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SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis., S. Castillo-Lluva was the recipient of a Ramón y Cajal research contract from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; MINECO), and the work was supported by a MINECO/FEDER research grant (SAF2015-64499-R; RTI2018-094130-B-100). N. García-Sancha was partially supported by the RTI2018-094130-B-100 budget. J. Pérez-Losada was partially supported by FEDER funds, the Carlos III Health Institute (PIE14/00066), MINECO (SAF2014-56989-R, SAF2017-88854R), Castile and León (CSI234P18), the Sandra Ibarra Foundation for Solidarity against Cancer and the “We can be heroes” Foundation. N. García-Sancha is a recipient of an FPU fellowship (MINECO/FEDER). R. Corchado-Cobos, M.d.M. Sáez-Freire, and A. Blanco-Gómez were funded by fellowships from the Spanish Regional Government of Castile and León. The development of the Snai2 KO mice was supported by NIH grant R01HD034883 (to T. Gridley)

NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse., Ministerio de Economia y Competitividad (MINECO) PLE-2009-0110, SAF2010-15106, SAF2013-44857-R, and SAF2016-75442-R (Agencia Estatal de Investigacion/European Regional Development Fund, European Union), the Fundacion Sandra Ibarra, the Fundacion Asociacion Espanola Contra el Cancer (AECC CI13131229), the Instituto de Salud Carlos III (RTICC RD06/0014/1012), and the European Union Seventh Framework Programme (FP7/2007-20013) ThymiStem project (602587). Institutional grants from the Fundacion Ramon Areces and Banco de Santander

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging., JPL was partially supported by FEDER and the MICINN (SAF2014-56989-R and SAF2017-88854R), the Instituto de Salud Carlos III (PIE14/00066), >Proyectos Integrados IBSAL 2015> (IBY15/00003), the Sandra Ibarra Foundation >de Solidaridad Frente al Cáncer> Foundation and >We can be heroes> Foundation. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological & Environmental Research, US Department of Energy (DE-AC02-05CH11231).

Under a Creative Commons license.-- et al., Snail1 transcriptional repressor is a major inducer of epithelial-to mesenchymal transition but is very limitedly expressed in adult animals. We have previously demonstrated that Snail1 is required for the maintenance of mesenchymal stem cells (MSCs), preventing their premature differentiation. Now, we show that Snail1 controls the tumorigenic properties of mesenchymal cells. Increased Snail1 expression provides tumorigenic capabilities to fibroblastic cells; on the contrary, Snail1 depletion decreases tumor growth. Genetic depletion of Snail1 in MSCs that are deficient in p53 tumor suppressor downregulates MSC markers and prevents the capability of these cells to originate sarcomas in immunodeficient SCID mice. Notably, an analysis of human sarcomas shows that, contrarily to epithelial tumors, these neoplasms display high Snail1 expression. This is particularly clear for undifferentiated tumors, 9which are associated with poor outcome. Together, our results indicate a role for Snail1 in the generation of sarcomas., This study was funded by grants awarded by la Fundación Científica de la Asociación Española contra el Cáncer (to A.G.H., J.I.C., and F.B.), Fundación Sandra Ibarra and Ministerio de Ciencia y Tecnología (SAF2010-16089) to A.G.H. and also by RD12/0036/0005, part of “Plan Nacional de I+D+I” and cofunded by “Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER)”. We also acknowledge support from Fundació La Marató de TV3 (120130), to A.G.H., ISCIII/FEDER (RD12/0036/041, RD12/0036/051, and RD12/0036/021), Generalitat de Catalunya (2009SGR867 and 2009SGR321; Xarxa de Bancs de Tumors), CAM (CAM S2010-BMD2344-Colomics2), and Fundació Cellex (Barcelona). R.B. and L.A.-C. were recipients from “Formación de Personal Investigador” predoctoral fellowships.

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases., JPL was partially supported by FEDER and MICINN (PLE2009-119, SAF2014-56989-R), Instituto de Salud Carlos III (PI07/0057, PI10/00328, PIE14/00066), Junta de Castilla y León (CSI034U13, BIO/SA31/15), “Proyectos integrados IBSAL 2015” (IBY15/00003), the Eugenio Rodriguez Pascual”, the “Fundacion Inbiomed” (Instituto Oncologico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), and the “Fundacion Sandra Ibarra de Solidaridad frente al Cancer”. CR-C is funded by Q3718001E (2009–2010) y GRS 612/A/11 (2011–2012) and “the Fundacion Eugenio Rodrıguez Pascual”. AC was supported by FIS (PI07/0057) and MICINN (PLE2009-119). SCLL was funded by a JAEdoc Fellowship (CSIC)/FSE. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological & Environmental Research, US Department of Energy (DE-AC02-05CH11231).

