tbuckley/cabot-search huggingface dataset:
Abstract 5089: The origin and contribution of the tumor stroma in colorectal cancer
Authors: Hiroki Kobayashi, Krystyna A. Gieniec, Tamsin RM Lannagan, Tongtong Wang, Samuel Asfaha, Yoku Hayakawa, Simon J. Leedham, Nicholas Arpaia, Siddhartha Mukherjee, Timothy C. Wang, Atsushi Enomoto, Masahide Takahashi, Susan L. Woods, Daniel L. Worthley
Journal: Cancer Research (2020)

Abstract Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment and play a critical part in cancer progression. However, the precise origin of the tumor stroma remains unknown, making it challenging to effectively target the cancer mesenchyme. Here, employing 4 different genetic fate mapping mouse models and a bone marrow transplantation model in combination with BrdU labeling, we uncovered a key contributor to the tumor stroma in colorectal cancer (CRC). We found that approximately half of a-smooth muscle actin (aSMA)+ CAFs emerge through proliferation in an AOM/DSS mouse model of CRC. Lineage tracing experiments revealed that intestinal leptin receptor (Lepr)-lineage stromal cells expanded and contributed to 75% of the aSMA+ proliferating CAFs. Notably, no aSMA+ CAFs in the tumor were derived from Krt19-lineage epithelial cells or bone marrow-transplanted cells, indicating no involvement of epithelial-mesenchymal transition and bone marrow recruitment to the tumor in this model. Moreover, RNA-sequencing of FACS-purified CRC mesenchymal cells identified MCAM (also known as CD146) as a CRC stroma-specific marker, which is expressed by Lepr-lineage cells. Analysis of human CRC samples showed that high MCAM expression was associated with a mesenchymal subtype of CRC and was independently prognostic of poor overall survival. Our data identify Lepr-lineage cells as a major source of the tumor stroma in CRC and suggest that targeting MCAM+ cells may serve as a novel therapeutic approach to restrain CRC progression. Citation Format: Hiroki Kobayashi, Krystyna A. Gieniec, Tamsin RM Lannagan, Tongtong Wang, Samuel Asfaha, Yoku Hayakawa, Simon J. Leedham, Nicholas Arpaia, Siddhartha Mukherjee, Timothy C. Wang, Atsushi Enomoto, Masahide Takahashi, Susan L. Woods, Daniel L. Worthley. The origin and contribution of the tumor stroma in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5089.
Abstract 4790: An <i>in situ</i> hybridization assay reveals high mitochondrial DNA copy number in stem cell/proliferative cell compartments
Authors: JIAYU CHEN, Qizhi Zheng, Lauren B. Peiffer, Jessica L. Hicks, Michael C. Haffner, Avi Z. Rosenberg, Moshe Levi, Xiaoxin Wang, Busra Ozbek, Srinivasan Yegnasubramanian, Angelo M. De Marzo
Journal: Cancer Research (2020)

Abstract Mitochondria are critical regulators of energy production, metabolism and cell death. Warburg observed that in the presence of oxygen, many cancer cells take up abundant amounts of glucose, and excrete the carbon mainly as lactate. Warburg postulated that this aerobic glycolysis was essential and universal in cancer, and was caused by mitochondrial dysfunction. Yet, more recent findings suggest that aerobic glycolysis also occurs in rapidly dividing normal cells to support anabolic reactions needed for cell growth and replication. Furthermore, a number of metabolites generated by the tricarboxylic acid cycle and the electron transport chain are also used for macromolecular synthesis in proliferating cancer and normal cells. This suggests that an increase in mitochondrial activity, especially those functions related to anabolic metabolism, may be required for cancer development and progression. One mechanism to increase mitochondrial function is through mitochondrial biogenesis, which is partly regulated by regulating mitochondrial DNA (mtDNA) copy number. Alterations in mtDNA sequence and copy number have been implicated in various cancers. Since most prior measurements of mtDNA copy number have been performed using homogenates of complex tissues composed of multiple cell types, very little is known about cell type-specific mtDNA copy number heterogeneity. Here, we validated a quantitative in situ hybridization approach to study mtDNA levels at the single cell level in tissue sections. In hierarchically organized self-renewing tissues, higher levels of mtDNA were observed in stem/proliferative compartments than in differentiated compartments. Also, we found zonal heterogeneity of mtDNA levels in the liver that mirrors the known oxygen tension gradient. In the kidney, we observed markedly lower mtDNA levels in glomeruli and the collecting ducts compared to cortical proximal and distal tubules. This work provides visualization of mtDNA copy number in distinct cell populations in situ for the first time across normal mammalian tissues, and can serve as a foundation for quantifying cell type-specific mtDNA copy number dynamics in any relevant diseases, especially in cancers and their precursor lesions. Citation Format: JIAYU CHEN, Qizhi Zheng, Lauren B. Peiffer, Jessica L. Hicks, Michael C. Haffner, Avi Z. Rosenberg, Moshe Levi, Xiaoxin Wang, Busra Ozbek, Srinivasan Yegnasubramanian, Angelo M. De Marzo. An in situ hybridization assay reveals high mitochondrial DNA copy number in stem cell/proliferative cell compartments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4790.
Facial Masking for Covid-19 — Potential for “Variolation” as We Await a Vaccine
Authors: Monica Gandhi, George W. Rutherford
Journal: New England Journal of Medicine (2020)

