Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that ...patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate
gene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element-binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure.
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Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination-conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently ...available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy-SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BackgroundLow-dose radiation therapy (LD-RT) in combination with immune checkpoint inhibition (ICI) and/or cell therapy has emerged as an effective mediator to restore immune response in solid ...tumors. However, clinically available biomarkers still fail to effectively predict response and optimize therapy choices. Emerging evidence indicates that nanomechanical alterations of the tumor microenvironment are viable predictors of aggressiveness. We hypothesized that the benefit of LD-RT lies not only in immune activating, but also stromal and tumor nanomechanical remodulation by LD-RT. In this work we have investigated the nanomechanical signature of tumor response to LD-RT combined with immunotherapy, to study nanomechanical drivers of immune infiltration, and how they can be used to optimize cancer diagnosis and orientate therapy choice.MethodsFor the ICI study, 344SQ lung adenocarcinoma tumors resistant to anti-PD1 treatment were established in 129Sv/Ev mice. Mice were treated with a combination of anti-PD1 and anti-CTLA4 antibodies, with and without LD-RT pre-treatment. For the cell therapy study NSG mice were implanted with gastric carcinoma cells. Both low dose and high dose RT were used in combination with cell therapy. Survival and tumor growth were monitored for the various groups. Tumor biopsies were collected at early time points and at the end of each experiment. All tissues were examined via the ARTIDIS platform, to extract a multiparametric nanomechanical signature. The ARTIDIS technology used, combines atomic force microscopy with artificial intelligence proprietary algorithms to provide accurate and reliable characterization of the nanomechanical properties of cancer tissue. We also performed histopathology, multiplex immunofluorescence and Nanostring analyses to characterize stroma remodulation and immune infiltration.ResultsIn both studies we have identified a clear signature of radiation – induced enhanced response to immunotherapy, in the nanomechanical parameter space. In the radiation dataset we achieved almost perfect separation of responders vs non responders, with 90% sensitivity, 99.1% specificity and 96% AUC. In the cell therapy dataset, we can clearly detect the signature of T cell infiltration post radiation, with 92% sensitivity, 100% specificity and 95% accuracy, and this is valid across different doses of T cell infused and for both low and high dose radiation.ConclusionsIn these studies, we demonstrated for the first time a clear nanomechanical signature of LD-RT-mediated response to both immune checkpoint inhibitors and cell therapy in two different mouse models. Our findings open the way to using ARTIDIS nanomechanical signature as a clinically translatable predictor of response to combination radiation and immunotherapies.Ethics ApprovalAll mouse studies were conducted in accordance with guidelines from the M.D. Anderson Institutional Animal Care and Use Committee (IACUC).
Survival rates of patients with metastatic or recurrent cancers have remained virtually unchanged during the past 30 years. This fact makes the need for new therapeutic options even more urgent. An ...attractive option would be to target autophagy, an essential quality control process that degrades toxic aggregates, damaged organelles, and signaling proteins, and acts as a tumor suppressor pathway of tumor initiation. Conversely, other fascinating observations suggest that autophagy supports cancer progression, relapse, metastasis, dormancy and resistance to therapy. This review provides an overview of the contradictory roles that autophagy plays in cancer initiation and progression and discusses the promises and challenges of current strategies that target autophagy for cancer therapy.
Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we ...uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.
VEGF-C et vaisseaux lymphatiques Ndiaye, Papa Diogop; Pagès, Gilles
M.S. Médecine sciences,
02/2019, Volume:
35, Issue:
2
Journal Article
Peer reviewed
Le système lymphatique est formé de vaisseaux qui drainent les liquides interstitiels dans tout l’organisme. La circulation de la lymphe dans les vaisseaux lymphatiques est unidirectionnelle : des ...tissus vers les ganglions lymphatiques puis les veines. Les ganglions sont des filtres mécaniques mais aussi des barrières immunitaires pouvant bloquer la progression de certains pathogènes et des cellules cancéreuses. Cependant, la plupart des études portant sur le système lymphatique et la cancérogenèse mettent en évidence le rôle de ce réseau dans la dissémination métastatique, les cellules tumorales l’empruntant afin d’atteindre d’autres organes. Des travaux récents décrivent pourtant un rôle bénéfique du système lymphatique et du VEGF-C (
vascular endothelial growth factor C
), l’un des principaux facteurs responsables du développement des vaisseaux lymphatiques dans les tumeurs. Dans cette revue, nous illustrerons ce rôle ambivalent et émergeant du VEGF-C et du système lymphatique dans l’agressivité des cancers.
The lymphatic system is made up of vessels that drain interstitial fluids throughout the body. The circulation of the lymph (liquid in the lymphatic system) in the lymphatic vessels is unidirectional: tissues to the lymph nodes and then to the veins. Ganglia are mechanical filters but also immune barriers that can block the progression of certain pathogens as well as cancer cells. However, most studies on the lymphatic system and cancer highlight the role of the lymphatic network in metastatic dissemination as tumor cells use this network to reach other organs. However, recent studies describe a beneficial role of the lymphatic system and of the vascular endothelial growth factor C (VEGF-C) which is one of the main factors responsible for the development of lymphatic vessels in cancer. In this review, we will illustrate this ambivalent and emerging role of VEGF-C and the lymphatic system in cancer aggressiveness.
