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Innovative mouse models for the tumor suppressor activity of protocadherin-10 isoforms

(2022) BMC CANCER. 22(1).
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Abstract
Background Nonclustered mouse protocadherin genes (Pcdh) encode proteins with a typical single ectodomain and a cytoplasmic domain with conserved motifs completely different from those of classic cadherins. Alternative splice isoforms differ in the size of these cytoplasmic domains. In view of the compelling evidence for gene silencing of protocadherins in human tumors, we started investigations on Pcdh functions in mouse cancer models. Methods For Pcdh10, we generated two mouse lines: one with floxed exon 1, leading to complete Pcdh10 ablation upon Cre action, and one with floxed exons 2 and 3, leading to ablation of only the long isoforms of Pcdh10. In a mouse medulloblastoma model, we used GFAP-Cre action to locally ablate Pcdh10 in combination with Trp53 and Rb1 ablation. From auricular tumors, that also arose, we obtained tumor-derived cell lines, which were analyzed for malignancy in vitro and in vivo. By lentiviral transduction, we re-expressed Pcdh10 cDNAs. RNA-Seq analyses were performed on these cell families. Results Surprisingly, not only medulloblastomas were generated in our model but also tumors of tagged auricles (pinnae). For both tumor types, ablation of either all or only long isoforms of Pcdh10 aggravated the disease. We argued that the perichondrial stem cell compartment is at the origin of the pinnal tumors. Immunohistochemical analysis of these tumors revealed different subtypes. We obtained several pinnal-tumor derived (PTD) cell lines and analyzed these for anchorage-independent growth, invasion into collagen matrices, tumorigenicity in athymic mice. Re-expression of either the short or a long isoform of Pcdh10 in two PTD lines counteracted malignancy in all assays. RNA-Seq analyses of these two PTD lines and their respective Pcdh10-rescued cell lines allowed to identify many interesting differentially expressed genes, which were largely different in the two cell families. Conclusions A new mouse model was generated allowing for the first time to examine the remarkable tumor suppression activity of protocadherin-10 in vivo. Despite lacking several conserved motifs, the short isoform of Pcdh10 was fully active as tumor suppressor. Our model contributes to scrutinizing the complex molecular mechanisms of tumor initiation and progression upon PCDH10 silencing in many human cancers.
Keywords
Cancer Research, Genetics, Oncology, Protocadherin-10 isoforms, Tumor suppression, Conditional gene knockout, GFAP-Cre, Mouse medulloblastoma model, Mouse auricular tumors, Somatic stem cells, Tumor-derived cells, Allografts, RNA-Seq, INHIBITS CELL-PROLIFERATION, MICE LACKING PCDH10, PROMOTER METHYLATION, DELTA-PROTOCADHERINS, OL-PROTOCADHERIN, DOWN-REGULATION, POOR-PROGNOSIS, GENE, CANCER, MULTIPLE

