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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known about the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs, as well as lymphocyte subpopulations, including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with mild COVID-19 in comparison with data obtained from control donors. We have found that 20 hospitalized patients with COVID-19 and no health history of immunosuppression had a significant increase in the number of peripheral monocytic MDSCs (M-MDSC), but a decrease in Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation (r = 0.496) between the number of M-MDSC and the number of activated T cells. Therefore, M-MDSC rather than Tregs may contribute to the immunosuppression observed in patients with COVID-19., S.-M. received support from Junta de Andalucia and University of Seville (PAIDI CTS-151 group), A.P. and J.R.-B. receive support for research from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001), cofinanced by European Development Regional Fund “A way to achieve Europe,” Operative Program Intelligence Growth 2014–2020. LdC-M received support from the Asociación de Mujeres con Cáncer de Mama (AMAMA Sevilla), Fundación Sandra Ibarra, and Asociación de Cáncer de Mama de Brenes.

[Background]: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans after basal cell carcinoma, and its incidence is dramatically rising. CSCC is rarely problematic, but given its high frequency, the absolute number of complicated cases is also high. It is necessary to identify molecular markers in order to recognize those CSCCs with poor prognosis. There is controversy concerning the role of epidermal growth factor receptor (EGFR) as a marker of prognosis in CSCC. In addition, EGFR-targeted therapies have emerged in recent years and a better understanding of the role of EGFR in CSCC may be of help for some patients in predicting prognosis and guiding curative management. [Objectives]: To evaluate the role of EGFR as a prognostic factor in CSCC. [Methods]: We evaluated clinical and histopathological features, including events of poor clinical evolution, in a series of 94 cases of CSCC. We also analysed EGFR expression by immunohistochemistry, fluorescent in situ hybridization and quantitative polymerase chain reaction. [Results]: We detected EGFR in 85 cases (90%), with overexpression in 33 cases (35%), and aberrant EGFR expression in the cytoplasm in 50 cases (53%). EGFR overexpression in the primary tumours was associated with lymph node progression, tumour–nodes–metastasis stage progression and proliferation (Ki-67 staining) in CSCC. EGFR overexpression and poor grade of differentiation were the strongest independent variables defining lymph node metastasis and progression in CSCC in a logistic regression model. [Conclusions]: We demonstrate that EGFR overexpression has prognostic implications associated with lymph node metastasis and progression in CSCC., J.P.‐L. 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, BIO/SA31/15), IBSAL (IBY15/00003), the ‘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’. C.R.‐C. is funded by Q3718001E (2009‐2010) and GRS 612/A/11 (2011‐2012) and ‘the Fundación Eugenio Rodríguez Pascual’. A.C.‐M. was supported by FIS (PI07/0057) and MICINN (PLE2009‐119).

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).

[Background]: Cutaneous squamous cell carcinoma (cSCC) represents the most common form of skin cancer after basal cell carcinoma, and can be both locally invasive and metastatic to distant sites. Growth rate (GR) has been poorly evaluated in cSCC, despite clinical evidence suggesting that GR is an important risk factor in cSCC., [Aim]: To analyse the influence of GR in cSCC prognosis., [Methods]: We retrospectively evaluated GR in a series of 90 cSCCs and tried to correlate GR with prognosis in cSCC., [Results]: We demonstrated that tumours with a GR of > 4 mm/month exhibit a higher risk of nodal progression and a shorter progression time to lymph node metastasis in cSCC than those with GR of < 4 mm/month. As expected, GR correlated with tumour proliferation, as determined by Ki-67 expression., [Conclusions]: We consider a GR of 4 mm/month as the cutoff point that distinguishes between rapid- and slow-progressing tumours and, more importantly, to identify a subset of high-risk cSCCs., JC was partially supported by Gerencia Regional de Salud, Junta de Castilla y León (GRS 1342/A/16) and by the programme INT/M/16/17. JPL was partially supported by FEDER and MICINN (SAF2014–56989-R), Instituto de Salud Carlos III (PIE14/00066), Junta de Castilla y León (BIO/SA31/15, CSI001416), IBSAL (IBY15/00003), the Eugenio Rodríguez Pascual, the Fundación Sandra Ibarra de Solidaridad frente al Cáncer and We can be Heroes Foundation. CR-C is funded by Q3718001E (2009–2010) and GRS 612/A/11 (2011–2012) and the Fundación Eugenio Rodríguez Pascual.

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.

