scholarly journals A local tumor microenvironment acquired super-enhancer induces an oncogenic driver for efficient growth under oxidative conditions in colorectal carcinoma

2021 ◽  
Author(s):  
Royce Zhou ◽  
Jia Xu ◽  
Tiphaine Martin ◽  
Sait Ozturk ◽  
Alexis Zachem ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
De Novo ◽  
Tumor Biology ◽  
Local Tumor ◽  
Normal Epithelium ◽  
Super Enhancer ◽  
Oncogenic Driver

Abstract Tumors exhibit widespread enhancer landscape reprogramming compared to normal tissue. The etiology is believed to be largely cell-intrinsic in non-hormonal cancers, attributed to such genomic alterations as focal amplification of non-coding regions, aberrant activation of transcription factors, and non-coding mutations creating de novo transcription factor binding sites. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon epithelia, we find divergent epigenetic landscapes between primary CRC tumors and CRC cell lines. We identify a unique super-enhancer signature largely absent in cell culture. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over patient-matched normal epithelium suggesting novel insight into the etiology of enhancer reprogramming in CRC and its downstream relevance to tumor biology. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating its etiology via local tumor microenvironment acquisition. Building on its known role in glucose uptake via SGLT receptors, we demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway using polar metabolomic profiling. We show this activation enables efficient growth under oxidative conditions both in vitro and in vivo, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the biologic significance of epigenomic profiling on patient-matched primary specimens and identify this microenvironment-acquired super-enhancer as an oncogenic driver in the setting of the inflamed tumor.

scholarly journals TAMI-06. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Jenna Minami ◽  
Nicholas Bayley ◽  
Christopher Tse ◽  
Henan Zhu ◽  
Danielle Morrow ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cultured Cells ◽  
Tumor Biology ◽  
Metabolic Reprogramming ◽  
Neoplastic Progression ◽  
Extracellular Milieu ◽  
Metabolic Defects ◽  
Metabolic Heterogeneity

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM, and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.

scholarly journals Diet, Obesity, and Cancer Progression: Are Adipocytes the Link?

2013 ◽  
Vol 6 ◽  
pp. LPI.S10871 ◽  
Author(s):  
Paul Toren ◽  
Benjamin C. Mora ◽  
Vasundara Venkateswaran
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Model Systems ◽  
In Vivo Model ◽  
Diet Induced Obesity ◽  
Breast And Prostate Cancer ◽  
Obesity And Cancer

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

scholarly journals Investigation of Nano-Bio Interactions within a Pancreatic Tumor Microenvironment for the Advancement of Nanomedicine in Cancer Treatment

2021 ◽  
Vol 28 (3) ◽  
pp. 1962-1979
Author(s):  
Abdulaziz Alhussan ◽  
Kyle Bromma ◽  
Ece Pinar Demirci Bozdoğan ◽  
Andrew Metcalfe ◽  
Joanna Karasinska ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Pancreatic Tumor ◽  
Cell Types ◽  
Time Period ◽  
Physical And Chemical ◽  
Pancreatic Origin

Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of only 10%. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy and chemotherapy. However, the interaction of nanoparticles (NPs) with cancer cells and with other major cell types within the pancreatic tumor microenvironment (TME) is yet to be understood. Therefore, our goal is to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined in this study due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles were used as the model NP system due to their biocompatibility and physical and chemical proprieties, and their dynamics were studied both quantitatively and qualitatively in vitro and in vivo. The in vitro studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. Most importantly, they all managed to retain 70–80% of NPs over a 24-h time period. Uptake and retention of NPs within an in vivo environment was also consistent with in vitro results. This study shows the paradigm-changing potential of NPs to combat the disease.

scholarly journals Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases

2021 ◽  
Author(s):  
Maya Kaduri ◽  
Mor Sela ◽  
Shaked Kagan ◽  
Maria Poley ◽  
Hanan Abumanhal-Masarweh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Opioid Analgesic ◽  
Neurite Growth

Neurons within the tumor microenvironment promote cancer progression, thus their local targeting has potential clinical benefits. We designed PEGylated lipid nanoparticles loaded with a non-opioid analgesic, bupivacaine, to target neurons within breast cancer tumors and suppress nerve-to-cancer crosstalk. In vitro, 100-nm nanoparticles were taken up readily by primary neurons, trafficking from the neuronal body and along the axons. We demonstrate that signaling between triple-negative breast cancer cells (4T1) and neurons involves secretion of cytokines stimulating neurite outgrowth. Reciprocally, neurons stimulated 4T1 proliferation, migration and survival through secretion of neurotransmitters. Bupivacaine curbs neurite growth and signaling with cancer cells, inhibiting cancer-cell viability. In vivo, bupivacaine-loaded nanoparticles administered intravenously, suppressed neurons in orthotopic triple-negative breast cancer tumors, inhibiting tumor growth and metastatic dissemination. Overall, our findings suggest that reducing nerve involvement in tumors is important for treating cancer.