Facial Masking for Covid-19 Increasing the proportion of SARS-CoV-2 infections that are asymptomatic with the simple public health measure of universal masking might help make the infection less de...
Impact of sedation on the Performance Indicator of Colonic Intubation
Authors: Karlijn J. Nass, Sascha C. van Doorn, Manon van der Vlugt, Paul Fockens, Evelien Dekker
Journal: Endoscopy (2020)

Abstract Background The Performance Indicator of Colonic Intubation (PICI) is a new measure of high-quality colonic intubation. Adequate PICI was defined as cecal intubation without significant discomfort and use of minimal sedation. This study assessed achievement of PICI within the Dutch colorectal cancer (CRC) screening program, and determined the association between PICI and adenoma detection rate (ADR). PICI achievement when using the Dutch median midazolam dose was also assessed. Methods This retrospective study was conducted within the Dutch fecal immunochemical test-based CRC screening program. Colonoscopy and pathology data were prospectively collected in a national database. Data between January 2016 through January 2018 were analyzed. Adequate PICI was defined as successful cecal intubation, Gloucester Comfort Scale (GCS) of 1 – 3, and use of ≤ 2.5 mg midazolam. Results 107 328 colonoscopies were performed during the study period. Adequate PICI was achieved in 49 500 colonoscopies (46.1 %). In colonoscopies with inadequate PICI, inadequacy was due to higher sedation doses in 87.8 %. Adequate PICI was associated with higher ADR (odds ratio 1.16, 95 % confidence interval 1.12 – 1.20). When using a cutoff of 5 mg midazolam, median dose in this Dutch population, adequate PICI was achieved in 95 410 colonoscopies (88.9 %). Conclusion PICI appeared to be heavily dependent on sedation practice. Because of wide variation in sedation practice between individual endoscopists and countries, the benefit of PICI as a quality indicator is limited.
Abstract 4868: <i>In vitro</i> and <i>in cellulo</i> mass spectrometry study of TEAD1 palmitoylation
Authors: Armelle Buzy, Olivier Guichard, Jean-Luc Zacchayus, Olivier Venier, Olivier Courtin, Iris Valtingojer, Laurent Debussche, Vincent Mikol, Jean-Claude Guillemot
Journal: Cancer Research (2020)

