alessandro Carrer Annalisa Di Domenico Tea Teresa Iavazzo Gennaro Andolfi Carme Cortina Marta Sevillano Christopher Heeschen Vincenza Colonna Marco Corona Antonio Cucciardi Martina Di Guida Eduard Batlle Annachiara De Luca Enza Lonardo |
| author_facet | Donatella Delle Cave Silvia Buonaiuto Bruno Sainz Marco Fantuz Maria Mangini Alessandro Carrer Annalisa Di Domenico Tea Teresa Iavazzo Gennaro Andolfi Carme Cortina Marta Sevillano Christopher Heeschen Vincenza Colonna Marco Corona Antonio Cucciardi Martina Di Guida Eduard Batlle Annachiara De Luca Enza Lonardo |
| author_sort | Donatella Delle Cave |
| collection | DOAJ |
| description | Abstract Background Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood. Methods LAMC2 transcriptional levels were evaluated using publicly available transcriptome data sets, and LAMC2 immunohistochemistry was performed using a tissue microarray composed of PDAC and normal pancreas tissues. Silencing and tracing of LAMC2 was performed using lentiviral shRNA constructs and CRISPR/Cas9-mediated homologous recombination, respectively. The contribution of LAMC2 to PDAC tumorigenicity was explored in vitro by tumor cell invasion, migration, sphere-forming and organoids assays, and in vivo by tumor growth and metastatic assays. mRNA sequencing was performed to identify key cellular pathways upregulated in LAMC2 expressing cells. Metastatic spreading induced by LAMC2- expressing cells was blocked by pharmacological inhibition of transforming growth factor beta (TGF-β) signaling. Results We report a LAMC2-expressing cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation and differentiation, and drives metastasis. mRNA profiling of these cells indicates a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-β signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of the TGF-β type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated lung metastasis, primarily originating from LAMC2-expressing cells. Conclusions We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker. |
| first_indexed | 2024-04-13T17:18:35Z |
| format | Article |
| id | doaj.art-7a66930b577747c385f65ad7170426ec |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-13T17:18:35Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-7a66930b577747c385f65ad7170426ec2022-12-22T02:38:04ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-10-0141112010.1186/s13046-022-02516-wLAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancerDonatella Delle Cave0Silvia Buonaiuto1Bruno Sainz2Marco Fantuz3Maria Mangini4Alessandro Carrer5Annalisa Di Domenico6Tea Teresa Iavazzo7Gennaro Andolfi8Carme Cortina9Marta Sevillano10Christopher Heeschen11Vincenza Colonna12Marco Corona13Antonio Cucciardi14Martina Di Guida15Eduard Batlle16Annachiara De Luca17Enza Lonardo18Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Department of Cancer Biology, Instituto de Investigaciones Biomedicas “Alberto Sols” (IIBM), CSIC-UAMDepartment of Biology, University of PadovaInstitute for Experimental Endocrinology and Oncology, “G. Salvatore” (IEOS), Second Unit, Consiglio Nazionale Delle Ricerche (CNR)Department of Biology, University of PadovaInstitute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of MedicineInstitute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)Institute for Experimental Endocrinology and Oncology, “G. Salvatore” (IEOS), Second Unit, Consiglio Nazionale Delle Ricerche (CNR)Institute of Genetics and Biophysics “A. Buzzati-Traverso”, National Research Council (CNR-IGB)Abstract Background Tumor-initiating cells (TIC), also known as cancer stem cells, are considered a specific subpopulation of cells necessary for cancer initiation and metastasis; however, the mechanisms by which they acquire metastatic traits are not well understood. Methods LAMC2 transcriptional levels were evaluated using publicly available transcriptome data sets, and LAMC2 immunohistochemistry was performed using a tissue microarray composed of PDAC and normal pancreas tissues. Silencing and tracing of LAMC2 was performed using lentiviral shRNA constructs and CRISPR/Cas9-mediated homologous recombination, respectively. The contribution of LAMC2 to PDAC tumorigenicity was explored in vitro by tumor cell invasion, migration, sphere-forming and organoids assays, and in vivo by tumor growth and metastatic assays. mRNA sequencing was performed to identify key cellular pathways upregulated in LAMC2 expressing cells. Metastatic spreading induced by LAMC2- expressing cells was blocked by pharmacological inhibition of transforming growth factor beta (TGF-β) signaling. Results We report a LAMC2-expressing cell population, which is endowed with enhanced self-renewal capacity, and is sufficient for tumor initiation and differentiation, and drives metastasis. mRNA profiling of these cells indicates a prominent squamous signature, and differentially activated pathways critical for tumor growth and metastasis, including deregulation of the TGF-β signaling pathway. Treatment with Vactosertib, a new small molecule inhibitor of the TGF-β type I receptor (activin receptor-like kinase-5, ALK5), completely abrogated lung metastasis, primarily originating from LAMC2-expressing cells. Conclusions We have identified a highly metastatic subpopulation of TICs marked by LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in PDAC patients. Our results prompt further study of this TIC population in pancreatic cancer and exploration as a potential therapeutic target and/or biomarker.https://doi.org/10.1186/s13046-022-02516-wPancreatic ductal adenocarcinoma (PDAC)Laminin γ2 (LAMC2)Tumor-initiating cells (TICs)TGF-β signalingVactosertib |
| spellingShingle | Donatella Delle Cave Silvia Buonaiuto Bruno Sainz Marco Fantuz Maria Mangini Alessandro Carrer Annalisa Di Domenico Tea Teresa Iavazzo Gennaro Andolfi Carme Cortina Marta Sevillano Christopher Heeschen Vincenza Colonna Marco Corona Antonio Cucciardi Martina Di Guida Eduard Batlle Annachiara De Luca Enza Lonardo LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer Journal of Experimental & Clinical Cancer Research Pancreatic ductal adenocarcinoma (PDAC) Laminin γ2 (LAMC2) Tumor-initiating cells (TICs) TGF-β signaling Vactosertib |
| title | LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer |
| title_full | LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer |
| title_fullStr | LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer |
| title_full_unstemmed | LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer |
| title_short | LAMC2 marks a tumor-initiating cell population with an aggressive signature in pancreatic cancer |
| title_sort | lamc2 marks a tumor initiating cell population with an aggressive signature in pancreatic cancer |
| topic | Pancreatic ductal adenocarcinoma (PDAC) Laminin γ2 (LAMC2) Tumor-initiating cells (TICs) TGF-β signaling Vactosertib |
| url | https://doi.org/10.1186/s13046-022-02516-w |
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