Spinophilin, a new tumor suppressor at 17q21

The scaffold protein spinophilin is a regulatory subunit of phosphatase 1a (PP1a) located at 17q21.33. This region is frequently associated with microsatellite instability and LOH and contains a relatively high density of known tumor suppressor genes (such as BRCA1), putative tumor suppressor genes, and several unidentified candidate tumor suppressor genes located distal to BRCA1.Peer reviewe

The PTEN/PI3K/AKT Pathway in vivo, cancer mouse models

© 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.Peer Reviewe

Dr. Jekyll and Mr. Hyde: MAP17’s up-regulation, a crosspoint in cancer and inflammatory diseases

Inflammation is a common defensive response that is activated after different harmful stimuli. This chronic, or pathological, inflammation is also one of the causes of neoplastic transformation and cancer development. MAP17 is a small protein localized to membranes with a restricted pattern of expression in adult tissues. However, its expression is common in destabilized cells, as it is overexpressed both in inflammatory diseases and in cancer. MAP17 is overexpressed in most, if not all, carcinomas and in many tumors of mesenchymal origin, and correlates with higher grade and poorly differentiated tumors. This overexpression drives deep changes in cell homeostasis including increased oxidative stress, deregulation of signaling pathways and increased growth rates. Importantly, MAP17 is associated in tumors with inflammatory cells infiltration, not only in cancer but in various inflammatory diseases such as Barret’s esophagus, lupus, Crohn’s, psoriasis and COPD. Furthermore, MAP17 also modifies the expression of genes connected to inflammation, showing a clear induction of the inflammatory profile. Since MAP17 appears highly correlated with the infiltration of inflammatory cells in cancer, is MAP17 overexpression an important cellular event connecting tumorigenesis and inflammation?España Ministerio de Economía y Competitividad Fis: PI15/00045España Consejeria de Ciencia e Innovacion CTS-1848España Consejeria de Salud de la Junta de Andalucía PI-0096-201

NUMB and NUMBL differences in gene regulation

NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network. We have also found differences in gene expression due to NUMB or NUMBL downregulation. These differences in gene regulation extend to pathways, such as WNT or Hedgehog. In addition to these differences, the downregulation of either gene triggers a cancer stem cell-like related phenotype. These results show the importance of both genes as an intersection with different effects over cancer stem cell signaling pathways.España MINECO I+D+I 2013-2016ISCIII (Fis: PI15/00045)CIBER de Cáncer (CB16/12/00275

The cargo protein MAP17 (PDZK1IP1) regulates the immune microenvironment

Inflammation is a complex defensive response activated after various harmful stimuli allowing the clearance of damaged cells and initiating healing and regenerative processes. Chronic, or pathological, inflammation is also one of the causes of neoplastic transformation and cancer development. MAP17 is a cargo protein that transports membrane proteins from the endoplasmic reticulum. Therefore, its overexpression may be linked to an excess of membrane proteins that may be recognized as an unwanted signal, triggering local inflammation. Therefore, we analyzed whether its overexpression is related to an inflammatory phenotype. In this work, we found a correlation between MAP17 expression and inflammatory phenotype in tumors and in other inflammatory diseases such as Crohn's disease, Barrett's esophagus, COPD or psoriasis. MAP17 expression correlated also with the markers of inflammation HLAs, BBS10, HERC2, ADNP and PYCARD. Furthermore, we found that MAP17 expression directly regulates NFAT2 and IL-6 activation, inducing the differentiation of monocytes to dendritic cells and suggesting a causal role of MAP17 in inflammation. Immunohistochemistry confirms local inflammation, mainly CD45+ cells, at the site of expression of MAP17, at least in tumors, Crohn's and psoriasis. Therefore, our data indicates that the overexpression of the protein MAP17 plays important role in diseases involving chronic inflammation.España Ministerio de Economía y Competitividad FIS: PI15/00045Junta de Andalucía PI-0096-201

Role of Mitochondria in Cancer Stem Cell Resistance

Cancer stem cells (CSC) are associated with the mechanisms of chemoresistance to different cytotoxic drugs or radiotherapy, as well as with tumor relapse and a poor prognosis. Various studies have shown that mitochondria play a central role in these processes because of the ability of this organelle to modify cell metabolism, allowing survival and avoiding apoptosis clearance of cancer cells. Thus, the whole mitochondrial cycle, from its biogenesis to its death, either by mitophagy or by apoptosis, can be targeted by different drugs to reduce mitochondrial fitness, allowing for a restored or increased sensitivity to chemotherapeutic drugs. Once mitochondrial misbalance is induced by a specific drug in any of the processes of mitochondrial metabolism, two elements are commonly boosted: an increment in reactive nitrogen/oxygen species and, subsequently, activation of the intrinsic apoptotic pathway.Ministerio de Ciencia, Innovación y Universidades RTI2018-097455-B-I00, RED2018-102723-TJunta de Andalucía PI-0397-2017, P18-RT-250

Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer

Estévez-García, Purificación et al.Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip® HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan®Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs 13%, p = 0.024), progression-free survival (61% vs 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice.This work was supported by a grant of the Fundacion Mutua Madrileña (FMM) (P0497/2006) and from the Fondo de Investigación Sanitaria/Instituto de Salud Carlos III Spanish Cancer Networks RTICC (R12/0036/0008 and R12/0036/0028). RGC is funded by Fondo de Investigación Sanitaria (PI10/02164, PI13/02295), Servicio Andaluz de Salud (PI-0259/2007) and RTICC (R12/0036/0028). PEG is funded by a Rio Hortega grant (09/00207) from the Instituto de Salud Carlos III (ISCiii), Ministerio de Sanidad, Spain and Consejeria de Salud of the Junta de Andalucia (PI-0135–2010). SMP is funded by Fondo de Investigación Sanitaria (CD1100153) and Fundación Científica de la Asociación Española Contra el Cáncer. MDP is funded by Fondo de Investigación Sanitaria (CD0900148). LPA is funded by the ISCiii (PI081156, PI1102688, RTICC R12/0036/0008), Consejería de Innovacion, Ciencia y Empresa – Junta de Andalucia (P08-CVI-04090) and the 75th Anniversary Roche Spain Fellowship. AC is funded by the Spanish Ministry of Science and Innovation (SAF2009–08605), FIS (PI12/00137), Consejeria de Ciencia e Innovacion and Consejeria de Salud of the Junta de Andalucia (CTS-6844 and PI-0142), and by Fundacion Oncologica FERO, supported by Fundació Josep Botet.Peer Reviewe

Synthesis, reactivity studies, and cytotoxicity of two trans-Iodidoplatinum(II) complexes. Does photoactivation work?

trans-Platinum complexes have been the landmark in unconventional drugs prompting the development of innovative structures that might exhibit chemical and biological profiles different to cisplatin. Iodido complexes signaled a new turning point in the platinum drug design field when their cytotoxicity was reevaluated and reported. In this new study, we have synthesized and evaluated diodidoplatinum complexes trans-[PtI2(amine)(pyridine)] bearing aliphatic amines (isopropylamine and methylamine) and pyridines in trans configuration. X-ray diffraction data support the structural characterization. Their cytotoxicity has been evaluated in tumor cell lines such as SAOS-2, A375, T-47D, and HCT116. Moreover, we report their solution behavior and reactivity with biological models. Ultraviolet-a (UVA) irradiation induces an increase in their reactivity towards model nucleobase 5′-GMP in early stages, and promotes the release of the pyridine ligand (spectator ligand) at longer reaction times. Density Functional calculations have been performed and the results are compared with our previous studies with other iodido derivatives.MINECO CTQ-2015-68779

Cellular Senescence as a Target in Cancer Control

Somatic cells show a spontaneous decline in growth rate in continuous culture. This is not related to elapsed time but to an increasing number of population doublings, eventually terminating in a quiescent but viable state termed replicative senescence. These cells are commonly multinucleated and do not respond to mitogens or apoptotic stimuli. Cells displaying characteristics of senescent cells can also be observed in response to other stimuli, such as oncogenic stress, DNA damage, or cytotoxic drugs and have been reported to be found in vivo. Most tumors show unlimited replicative potential, leading to the hypothesis that cellular senescence is a natural antitumor program. Recent findings suggest that cellular senescence is a natural mechanism to prevent undesired oncogenic stress in somatic cells that has been lost in malignant tumors. Given that the ultimate goal of cancer research is to find the definitive cure for as many tumor types as possible, exploration of cellular senescence to drive towards antitumor therapies may decisively influence the outcome of new drugs. In the present paper, we will review the potential of cellular senescence to be used as target for anticancer therapy

The cargo protein MAP17 (PDZK1IP1) regulates the cancer stem cell pool activating the Notch pathway by abducting NUMB

Purpose: Cancer stem cells (CSC) are self-renewing tumor cells, with the ability to generate diverse differentiated tumor cell subpopulations. They differ from normal stem cells in the deregulation of the mechanisms that normally control stem cell physiology. CSCs are the origin of metastasis and highly resistant to therapy. Therefore, the understanding of the CSC origin and deregulated pathways is important for tumor control. Experimental Design: We have included experiments in vitro, in cell lines and tumors of different origins. We have used patient-derived xenografts (PDX) and public transcriptomic databases of human tumors. Results: MAP17 (PDZKIP1), a small cargo protein overexpressed in tumors, interacts with NUMB through the PDZ-binding domain activating the Notch pathway, leading to an increase in stem cell factors and cancer-initiating–like cells. Identical behavior was mimicked by inhibiting NUMB. Conversely, MAP17 downregulation in a tumor cell line constitutively expressing this gene led to Notch pathway inactivation and a marked reduction of stemness. In PDX models, MAP17 levels directly correlated with tumorsphere formation capability. Finally, in human colon, breast, or lung there is a strong correlation of MAP17 expression with a signature of Notch and stem cell genes. Conclusions: MAP17 overexpression activates Notch pathway by sequestering NUMB. High levels of MAP17 correlated with tumorsphere formation and Notch and Stem gene transcription. Its direct modification causes direct alteration of tumorsphere number and Notch and Stem pathway transcription. This defines a new mechanism of Notch pathway activation and Stem cell pool increase that may be active in a large percentage of tumors.Ministerio de Economía y Competitividad PI15/00045, CTS-1848Junta de Andalucía PI-00-96-2014, PI-0306-201