Abstract The HIPPO pathway plays an important role in cancer progression and one of its essential components are the transcription factor proteins from the TEAD family. The TEAD family consists of 4 different family members (TEAD1-TEAD4) who modulate gene expression through the interaction with co-activator proteins such as YAP1 and TAZ. Recent studies have shown that TEADs are partially palmitoylated. Activity and stability of TEAD proteins are regulated by this modification. Here, we attempt to better understand the palmitoylation status of TEAD proteins in cells. In a first step, we have developed LC/MS/MS-based assays for the detection of palmitoylated TEAD peptides using recombinant TEAD1 protein. Subsequently, we have set out to analyze endogenous TEAD proteins using YAP1 activated malignant mesothelioma H2052 tumor cells. H2052 tumor cells express preferentially TEAD1 protein. TEAD1 was immunoprecipitated from H2052 tumor cells and subjected to peptidic digest and LC/MS/MS analysis. Peptide mapping permitted to confirm the expected site of palmitoylation (cysteine 359 of TEAD1). In addition, novel sites of both palmitoylation and myristoylation were detected on the lysine residue 336 of TEAD1. While these hydrophobic peptides could not be recovered after in-gel digestion of immunoprecipitation enriched TEAD1 of H2052 cells, digestion performed directly on immunoprecipitation beads allowed us to recover those peptides and hence to confirm the existence of TEAD lysine-myristoylation and lysine-palmitoylation in cells. In this study, we show the development of an MS-based strategy to characterize post translational modifications directly on endogenous TEAD1 proteins present in H2052 tumor cells. Citation Format: Armelle Buzy, Olivier Guichard, Jean-Luc Zacchayus, Olivier Venier, Olivier Courtin, Iris Valtingojer, Laurent Debussche, Vincent Mikol, Jean-Claude Guillemot. In vitro and in cellulo mass spectrometry study of TEAD1 palmitoylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4868.
Abstract 3737: Mutant isocitrate dehydrogenase driven metabolic reprogramming results in therapeutic vulnerability to lactate dehydrogenase inhibition
Authors: Aiwei Bi, Jun Xu, Nan Jin, Xiaojing Lan, Shuai Tang, Matthew Shou, Jia Liu, Jian Ding, Meiyu Geng, Shuhai Lin, Min Huang
Journal: Cancer Research (2020)

Abstract Mutant isocitrate dehydrogenase (mIDH), with a gain-of-function in the production of an oncometabolite (R)-2-hydroxyglutarate (2-HG), is considered as a promising target for cancers carrying IDH mutations. IDH1 mutations, typically involving an amino acid substitution in the active site of the enzyme in codon 132, have been identified in a broad spectrum of solid tumors. The massive production of 2-HG remodels the metabolic network in cancer cells and results in epigenetic alterations facilitating malignant phenotypes. Of note, while the pharmacological inhibition of mIDH1 effectively leads to the remarkable reduction in the intracellular 2-HG level, it seems not associated with the sufficient suppression of solid tumor growth. We hence asked whether it is possible to identify extra metabolic vulnerability in IDH1 mutant tumors. To this end, we performed 13C isotope tracing analysis of glucose and glutamine, two major nutrient supply for 2-HG production, in solid tumor cell lines including HT1080 cells with spontaneous IDH1 mutation and IDH1 mutant glioma cell lines expressing mIDH1. [U-13C6]-glucose tracking enabled us to discover that IDH1 mutated tumors exhibit increased glycolysis and decreased tricarboxylic acid (TCA) metabolism, which can be reversed by mIDH1 inhibition. Meanwhile, cell mitochondrial stress test indicated decreased oxygen consumption rate (OCR) compared with the wildtype counterpart. These data suggest that 2-HG production paralyzes TCA metabolism and subsequent oxidative phosphorylation but enhances aerobic glycolysis, thus reprogramming tumor cells prone to Warburg effect. In line with this hypothesis, lactate dehydrogenase (LDH) inhibition that shut down lactate production increased 2-HG levels in IDH1 mutant cells. Further, LDH inhibition obtained the improved response in IDH1 mutant tumors while combined inhibition of mIDH1 abolished this effect. Together, we discovered that mutant IDH1 impaired TCA cycle by production of millimolar level 2HG which may lead to more dependency on glycolysis. Citation Format: Aiwei Bi, Jun Xu, Nan Jin, Xiaojing Lan, Shuai Tang, Matthew Shou, Jia Liu, Jian Ding, Meiyu Geng, Shuhai Lin, Min Huang. Mutant isocitrate dehydrogenase driven metabolic reprogramming results in therapeutic vulnerability to lactate dehydrogenase inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3737.
Abstract 1225: Co-inhibition of autophagy and MAPK signaling in RAS-driven cancers
Authors: Mona Foth, Conan Kinsey, Sophia Schuman, Benjamin Battistone, Emilio Cortes Sanchez, David Kircher, Bryan Welm, Sheri Holmen, Martin McMahon
Journal: Cancer Research (2020)