Cancer is a complex and highly dynamic process. Genetically engineered mouse models (GEMs) that develop cancer are essential systems for dissecting the processes that lead to human cancer. These animal models provide a means to determine the causes of malignancy and to develop new treatments, thus representing a resource of immense potential for medical oncology. The sophistication of modeling cancer in mice has increased to the extent that now we can induce, study and manipulate the cancer disease process in a manner that is impossible to perform in human patients. However, all GEMs described so far have diverse shortcomings in mimicking the hierarchical structure of human cancer tissues. In recent years, a more detailed picture of the cellular and molecular mechanisms determining the formation of cancer has emerged. This Commentary addresses new experimental approaches toward a better understanding of carcinogenesis and discusses the impact of new animal models., Research in I.S.-G.’s group is supported partially by FEDER and by MICINN (SAF2006-03726 and SAF2009-08803), and by Junta de Castilla y León (CSI13A08 and proyecto Biomedicina 2009-2010), MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), an NIH grant (2R01 CA109335-04A1) and by a Group of Excellence Grant (GR15) from Junta de Castilla y León. Research in C.C.’s lab is supported partially by FEDER and by Fondo de Investigaciones Sanitarias (PI080164) and Junta de Castilla y León (SA060A09 and proyecto Biomedicina 2009-2010). Research at J.P.-L.’s lab is supported partially by FEDER and by Fondo de Investigaciones Sanitarias (PI070057), and by MICINN (PLE2009-O119), Junta de Castilla y León (SA078A09 and Proyecto Biomedicina 2009-2010) and Sandra Ibarra Foundation.

PMCID: PMC4560637, Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects - latency and tumor load - were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice., JPL was partially supported by FEDER and MICINN (PLE2009-119, SAF2014-56989-R), Instituto de Salud Carlos III (PI07/0057, PI10/00328, PIE14/00066), Junta de Castilla y León (SAN673/SA26/08, SAN126/SA66/09, SA078A09, CSI034U13), the “Fundación Eugenio Rodríguez Pascual”, the “Fundación Inbiomed” (Instituto Oncológico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), and the “Fundación Sandra Ibarra de Solidaridad frente al Cáncer”. AC was supported by FIS (PI07/0057) and MICINN (PLE2009-119). SCLL was funded by a JAEdoc Fellowship (CSIC)/FSE. MMSF and ABG are funded by fellowships from the Junta de Castilla y Leon. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological & Environmental Research, US Department of Energy (DE-AC02-05CH11231).

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al., [Background]: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. [Results]: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. [Conclusions]: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations., JPL was partially supported by FEDER and MICINN (PLE2009-119), FIS (PI07/0057, PI10/00328, PIE14/00066), the Junta de Castilla y León (SAN673/SA26/08; SAN126/SA66/09, SA078A09, CSI034U13), the “Fundación Eugenio Rodríguez Pascual”, the Fundación Inbiomed (Instituto Oncológico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), and the “Fundación Sandra Ibarra de Solidaridad frente al Cáncer”. AC was supported by MICINN (PLE2009-119). SCLL is funded by a JAEdoc Fellowship (CSIC)/FSE. MMSF and ABG are funded by fellowships from the Junta de Castilla y Leon. WR was supported by a Forschungsstipendium of the Deutsche Forschungsgemeinschaft (DFG) [RE 3108/1-1]. TN, BPB and DYL acknowledge support from the US Department of Energy Low-Dose SFA Program at Berkeley Lab [DE-AC02-05CH11231], the National Institutes of Health [RC1NS069177] and the California Breast Cancer Research Program [15IB-0063]. JHM was supported by the National Institutes of Health, a National Cancer Institute grant (R01 CA116481), and the Low-Dose Scientific Focus Area, Office of Biological and Environmental Research, US Department of Energy (DE-AC02-05CH11231).