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MLA
Kleinberger, Irene, et al. “Innovative Mouse Models for the Tumor Suppressor Activity of Protocadherin-10 Isoforms.” BMC CANCER, vol. 22, no. 1, 2022, doi:10.1186/s12885-022-09381-y.
APA
Kleinberger, I., Sanders, E., Staes, K., Van Troys, M., Hirano, S., Hochepied, T., … Van Roy, F. (2022). Innovative mouse models for the tumor suppressor activity of protocadherin-10 isoforms. BMC CANCER, 22(1). https://doi.org/10.1186/s12885-022-09381-y
Chicago author-date
Kleinberger, Irene, Ellen Sanders, Katrien Staes, Marleen Van Troys, Shinji Hirano, Tino Hochepied, Kelly Lemeire, Liesbet Martens, Christophe Ampe, and Frans Van Roy. 2022. “Innovative Mouse Models for the Tumor Suppressor Activity of Protocadherin-10 Isoforms.” BMC CANCER 22 (1). https://doi.org/10.1186/s12885-022-09381-y.
Chicago author-date (all authors)
Kleinberger, Irene, Ellen Sanders, Katrien Staes, Marleen Van Troys, Shinji Hirano, Tino Hochepied, Kelly Lemeire, Liesbet Martens, Christophe Ampe, and Frans Van Roy. 2022. “Innovative Mouse Models for the Tumor Suppressor Activity of Protocadherin-10 Isoforms.” BMC CANCER 22 (1). doi:10.1186/s12885-022-09381-y.
Vancouver
1.
Kleinberger I, Sanders E, Staes K, Van Troys M, Hirano S, Hochepied T, et al. Innovative mouse models for the tumor suppressor activity of protocadherin-10 isoforms. BMC CANCER. 2022;22(1).
IEEE
[1]
I. Kleinberger et al., “Innovative mouse models for the tumor suppressor activity of protocadherin-10 isoforms,” BMC CANCER, vol. 22, no. 1, 2022.
@article{8750738,
  abstract     = {{Background Nonclustered mouse protocadherin genes (Pcdh) encode proteins with a typical single ectodomain and a cytoplasmic domain with conserved motifs completely different from those of classic cadherins. Alternative splice isoforms differ in the size of these cytoplasmic domains. In view of the compelling evidence for gene silencing of protocadherins in human tumors, we started investigations on Pcdh functions in mouse cancer models. Methods For Pcdh10, we generated two mouse lines: one with floxed exon 1, leading to complete Pcdh10 ablation upon Cre action, and one with floxed exons 2 and 3, leading to ablation of only the long isoforms of Pcdh10. In a mouse medulloblastoma model, we used GFAP-Cre action to locally ablate Pcdh10 in combination with Trp53 and Rb1 ablation. From auricular tumors, that also arose, we obtained tumor-derived cell lines, which were analyzed for malignancy in vitro and in vivo. By lentiviral transduction, we re-expressed Pcdh10 cDNAs. RNA-Seq analyses were performed on these cell families. Results Surprisingly, not only medulloblastomas were generated in our model but also tumors of tagged auricles (pinnae). For both tumor types, ablation of either all or only long isoforms of Pcdh10 aggravated the disease. We argued that the perichondrial stem cell compartment is at the origin of the pinnal tumors. Immunohistochemical analysis of these tumors revealed different subtypes. We obtained several pinnal-tumor derived (PTD) cell lines and analyzed these for anchorage-independent growth, invasion into collagen matrices, tumorigenicity in athymic mice. Re-expression of either the short or a long isoform of Pcdh10 in two PTD lines counteracted malignancy in all assays. RNA-Seq analyses of these two PTD lines and their respective Pcdh10-rescued cell lines allowed to identify many interesting differentially expressed genes, which were largely different in the two cell families. Conclusions A new mouse model was generated allowing for the first time to examine the remarkable tumor suppression activity of protocadherin-10 in vivo. Despite lacking several conserved motifs, the short isoform of Pcdh10 was fully active as tumor suppressor. Our model contributes to scrutinizing the complex molecular mechanisms of tumor initiation and progression upon PCDH10 silencing in many human cancers.}},
  articleno    = {{451}},
  author       = {{Kleinberger, Irene and Sanders, Ellen and Staes, Katrien and Van Troys, Marleen and Hirano, Shinji and Hochepied, Tino and Lemeire, Kelly and Martens, Liesbet and Ampe, Christophe and Van Roy, Frans}},
  issn         = {{1471-2407}},
  journal      = {{BMC CANCER}},
  keywords     = {{Cancer Research,Genetics,Oncology,Protocadherin-10 isoforms,Tumor suppression,Conditional gene knockout,GFAP-Cre,Mouse medulloblastoma model,Mouse auricular tumors,Somatic stem cells,Tumor-derived cells,Allografts,RNA-Seq,INHIBITS CELL-PROLIFERATION,MICE LACKING PCDH10,PROMOTER METHYLATION,DELTA-PROTOCADHERINS,OL-PROTOCADHERIN,DOWN-REGULATION,POOR-PROGNOSIS,GENE,CANCER,MULTIPLE}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{33}},
  title        = {{Innovative mouse models for the tumor suppressor activity of protocadherin-10 isoforms}},
  url          = {{http://dx.doi.org/10.1186/s12885-022-09381-y}},
  volume       = {{22}},
  year         = {{2022}},
}

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