Abstract RASis mutated in a number of cancers, including KRAS-driven colorectal and pancreatic cancer, HRAS-driven bladder cancer, and NRAS-driven melanoma, all of which result in downstream activation of the RAF&amp;gt;MEK&amp;gt;ERK (MAPK) and PI3K&amp;gt;AKT signaling pathways. Most RAS GTPases cannot be targeted directly, and strategies blocking both MAPK and PI3K signaling simultaneously are limited by high toxicity and compensatory signaling mechanisms. Interestingly, oncogene-activated MAPK or PI3K signaling pathways are reasonably well described orchestrators of metabolic transformation through multiple pathways. Our lab has recently shown that autophagy,a conserved metabolic process of self-digestion that recycles intracellular components, is increased in KRAS-driven pancreatic ductal adenocarcinoma (PDA) upon MAPK pathway inhibition. We further showed that co-inhibition of autophagy and MEK1/2, a MAPK component, leads to tumor regression of patient-derived PDA xenografts in mice. Our proposed combination therapy has recently been translated into a phase I/II clinical trial for PDA patients with advanced disease. Our most recent data show that inhibition of RAS&amp;gt;RAF&amp;gt;MEK&amp;gt;ERK signaling also results in induction of autophagy in other RAS-driven cancers, including KRAS-driven colorectal cancer, HRAS-driven bladder cancer and NRAS-driven melanoma. Furthermore, ourin vivodata demonstrate a robust regression of tumors upon combined inhibition of autophagy and MEK1/2 in engrafted KRAS-driven colorectal cancer cells xenografted in mice. Patient data from two KRAS-driven colorectal cancer patients, who were recently treated off-label, indicated clinical responses to the combination treatment co-targeting autophagy and MEK1/2. Altogether, these data suggest that co-inhibition of autophagy and oncogenic signaling may represent a potential new treatment strategy for multiple RAS-driven cancer types. Future experiments aim for a better mechanistic understanding of the combination treatment co-targeting autophagy and oncogenic signaling, with the objective to propose novel therapeutic strategies for cancer patients with RASmutations. Citation Format: Mona Foth, Conan Kinsey, Sophia Schuman, Benjamin Battistone, Emilio Cortes Sanchez, David Kircher, Bryan Welm, Sheri Holmen, Martin McMahon. Co-inhibition of autophagy and MAPK signaling in RAS-driven cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1225.
Abstract 942: HPK1, hematopoietic progenitor kinase 1, is a promising therapeutic target for cancer immunotherapy
Authors: David Ciccone, Jennifer Rocnik, Vad Lazari, Ian Linney, Michael Briggs, Alan Collis, Christine Loh, Mark Ashwell, John Montana, Peter Tummino, Neelu Kaila
Journal: Cancer Research (2020)

Abstract Introduction: HPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in regulating signal transduction cascades in cells of hematopoietic lineage. Recent data from HPK1 knockout animals and kinase-inactive knock-in animals underscores the role of HPK1 in negatively regulating lymphocyte activation. This negative-feedback role of HPK1 downstream of lymphocyte activation and function combined with its restricted expression in cells of hematopoietic origin make it an ideal drug target for enhancing anti-tumor immunity. Experimental Procedures: A structure-based drug design approach was used to identify potent and selective inhibitors of HPK1. Various biochemical and biophysical assays, as well as a primary in vitro T cell activation assay, were utilized for multiple rounds of structure-activity relationship (SAR) studies. In vivo target engagement and pharmacodynamic data were generated using an anti-CD3 mouse model. Results: In vitro, HPK1 small molecule inhibition resulted in enhanced IL-2 production in primary mouse T cells and in purified human T cells stimulated with a suboptimal dose of anti-CD3/anti-CD28. Increased selectivity of HPK1 inhibitors relative to T cell-specific kinases and within the MAP4K family was responsible for further enhancing the IL-2 response in activated T cells. In vivo, qd oral dosing of an HPK1 inhibitor completely abrogated phosphorylated SLP-76, induced by administration of anti-CD3. Furthermore, inflammatory cytokine production was enhanced in vivo upon HPK1 inhibition. Conclusion: Pharmacological blockade of HPK1 kinase activity represents a novel and powerful immunomodulatory approach for anti-tumor immunity. Citation Format: David Ciccone, Jennifer Rocnik, Vad Lazari, Ian Linney, Michael Briggs, Alan Collis, Christine Loh, Mark Ashwell, John Montana, Peter Tummino, Neelu Kaila. HPK1, hematopoietic progenitor kinase 1, is a promising therapeutic target for cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 942.
Abstract 5452: Neuroendocrine negative RB1 WT SCLC and LCNEC
Authors: Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher
Journal: Cancer Research (2020)

