title: Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept.
abstract: There is a paradox offered up by the cancer stem cell hypothesis. How are the mixed populations that are characteristic of heterogeneous solid tumors maintained at constant proportion, given their high, and different, mitotic indices? In this study, we evaluate a well-characterized mouse model of human basaloid tumors (induced by the oncogene Wnt1), which comprise mixed populations of mammary epithelial cells resembling their normal basal and luminal counterparts. We show that these cell types are substantially inter-dependent, since the MMTV LTR drives expression of Wnt1 ligand in luminal cells, whereas the functional Wnt1-responsive receptor (Lrp5) is expressed by basal cells, and both molecules are necessary for tumor growth. There is a robust tumor initiating activity (tumor stem cell) in the basal cell population, which is associated with the ability to differentiate into luminal and basal cells, to regenerate the oncogenic paracrine signaling cell pair. However, we found an additional tumor stem cell activity in the luminal cell population. Knowing that tumors depend upon Wnt1-Lrp5, we hypothesized that this stem cell must express Lrp5, and found that indeed, all the stem cell activity could be retrieved from the Lrp5-positive cell population. Interestingly, this reflects post-transcriptional acquisition of Lrp5 protein expression in luminal cells. Furthermore, this plasticity of molecular expression is reflected in plasticity of cell fate determination. Thus, in vitro, Wnt1-expressing luminal cells retro-differentiate to basal cell types, and in vivo, tumors initiated with pure luminal cells reconstitute a robust basal cell subpopulation that is indistinguishable from the populations initiated by pure basal cells. We propose this is an important proof of concept, demonstrating that bipotential tumor stem cells are essential in tumors where oncogenic ligand-receptor pairs are separated into different cell types, and suggesting that Wnt-induced molecular and fate plasticity can close paracrine loops that are usually separated into distinct cell types.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Kim
authors.forename: Shruti
authors.initials: S
authors.lastname: Goel
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Alexander
mesh_terms: D000818:Animals; D060466:Axin Protein; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D003598:Cytoskeletal Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D051155:Wnt1 Protein