PMCID: PMC3545406.-- et al., The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation., National Institutes of Health (NIH) grants NIH CA109335 and NIH CA122105; the Dwoskin Family Foundations; NIH P01 CA34233 FEDER and by MICINN (SAF2009-08803 and SAF2012-32810 to ISG); Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010); MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017); Sandra Ibarra Foundation; Group of Excellence Grant (GR15) from Junta de Castilla y Leon; the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Programme)

Human VRK2 (vaccinia-related kinase 2), a kinase that emerged late in evolution, affects different signaling pathways, and some carcinomas express high levels of VRK2. Invasion by cancer cells has been associated with NFAT1 (nuclear factor of activated T cells) activation and expression of the COX-2 (cyclooxygenase 2) gene. We hypothesized that VRK proteins might play a regulatory role in NFAT1 activation in tumor cells. We demonstrate that VRK2 directly interacts and phosphorylates NFAT1 in Ser-32 within its N-terminal transactivation domain. VRK2 increases NFAT1-dependent transcription by phosphorylation, and this effect is only detected following cell phorbol 12-myristate 13-acetate and ionomycin stimulation and calcineurin activation. This NFAT1 hyperactivation by VRK2 increases COX-2 gene expression through the proximal NFAT1 binding site in the COX-2 gene promoter. Furthermore, VRK2A down-regulation by RNA interference reduces COX-2 expression at transcriptional and protein levels. Therefore, VRK2 down-regulation reduces cell invasion by tumor cells, such as MDA-MB-231 and MDA-MB-435, upon stimulation with phorbol 12-myristate 13-acetate plus ionomycin. These findings identify the first reported target and function of human VRK2 as an active kinase playing a role in regulation of cancer cell invasion through the NFAT pathway and COX-2 expression., Supported by a Junta para Ampliación de Estudios e Investigaciones Científicas-Consejo Superior de Investigaciones Científicas-Fondo Social Europeo fellowship. This work was supported by grants from Ministerio de Educación, Ciencia e Innovación Grant SAF2010-14935, Consolider-Ingenio 2010 Grant CSD07-0017, Junta de Castilla y León (Consejería de Educación, Grant CSI-006A11-2), Fundación Sandra Ibarra, and Kutxa-Fundación Inbiomed.

The existence of leukemia stem cells (LSCs) responsible for tumor maintenance has been firmly established. Therefore, therapeutic targeting of these LSCs may have a profound impact on cancer eradication. The anti-apoptotic protein Bcl2 has been proposed as a therapeutic target, but its role in LSC biology has not been investigated. In order to understand the role of Bcl2 in LSC generation and maintenance, we have taken advantage of our Sca1-BCRABLp210 mouse model of human chronic myeloid leukemia and bcl2 gene-targeted mice. This study provides genetic evidence that the inhibition of Bcl2 is not critical for the generation, selection or maintenance of the tumor initiating and maintaining cells in mice., Fondo Europeo de Desarrollo Regional to I.S.G. group; Ministerio de Ciencia e innovación (SAF2009-08803) I.S.G. group; Junta de Castilla y León (CSI13A08, proyecto Biomedicina 2009–2010); Ministerio de Educación y Cicencia-MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017); National Institutes of Health (2R01 CA109335-04A1); Sandra Ibarra Foundation; Group of Excellence Grant (GR15), Junta de Castilla y Leon. Fondo Europeo de Desarrollo Regional to C.C.; Fondo de Investigaciones Sanitarias (PI080164), Junta de Castilla y León (SA060A09, proyecto Biomedicina 2009–2010); Fundación de Investigación Médica MM.

This work is licensed under a Creative Commons Attribution 3.0 License., The telomerase protein is constitutively activated in malignant cells from many patients with cancer, including the chronic myeloid leukemia (CML), but whether telomerase is essential for the pathogenesis of this disease is not known. Here, we used telomerase deficient mice to determine the requirement for telomerase in CML induced by BCR-ABL in mouse models of CML. Loss of one telomerase allele or complete deletion of telomerase prevented the development of leukemia induced by BCR-ABL. However, BCR-ABL was expressed and active in telomerase heterozygous and null leukemic hematopoietic stem cells. These results demonstrate that telomerase is essential for oncogene-induced reprogramming of hematopoietic stem cells in CML development and validate telomerase and the genes it regulates as targets for therapy in CML., Research in ISG group was partially supported by FEDER and by MICINN (SAF2009-08803 to ISG), by Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), by Sandra Ibarra Foundation, and the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and by Proyecto en Red de Investigación en Celulas Madre Tumorales en Cancer de Mama, supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. All Spanish funding is co-sponsored by the European Union FEDER program. ISG is an API lab of the EuroSyStem project.