Abstract Background: Based on genomics data generated in last few years about 15% of tumors diagnosed as large cell neuroendocrine carcinomas (LCNEC) are actually neuroendocrine negative. Interestingly, approximately similar percentage of small cell lung cancers (SCLC) are also neuroendocrine negative, historically known as SCLC variant and are enriched for RB1 WT tumors. Here we compare the morphological, genomic and other features of neuroendocrine negative RB1 WT SCLC and LCNEC. Methods: To comprehensively compare neuroendocrine RB1 WT SCLC and LCNEC, we examined morphological, genomic and other features of these rare lung cancer subtypes using publicly available data. From a genomics perspective, we payed special attention to key oncogenic genetic alterations and expression pattern of transcription factors known to play critical role in SCLC and LCNEC. Results/Conclusions: The expression pattern of transcription factors ASCL1, POU2F3, NEUROD1, YAP1 in LCNEC has number of similarities to expression pattern of these transcription factors in SCLC. Neuroendocrine negative/low RB1 WT SCLC and neuroendocrine negative/low, RB1 WT, KEAP1 WT, STK11 WT LCNEC have similar genomics and morphological characteristics and might be in fact the same entity. Based on differences in distribution of different lung cell types at different anatomical locations such as: peripheral, midzone or central, collecting information on lung tumor location along with genomic information and neuroendocrine markers staining could be important for better understanding of rare lung tumor subtypes. Clinical trial NCT04010357 is going to investigate efficacy of CDK4/6 inhibitor abemaciclib in RB1WT SCLC. Based on our observations patients with neuroendocrine negative/low RB1 WT, KEAP1 WT, STK11 WT LCNEC subtype might be also candidates for clinical trial-based treatment with CDK4/6 inhibitors. Citation Format: Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher. Neuroendocrine negative RB1 WT SCLC and LCNEC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5452.
Abstract 6316: High throughput small molecule screening with synthetic 3D lung-mimetic hydrogels in the rare lung cancer lymphangioleiomyomatosis
Authors: Adam Pietrobon, Julien Yockell-Lelievre, Carole Doré, Roger Y. Tam, Sean P. Delaney, Molly Shoichet, William L. Stanford
Journal: Cancer Research (2020)

Abstract Lymphangioleiomyomatosis (LAM) is a rare lung cancer characterized by immature smooth muscle-like cell invasion of the lung parenchyma, leading to cystonodular destruction and respiratory decline. Interestingly, LAM is a monogetic disease caused by loss of TSC2, conferring constitutive mTORC1 activation. Currently, there are no approved therapeutics which exhibit LAM cell-specific cytotoxicity. Here, we describe a novel 3D drug screening platform which couples a rationally designed, synthetic, lung-mimetic hydrogel to high content imaging. We have designed and synthesized a hyaluronic acid-based hydrogel which mimics endogenous lung tissue. Human LAM cell models maintain mTORC1 activation in the hydrogel compared to matched controls, reflective of human LAM lesions. We observe LAM cells to exhibit both protease-dependent and independent modes of invasion: the former imparted by gel crosslinking with an MMP-cleavable peptide, the latter enabled by methylcellulose conjugation. Proliferation is inhibited as LAM cells actively invade through the gel. We coupled our culture system to high content confocal microscopy, permitting measurements of cell viability and invasion depth in response to therapeutic screening. We subsequently tested an 800-drug library of Health Canada-approved small molecule cancer therapeutics on LAM cells and matched controls. Surprisingly, LAM cells exhibited pan-therapeutic resistance as measured by both invasion and viability metrics. Enrichment analysis revealed categories of therapeutics which demonstrated LAM-selective cytotoxicity and/or anti-invasiveness. We performed a refinement screen on select therapeutics and identified AURA inhibition as an effective LAM cell-specific therapeutic avenue. Work is ongoing to establish the most efficacious small molecule inhibitor. In conclusion, we describe a novel drug screening platform which enables high content measurements of viability and invasion in response to drug screening in a lung-mimetic system. We have identified AURA inhibition as a potential therapeutic avenue for LAM patients using this screening platform. Future work will involve target validation, elucidation of the mechanism of action, and testing in a pre-clinical mouse model. As these small molecules are Health Canada-approved, we anticipate rapid clinical translation of our preferred candidate. Citation Format: Adam Pietrobon, Julien Yockell-Lelievre, Carole Doré, Roger Y. Tam, Sean P. Delaney, Molly Shoichet, William L. Stanford. High throughput small molecule screening with synthetic 3D lung-mimetic hydrogels in the rare lung cancer lymphangioleiomyomatosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6316.