[Background]: Cutaneous squamous cell carcinoma (CSCC) is the second most widespread cancer in humans and its incidence is rising. These tumours can evolve as diseases of poor prognosis, and therefore it is important to identify new markers to better predict its clinical evolution. [Objectives]: We aimed to identify the expression pattern of microRNAs (miRNAs or miRs) at different stages of skin cancer progression in a panel of murine skin cancer cell lines. Owing to the increasing importance of miRNAs in the pathogenesis of cancer, we considered the possibility that miRNAs could help to define the prognosis of CSCC and aimed to evaluate the potential use of miR-203 and miR-205 as biomarkers of prognosis in human tumours. [Methods]: Seventy-nine human primary CSCCs were collected at the University Hospital of Salamanca in Spain. We identified differential miRNA expression patterns at different stages of CSCC progression in a well-established panel of murine skin cancer cell lines, and then selected miR-205 and miR-203 to evaluate their association with the clinical prognosis and evolution of human CSCC. [Results]: miR-205 was expressed in tumours with pathological features recognized as indicators of poor prognosis such as desmoplasia, perineural invasion and infiltrative growth pattern. miR-205 was mainly expressed in undifferentiated areas and in the invasion front, and was associated with both local recurrence and the development of general clinical events of poor evolution. miR-205 expression was an independent variable selected to predict events of poor clinical evolution using the multinomial logistic regression model described in this study. In contrast, miR-203 was mainly expressed in tumours exhibiting the characteristics associated with a good prognosis, was mainly present in well-differentiated zones, and rarely expressed in the invasion front. Therefore, the expression and associations of miR-205 and miR-203 were mostly mutually exclusive. Finally, using a logistic biplot we identified three clusters of patients with differential prognosis based on miR-203 and miR-205 expression, and pathological tumour features. [Conclusions]: miR-205 and miR-203 tended to exhibit mutually exclusive expression patterns in human CSCC. This work highlights the utility of miR-205 and miR-203 as prognostic markers in CSCC., J.P.-L. 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 Leon (SA078A09, CSI034U13, CSI001U16), the ‘Eugenio Rodriguez Pascual’, the ‘Fundacion Inbiomed’ (Instituto Oncologico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa), IBSAL (IBY15/00003) and the ‘Fundacion Sandra Ibarra de Solidaridad frente al Cancer’. C.R.-C. is funded by Q3718001E (2009–2010) y GRS 612/A/11 (2011–2012) and the ‘Fundacion Eugenio Rodriguez Pascual’. A.C.-M. was supported by FIS (PI07/0057) and MICINN (PLE2009-119). J.H.M. 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, U.S. Department of Energy (DE-AC02-05CH11231). J.C. was partially supported by Gerencia Regional de Salud (Junta de Castilla y Leon), GRS 1342 / A / 16.

Trabajo presentado por el doctorando D. Adrián Blanco Gómez, que ha sido realizado en el Instituto de Biología Molecular y Celular del Cáncer de Salamanca, para optar al Título de Doctor por la Universidad de Salamanca., El cáncer de mama es una enfermedad de génesis compleja, con un componente de genética cuantitativa que contribuye a la variabilidad en la susceptibilidad y en la evolución de la enfermedad entre individuos. La distinta respuesta a la quimioterapia entre pacientes con aparentemente la misma enfermedad es el resultado de diferencias en interacciones entre múltiples fenotipos intermedios que participan en el proceso patogénico del cáncer de mama. Muy a menudo, cada uno de estos fenotipos intermedios es a su vez un rasgo complejo que sigue un patrón de herencia de genética cuantiativa. En este trabajo, proponemos que el análisis de estos fenotipos intermedios podría ser una estrategia para explicar parte de la variabilidad en la evolución del cáncer de mama en presencia de quimioterapia y sin ella. Con este objetivo, hemos estudiado diferentes aspectos de la evolución tumoral sin tratamiento, y en respuesta a docetaxel y doxorrubicina, en poblaciones de ratones genéticamente heterogéneas con cáncer de mama HER2 positivo. A continuación, analizamos varios fenotipos de la biología tumoral como la presencia de distintas mutaciones oncogénicas, la longitud telomérica tumoral, la actividad de varias vías de señalización tumorales, la composición celular del tumor y su índice proliferativo. Hemos encontrado numerosas asociaciones entre estos parámetros tumorales y la evolución clínica de la enfermedad que sugieren que estos parámetros tumorales pudieron contribuir a la heterogeneidad en la evolución clínica observada en los ratones estudiados. Finalmente, hemos identificado un número de regiones genómicas donde las diferencias en el genotipo se asociaron con diferencias en la evolución clínica del tumor y en los fenotipos tumorales intermedios estudiados. Todas estas regiones podrían contener determinantes genéticos de la evolución del cáncer de mama sin tratamiento y de la respuesta a la quimioterapia con docetaxel y doxorrubicina., La investigación en nuestro laboratorio ha estado financiada por el Fondo Europeo de Desarrollo Regional (FEDER), el Ministerio de Economía y Competitividad (MICINN) (PLE2009-119, SAF2014-56989-R), el 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) y la “Fundación Sandra Ibarra de Solidaridad frente al Cáncer”. Durante el transcurso de este trabajo, he sido beneficiario de una ayuda destinada a financiar la contratación predoctoral de personal investigador de la Junta de Castilla y León cofinanciada por el Fondo Social Europeo (ORDEN EDU/1084/2012); y de una beca con cargo a la investigación (Contrato Art.83 LOU (GRIFOLS-USAL)) con referencia LBNL y de un contrato para titulado superior financiado por la asociación “We Can Be Heroes”.