VEGF-C et vaisseaux lymphatiques Ndiaye, Papa Diogop; Pagès, Gilles
M.S. Médecine sciences,
2019, Volume:
35, Issue:
2
Journal Article
Peer reviewed
Open access
Le système lymphatique est formé de vaisseaux qui drainent les liquides interstitiels dans tout l’organisme. La circulation de la lymphe dans les vaisseaux lymphatiques est unidirectionnelle : des ...tissus vers les ganglions lymphatiques puis les veines. Les ganglions sont des filtres mécaniques mais aussi des barrières immunitaires pouvant bloquer la progression de certains pathogènes et des cellules cancéreuses. Cependant, la plupart des études portant sur le système lymphatique et la cancérogenèse mettent en évidence le rôle de ce réseau dans la dissémination métastatique, les cellules tumorales l’empruntant afin d’atteindre d’autres organes. Des travaux récents décrivent pourtant un rôle bénéfique du système lymphatique et du VEGF-C (vascular endothelial growth factor C), l’un des principaux facteurs responsables du développement des vaisseaux lymphatiques dans les tumeurs. Dans cette revue, nous illustrerons ce rôle ambivalent et émergeant du VEGF-C et du système lymphatique dans l’agressivité des cancers.
The lymphatic system is made up of vessels that drain interstitial fluids throughout the body. The circulation of the lymph (liquid in the lymphatic system) in the lymphatic vessels is unidirectional: tissues to the lymph nodes and then to the veins. Ganglia are mechanical filters but also immune barriers that can block the progression of certain pathogens as well as cancer cells. However, most studies on the lymphatic system and cancer highlight the role of the lymphatic network in metastatic dissemination as tumor cells use this network to reach other organs. However, recent studies describe a beneficial role of the lymphatic system and of the vascular endothelial growth factor C (VEGF-C) which is one of the main factors responsible for the development of lymphatic vessels in cancer. In this review, we will illustrate this ambivalent and emerging role of VEGF-C and the lymphatic system in cancer aggressiveness.
After birth, the intestine undergoes major changes to shift from an immature proliferative state to a functional intestinal barrier. By combining inducible lineage tracing and transcriptomics in ...mouse models, we identify a prodifferentiation PDGFRαHigh intestinal stromal lineage originating from postnatal LTβR+ perivascular stromal progenitors. The genetic blockage of this lineage increased the intestinal stem cell pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRα in the LTBR stromal lineage demonstrates that PDGFRα has a major impact on the lineage fate and function, inducing a transcriptomic switch from prostemness genes, such as Rspo3 and Grem1, to prodifferentiation factors, including BMPs, retinoic acid, and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that the PDGFRα-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function.
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•Intestinal LTBR+PDGFRαHigh stromal lineage develops in the first weeks after birth•The LTBR stromal lineage restrains stemness and promotes intestinal maturation in vivo•PDGFRα orchestrates spatial and molecular specificities of intestinal stromal niches•Development of the LTBR lineage is required for postnatal growth and repair responses
After birth, the intestine undergoes villus and vascular remodeling to fulfill nutrient requirement and enhance intestinal barrier function. Peduto and colleagues show that postnatal PDGFRα-dependent intestinal stromal maturation is required to restrain stemness and promote epithelial differentiation and immunoregulation. Failure of stromal maturation leads to decreased postnatal growth and dysregulated intestinal inflammatory and repair responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The lymphatic system is made up of vessels that drain interstitial fluids throughout the body. The circulation of the lymph (liquid in the lymphatic system) in the lymphatic vessels is ...unidirectional: tissues to the lymph nodes and then to the veins. Ganglia are mechanical filters but also immune barriers that can block the progression of certain pathogens as well as cancer cells. However, most studies on the lymphatic system and cancer highlight the role of the lymphatic network in metastatic dissemination as tumor cells use this network to reach other organs. However, recent studies describe a beneficial role of the lymphatic system and of the vascular endothelial growth factor C (VEGF-C) which is one of the main factors responsible for the development of lymphatic vessels in cancer. In this review, we will illustrate this ambivalent and emerging role of VEGF-C and the lymphatic system in cancer aggressiveness.
Signalphagy Belaid, Amine; Ndiaye, Papa Diogop; Klionsky, Daniel J ...
Autophagy,
10/2013, Volume:
9, Issue:
10
Journal Article
Peer reviewed
Open access
A fundamental issue in cell biology is how the activation of a signaling pathway should lead to the appropriate cell response. Because of their oncogenic potential, the abundance, the duration and ...the localization of key signaling proteins must be carefully controlled. Negative feedback loops that combine transcription and protein-protein interactions are among the strategies by which a cell can turn off signaling. Our recent studies in Cancer Research and Autophagy show that degradation of key active proteins such as RHOA-GTP by constitutive autophagy represents one safeguard mechanism that limits signaling in a spatially and temporally restricted manner for faithful cytokinesis and directed migration. As a result, all autophagy compromises drive cytokinesis failure, aneuploidy, and motility-three processes that directly have an impact upon cancer progression. We therefore propose the term "signalphagy" to indicate a dedicated type of macroautophagy that degrades and thereby maintains the appropriate level of active signaling proteins to achieve tumor suppression.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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