Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with ...development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ERα) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric ...CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4-18 years) with CNS tumors (DIPG n = 3, high-grade glioma n = 5, medulloblastoma n = 2, ependymoma n = 3), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. ...Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.
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•Primary tumors that metastasize have distinct genomic and clinical profiles•TP53, SMARCA4, and CDKN2A alterations influence time to and site of metastasis•Driver mutations are frequently clonal and are shared by primaries and metastases•Alterations private to metastases are rarely actionable and relate to prior treatment
Lengel et al. identify clinicopathological and genomic features of lung adenocarcinoma associated with the development of metastasis, metastatic burden, organotropism, and metastasis-free survival. The findings illustrate that metastatic tumors have increased chromosomal instability, share the majority of driver mutations with the primary tumor, and rarely develop new clinically targetable alterations.
Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic ...progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining ...tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.
Tumor-derived exosomes have documented roles in accelerating the initiation and outgrowth of metastases, as well as in therapy resistance. Little information supports the converse, that exosomes or ...similar vesicles can suppress metastasis. We investigated the NME1 (Nm23-H1) metastasis suppressor as a candidate for metastasis suppression by extracellular vesicles. Exosomes derived from two cancer cell lines (MDA-MB-231T and MDA-MB-435), when transfected with the NME1 (Nm23-H1) metastasis suppressor, secreted exosomes with NME1 as the predominant constituent. These exosomes entered recipient tumor cells, altered their endocytic patterns in agreement with NME1 function, and suppressed in vitro tumor cell motility and migration compared to exosomes from control transfectants. Proteomic analysis of exosomes revealed multiple differentially expressed proteins that could exert biological functions. Therefore, we also prepared and investigated liposomes, empty or containing partially purified rNME1. rNME1 containing liposomes recapitulated the effects of exosomes from NME1 transfectants in vitro. In an experimental lung metastasis assay the median lung metastases per histologic section was 158 using control liposomes and 15 in the rNME1 liposome group, 90.5% lower than the control liposome group (P = 0.016). The data expand the exosome/liposome field to include metastasis suppressive functions and describe a new translational approach to prevent metastasis.
Background
The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the ...combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.
Procedure
We performed a standard 3+3 phase I, open‐label, dose‐escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated.
Results
Twenty‐three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma DIPG n = 8, high‐grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose‐limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single‐agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high‐grade glioma; no partial or complete responses were achieved.
Conclusions
The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.
Breast adipose tissue is an important contributor to the obesity–breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally ...or circulate to distant sites to modulate target cell functions. Here, we find that long‐term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O‐EVs) results in increased proliferation. RNA‐seq analysis of O‐EV‐educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O‐EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O‐EV‐induced cell proliferation. Several miRNAs—miR‐155‐5p, miR‐10a‐3p, and miR‐30a‐3p—which promote mitochondrial respiration and proliferation, are enriched in O‐EVs relative to EVs from lean women. O‐EV‐induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity‐breast cancer link with human breast adipose tissue‐derived EVs causing metabolic reprogramming of breast cancer cells.
Synopsis
Long‐term education of breast cancer cells with extracellular vesicles from breast adipose tissue of women who are overweight or with obesity (O‐EVs) promotes proliferation via Akt/mTOR/P70S6K signaling and increases mitochondrial density and respiration. Several miRNAs enriched in O‐EVs orchestrate these pro‐proliferative effects.
Long‐term education with O‐EVs promote proliferation of breast cancer cells in vitro and in vivo.
Enhanced mitochondrial respiration is essential for the mitogenic effect of O‐EVs.
Increased mitochondrial density occurs as a result of long‐term education with O‐EVs.
miRNAs enriched in O‐EVs—miR‐155‐5p, miR‐10a‐3p, and miR‐30a‐3p—mimic the effects caused by O‐EVs.
Inhibition of the Akt/mTOR/P70S6K pathway can reverse enhanced proliferation and respiration induced by O‐EVs.
Long‐term education of breast cancer cells with extracellular vesicles from breast adipose tissue of women who are overweight or with obesity (O‐EVs) promotes proliferation via Akt/mTOR/P70S6K signaling and increases mitochondrial density and respiration. Several miRNAs enriched in O‐EVs orchestrate these pro‐proliferative effects.
is the most common
mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of
inhibitors in the metastatic setting. We investigated ...disease-free survival (DFS) and tumor genomic features in patients with surgically resected
-mutant lung adenocarcinoma.
Patients who underwent resection of stage I-III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as
wild-type (
), G12C (
), or non-G12C (
). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed.
In total, 604 patients were included: 374
(62%), 95
(16%), and 135
(22%). Three-year DFS was not different between
-mutant and
tumors. However, 3-year DFS was worse in patients with
than
tumors (log-rank
= 0.029).
tumors had more lymphovascular invasion (51% vs. 37%;
= 0.032) and higher tumor mutation burden median (interquartile range), 7.0 (5.3-10.8) vs. 6.1 (3.5-9.7);
= 0.021, compared with
tumors.
mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort.
mutations are associated with worse DFS after complete resection of stage I-III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other
-mutant tumors. We identified a high-risk group for whom
inhibitors may be investigated to improve survival.
While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow-derived cells (BMDC) remains to be determined in neurologic ...tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.
We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b
/GR1
BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).
CD11b
myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b
/GR1
cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b
cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.
We demonstrate that impaired recruitment of CD11b
myeloid cells with a JAK1/2 inhibitor inhibits glioma progression
and prolongs survival in a murine glioma model.
.
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