[Background]: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and can be both locally invasive and metastatic at distant sites. While research efforts have been made to predict poor outcome of CSCC, there is a lack of knowledge regarding molecular markers. Podoplanin has been associated with poor outcome in several types of cancer including CSCC, but this is controversial and only a few studies have evaluated the prognostic implications of podoplanin in the development of this tumor. [Methods]: We evaluated podoplanin expression in a series of 94 CSCCs, and searched for associations between podoplanin expression and histopathological characteristics and with events of poor clinical evolution of the disease. [Results]: Podoplanin expression was observed in 48.9% of the cases and the expression was considered moderate to intense in 19 of the cases. Moderate/intense podoplanin was associated with infiltrative growth pattern, desmoplasia, lymphovascular invasion, higher risk of nodal progression (NP) and short disease-free survival, specifically with a short latency to NP. [Conclusions]: This article provides evidence supporting the implication of podoplanin expression as a marker of bad prognosis of CSCC., JPL laboratory is partially funded 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, CSI001416), IBSAL (IBY15/00003), 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’, Q3718001E (2009–2010) and GRS 612/A/11 (2011–2012). JC is partially funded by the Gerencia Regional de Salud (Junta de Castilla y León): GRS 1342/A/16.

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).

© 2014 Carnero and Paramio. When PI3K (phosphatidylinositol 3 kinase) is activated by receptor tyrosine kinases, itphosphorylates PIP2 to generate PIP3 and activates the signaling pathway. PTEN (phosphataseand tensin homologue deleted on chromosome 10) dephosphorylates PIP3 to PIP2, and thus, negatively regulates the pathway. AKT (v-akt murine thymoma viral oncogene homolog; Proteinkinase B) is activated downstream of PIP3 and mediates physiological processes. Furthermore, substantial crosstalk exists with other signaling networks at all levels of the PI3K pathway. Because of its diverse array gene mutations and amplifications and also as a consequence of itscentral role in several signal transduction pathways, the PI3K-dependent axis is frequentlyactivated in many tumors and is an attractive therapeutic target. The preclinical testing andanalysis of these novel therapies requires appropriate and well-tailored systems. Mouse models inwhich this pathway has been genetically modified have been essential in understanding therole this pathway plays in the tumorigenesis process. Here, we review cancer mouse models inwhich the PI3K/AKT pathway has been genetically modified., The Amancio Carnero lab is supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis:PI12/00137, RTICC:RD12/00360028), Consejeria de Ciencia e Innovacion (CTS-6844andCTS-1848), and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012).The Jesus M. Paramio lab is funded by the Spanish Ministry of Economy and Competitivity grants SAF2012-34378 and SAF2011-26122-C02-01, Comunidad Autónoma de Madrid grants S2006/BIO-0232 and S2010/BMD-2470 (OncocyclePrograms), MSyC grants ISCIII-RETIC RD06/0020/0029 and RD12/0036/0009, and Fundación Sandra Ibarra.

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.

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence., The research fields of developmental biology and oncology have always been tightly linked, since the times of Rudolf Virchow's cellular theory (>omnis cellula e cellula>) and embryonal rest hypothesis. On the other side, for many years, contemporary cancer research has been mainly focused on the altered controls of proliferation in tumoral cells. This has been reflected in the therapeutic approaches employed in the clinic to treat the patients: with very few exceptions, anti-cancer treatments are targeted at the mechanisms of abnormal tumoral growth. Such therapies, however, are very unspecific, highly toxic and, ultimately, inefficient in most cases. In the last years, a new recognition of the role of aberrant differentiation at the root of cancer has arisen, mainly driven by the coming of age of the >cancer stem cell> (CSC) theory. From this point of view, the comprehensive knowledge of the developmental mechanisms by which normal cells acquire their identity is essential to understand how these controls are deregulated in tumours. New insights into the mechanisms that maintain the molecular boundaries of cell identity have been gained from the study of induced pluripotency, showing that cell fate can be much more susceptible to change than previously thought. Applied to cancer, these findings imply that the oncogenic events that take place in an otherwise healthy cell lead to a reprogramming of the normal cellular fate and establish a new pathologic developmental program. Therefore, cancer reprogramming and cellular plasticity are closely related, since only some cells possess the plasticity required to allow reprogramming to occur, and only some oncogenic events can, in the right plastic cell, induce this change. Here we discuss the latest findings in the fields of cellular plasticity and reprogramming and we consider their consequences for our understanding of cancer development and treatment., Research in C.C. lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI080164), CSIC P.I.E. 200920I055 and 201120E060, from the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and from an institutional grant from the "Fundación Ramón Areces". 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, by Group of Excellence Grant (GR15) from Junta de Castilla y Leon, 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 León. All Spanish funding is co-sponsored by the European Union FEDER program. ISG is an API lab of the EuroSyStem project. ECS is the recipient of a JAE-predoc Fellowship from CSIC and a "Residencia de Estudiantes" Fellowship. The authors declare no conflict of interest.