scholarly journals Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models

2020 ◽  
Vol 21 (17) ◽  
pp. 6098
Author(s):  
Dina V. Antonova ◽  
Irina V. Alekseenko ◽  
Anastasiia K. Siniushina ◽  
Alexey I. Kuzmich ◽  
Victor V. Pleshkan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transgene Expression ◽  
Close Contact ◽  
Mouse Tumor ◽  
Cancer Associated Fibroblasts

Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo.

scholarly journals ETMM-02. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i14-i14
Author(s):  
Jenna Minami ◽  
Nicholas Bayley ◽  
Christopher Tse ◽  
Henan Zhu ◽  
Danielle Morrow ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cultured Cells ◽  
Tumor Biology ◽  
Metabolic Reprogramming ◽  
Neoplastic Progression ◽  
Extrinsic Factors ◽  
Extracellular Milieu ◽  
Metabolic Heterogeneity

Abstract Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations in response to a multitude of intrinsic and extrinsic factors to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.

Preclinical in vitro and in vivo study of UD-017, a novel highly selective and orally available CDK7 inhibitor, in a variety of cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14086-e14086 ◽  
Author(s):  
Kazuhiro Onuma ◽  
Yasuhiro Aga ◽  
Sayaka Ogi ◽  
Takashi Matsushita ◽  
Hidetoshi Sunamoto ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Xenograft Model ◽  
Antitumor Efficacy ◽  
Expression Levels ◽  
Oncogenic Driver ◽  
Xenograft Models

e14086 Background: Cyclin dependent kinase 7 (CDK7) modulates mRNA transcription and some oncogenes are reported to be sensitive to inhibition of transcription in certain cancer cells. CDK7 inhibitors have been considered as an intriguing approach to treat cancers that depend on transcriptional regulation of their oncogenes. We synthesized a novel highly selective CDK7 inhibitor, UD-017, and found that the compound showed antitumor potency in a variety of cancers in vitro and in vivo. We therefore explored underlying mechanisms especially focusing on an oncogenic driver, c-Myc. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated an antiproliferative activity of UD-017 in over 200 multiple types of cancer cell lines including patients-derived cancer cells. We then investigated the correlation between c-Myc expression levels and an antiproliferative activity of UD-017 in cancer cells. Antitumor efficacy of UD-017 was assessed in multiple types of cancer xenograft models and patients-derived xenograft model. We determined whether an intratumoral c-Myc expression levels correlated with in vivo antitumor efficacy of UD-017 in xenograft models. Results: UD-017 inhibited CDK7 enzyme (IC50= 16 nM) highly selectively among the CDKs (over 300-fold) and almost mono-specifically in a panel of 313 kinases assay. In a cellular antiproliferative panel assay, UD-017 broadly inhibited the proliferation of a variety of cancer cells and c-Myc expression levels showed the good correlation with antiproliferative activity. UD-017 showed favorable PK profile and good oral absorbability and showed the potent antitumor activity in multiple types of cancer xenograft models in mice. In correlation with the PK, UD-017 reduced the intratumoral c-Myc mRNA levels time-dependently after dosing of UD-017 in the colorectal cancer xenograft model. Conclusions: We identified a highly selective and orally available CDK7 inhibitor that showed the broad in vitro and in vivo antitumor activity in a variety of cancers, modulating c-Myc as an oncogenic driver. These data support the rationale for further advancing towards clinical development.

scholarly journals p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage

2021 ◽  
Vol 118 (28) ◽  
pp. e2019822118
Author(s):  
Gen Li ◽  
Jun Wu ◽  
Le Li ◽  
Peng Jiang
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Cancer Cells ◽  
De Novo ◽  
Chemotherapeutic Agents ◽  
Metabolic Reprogramming ◽  
Promote Cell Proliferation ◽  
Metabolic Remodeling

Cancer cells acquire metabolic reprogramming to satisfy their high biogenetic demands, but little is known about how metabolic remodeling enables cancer cells to survive stress associated with genomic instability. Here, we show that the mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) is transcriptionally suppressed by p53, and its up-regulation by p53 inactivation leads to increased folate metabolism, de novo purine synthesis, and tumor growth in vivo and in vitro. Moreover, MTHFD2 unexpectedly promotes nonhomologous end joining in response to DNA damage by forming a complex with PARP3 to enhance its ribosylation, and the introduction of a PARP3-binding but enzymatically inactive MTHFD2 mutant (e.g., D155A) sufficiently prevents DNA damage. Notably, MTHFD2 depletion strongly restrains p53-deficient cell proliferation and sensitizes cells to chemotherapeutic agents, indicating a potential role for MTHFD2 depletion in the treatment of p53-deficient tumors.

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