Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis.
Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length. Moreover, TRF1 inhibition reduced in vivo reprogramming efficiency. Importantly, we extend the finding of TRF1 upregulation to pathological tissue dedifferentiation associated with neoplasias, in particular during pancreatic acinar-to-ductal metaplasia, a process that involves transdifferentiation of adult acinar cells into ductal-like cells due to K-Ras oncogene expression. These findings place telomeres as important players in cellular plasticity both during in vivo reprogramming and in pathological conditions associated with increased plasticity, such as cancer.
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Rosa M
RM
Marión
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Isabel
I
López de Silanes
Tumour Suppression Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Lluc
L
Mosteiro
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Benjamin
B
Gamache
Tumour Suppression Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
María
M
Abad
Experimental Oncology Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Carmen
C
Guerra
Confocal Microscopy Unit, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Diego
D
Megías
Tumour Suppression Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
Manuel
M
Serrano
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain. Electronic address: mblasco@cnio.es.
Maria A
MA
Blasco
D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics; D054337:Cell Dedifferentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D065150:Cellular Reprogramming / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics; D005786:Gene Expression Regulation; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D059505:Telomere Homeostasis; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D021122:Protein Subunits; D019098:Telomerase; D035321:Telomeric Repeat Binding Protein 1; D000097722:Cohesins
ADM; TRF1; cancer; cellular plasticity; in vivo reprogramming; regeneration; stem cells; telomeres; transdifferentiation; tumorigenesis