This article is licensed under a Creative Commons Attribution-NoncommercialNo DerivativeWorks 3.0 Licence., Understanding the cellular origin of cancer can help to improve disease prevention and therapeutics. Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of Maf oncogenes (associated to human plasma cell neoplasias) is targeted to mouse B cells, the resulting animals fail to reproduce the human disease. Here, to explore early cellular changes that might take place in the development of plasma cell neoplasias, we engineered transgenic mice to express MafB in haematopoietic stem/progenitor cells (HS/PCs). Unexpectedly, we show that plasma cell neoplasias arise in the MafB-transgenic mice. Beyond their clinical resemblance to human disease, these neoplasias highly express genes that are known to be upregulated in human multiple myeloma. Moreover, gene expression profiling revealed that MafB-expressing HS/PCs were more similar to B cells and tumour plasma cells than to any other subset, including wild-type HS/PCs. Consistent with this, genome-scale DNA methylation profiling revealed that MafB imposes an epigenetic program in HS/PCs, and that this program is preserved in mature B cells of MafB-transgenic mice, demonstrating a novel molecular mechanism involved in tumour initiation. Our findings suggest that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias. © 2012 European Molecular Biology Organization | All Rights Reserved., MICINN (SAF2009-08803 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; Junta de Castilla y Leon; ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program); Obra Social Kutxa; Conserjería de Sanidad de la Junta de Castilla y Leon

Review.-- Creative Commons Attribution Non-Commercial No-Derivatives License., Cancer is the subject of intense research around the world, but many questions about how the disease works remain unanswered. How exactly does cancer start and how do tumours grow? In fact, at present there are ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. However, many of the new anticancer agents are predicted to show clinical benefit in only small subpopulations of patients. The cancer stem cell model could explain not only how some cancers work but also why patients suffer relapses, providing a good opportunity to gain insight into the reasons why agents work or, more commonly, don't work, before going into a clinical trial., 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 to ISG), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), by Sandra Ibarra Foundation, by Group of Excellence Grant (GR15) from Junta de Castilla y Leon, 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. J. Pérez-Losada is partially supported by FEDER and MICINN (PLE2009-119), FIS (PI10/00328), Fundación Eugenio Rodríguez Pascual, Fundación Inbiomed, Instituto Oncológico, Obra Social de la Caja Guipozkoa-San Sebastián (Kutxa). A. Castellanos-Martín is supported by FEDER and MICINN (PLE2009-119).

Notch receptors are master regulators of many aspects of development and tissue renewal in metazoans. Notch1 activation is essential for T-cell specification of bone marrow-derived multipotent progenitors that seed the thymus, and for proliferation and further progression of early thymocytes along the T-cell lineage. Deregulated activation of Notch1 significantly contributes to the generation of T-cell acute lymphoblastic leukaemia (T-ALL). In addition to Notch1 signals, survival and proliferation signals provided by the IL-7 receptor (IL-7R) are also required during thymopoiesis. Our understanding of the molecular mechanisms controlling stage-specific survival and proliferation signals provided by Notch1 and IL-7R has recently been improved by the discovery that the IL-7R is a transcriptional target of Notch1. Thus, Notch1 controls T-cell development, in part by regulating the stage- and lineage-specific expression of IL-7R. The finding that induction of IL-7R expression downstream of Notch1 also occurs in T-ALL highlights the important contribution that deregulated IL-7R expression and function may have in this pathology. Confirming this notion, oncogenic IL7R gain-of-function mutations have recently been identified in childhood T-ALL. Here we discuss the fundamental role of Notch1 and IL-7R signalling pathways in physiological and pathological T-cell development in mice and men, highlighting their close molecular underpinnings. © 2012 Springer-Verlag Berlin Heidelberg., Plan Nacional (SAF2010-15106) Subprograma de Fomento de la Cooperación Científica Internacional (PLE-2009-0110); Fundación Sandra Ibarra; Instituto de Salud Carlos III (RD06/0014/1012); Fundación Ramón Areces; Ministerio de Ciencia e Innovación (MICINN)