bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA19: Role of autophagy in cancer metabolism
Authors: White Eileen P.
Published: June 2020

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and enable survival in starvation. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect manifested by starvation intolerance and gradual loss of white adipose tissue, liver glycogen, and muscle mass. Cancer cells benefit from autophagy as deletion of essential autophagy genes impairs spontaneous tumor growth in autochthonous cancer models. Tumor cell autonomous autophagy is required to recycle macromolecules to sustain mitochondrial substrate supply and thereby energy and nucleotide pools essential for survival during nutrient limitation. In addition to promoting tumor cell survival, autophagy in the host also promotes tumorigenesis. Host-specific Atg7 or Atg5 deletion impairs growth of multiple different allografted tumors, by preventing the release of Arginase 1 from hepatocytes. Arginase 1 degrades circulating arginine that is essential for the growth of tumors, most of which are auxotrophic for arginine. Thus, autophagy sustains both tumor cell and host metabolism to enable tumor growth. In tumors with a high neoantigen load that can be recognized and killed by T cells, autophagy suppresses an antitumor T-cell response. Autophagy prevents tumor killing by T cells by suppressing production of interferon gamma in a T cell-dependent manner. Thus, autophagy promotes tumorigenesis by promoting intrinsic and extrinsic tumor metabolism and by suppressing the ability of the immune system to eliminate tumors. This suggests that autophagy inhibitors may be especially useful for cancer therapy when combined with immunotherapy. To better understand the toxicity of autophagy inhibition to normal tissues, we have examined the functional consequence of conditional Atg7 or Atg5 deletion in adult mice. Whereas Atg7 deletion causes neurodegeneration in 2-3 months, Atg5 deletion causes very specific loss of telocytes and stem cells in the ileum part of the intestine and rapid death due to a more abrupt loss of autophagy function. This indicates that there is a difference in the sensitivity of cell types and tissues to the loss of autophagy and that there are discrete functional dependencies on different ATGs.

Citation Format: Eileen P. White. Role of autophagy in cancer metabolism [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA19.
Abstract IA21: Elucidating and targeting mechanisms of single-cell state maintenance: From N-of-1 to N-of-1-of-1 studies
Authors: Califano Andrea
Published: June 2020

We have developed network-based methodologies for the systematic identification, validation, and pharmacologic targeting of a new class of therapeutic targets. These targets comprise Master Regulator proteins, whose concerted aberrant activity within tightly regulated modules (tumor checkpoints) is responsible for the mechanistic implementation and maintenance of specific tumor cell states. By leveraging these methodologies, we have developed OncoTreat, a NY CLIA-certified test that leverages large-scale drug-perturbation assays to systematically identify drugs and drug combinations whose mechanism of action is specifically effective in abrogating tumor checkpoint activity, on an individual patient basis. These tests have shown 60% validation rate across 39 predicted drugs that were validated in PDX models from patients who had failed multiple standard-of-care therapies. In this talk, we will introduce these concepts and then demonstrate their application to elucidating drugs capable of targeting transcriptionally distinct tumor niches by single-cell analysis (N-of-1-of-1 studies). In particular, we will show identification and validation, in vivo, of drugs targeting the stemlike progenitor niche of breast adenocarcinomas and the four transcriptionally distinct single-cell subtypes identified in glioblastoma patients.

Citation Format: Andrea Califano. Elucidating and targeting mechanisms of single-cell state maintenance: From N-of-1 to N-of-1-of-1 studies [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA21.
Abstract IA23: Single cell-resolution lineage tracing of tumors in a mouse xenograft model reveals rapid and multidirectional metastasis
Authors: Weissman Jonathan S.
Published: June 2020

The pairing of CRISPR/Cas9-based gene editing with massively parallel single-cell readouts now enables large-scale, single-cell lineage tracing exploration of the phylogenetic principles that govern important biologic processes at unprecedented resolution and scale. We recently described a flexible, high-information, multichannel molecular recorder with a single-cell readout and applied it as an evolving lineage tracer to define a mouse cell fate map from fertilization through gastrulation. In the present study, we now apply our Cas9-based lineage tracer to investigate metastatic progression in a lung cancer xenograft model in mouse. We describe >100 single cell-resolution phylogenies for tens of thousands of cancer cells from multiple tumors, and we observe a wide range of clade-specific behaviors. From these family trees, we infer the number of ancestral metastatic events and thus calculate the metastatic potential for every population, the frequency of metastasis, and the tissue routes through which metastases transit. We overlay single-cell transcriptomic signatures on the phylogenies and find distinct clone- or clade-specific expression signatures that correlate with metastatic potential, highlighting the diversity of cancer phenotypes even within this single xenograft model. We illustrate numerous examples of complex, multidirectional metastatic architectures, including self-seeding, monoclonal seeding, and seeding cascades. More generally, our approach provides an unprecedented ability to monitor tumor formation, evolution, growth, and spread in an in vivo setting.

Citation Format: Jonathan S. Weissman. Single cell-resolution lineage tracing of tumors in a mouse xenograft model reveals rapid and multidirectional metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA23.
Abstract IA24: Interrogating therapy response and resistance in engineered preclinical models
Authors: Dow Lukas E.
Published: June 2020

The past decade has produced a vast amount of clinical sequencing data that have defined the genetic landscape of human cancers. We know with greater detail than ever the number and type of mutation in any given gene, yet we have a limited understanding of how this mutational heterogeneity impacts cancer initiation, progression, or therapeutic response. Thus, despite the enormous resources invested in genome sequencing, the vast amount of information gathered is uninformative as we simply do not know how most cancer-associated mutations dictate tumor behavior. Even extremely well-studied genes such as KRAS and APC harbor an array of mutational variants that may have significant prognostic and therapeutic relevance but remain scarcely characterized. Further complicating the challenge is the number of mutational combinations that impact cancer behavior. To meet this challenge, we develop and exploit new genetic technologies to engineer organoid and animal model systems that faithfully represent the mutational events in human cancer. We use these tools to determine how specific mutational variants in major oncogenic pathways shape cancer progression and influence cancer cell vulnerabilities and response to therapy. I will describe our efforts to understand the contribution of recurrent alterations in APC and KRAS, as well as our ongoing work to prospectively define mechanism of response and resistance to new WNT-targeted therapies now entering clinical trials.

Citation Format: Lukas E. Dow. Interrogating therapy response and resistance in engineered preclinical models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA24.
Abstract IA26: Multiplexed functional cancer genomics
Authors: Cai Hongchen , Li Chuan , Chew Su Kit , Yousefi Maryam , Foggetti Giorgia , Lin Wen-Yang , Rogers Zoë N. , Winters Ian P. , McFarland Christopher D. , Politi Katherina , Swanton Charlie , Petrov Dmitri A. , Winslow Monte M.
Published: June 2020

Extensive cancer genotyping has identified a large number of putative tumor-suppressor genes. However, genome sequencing data alone are insufficient to uncover the importance and role of these genes during carcinogenesis. Moreover, whether tumor suppressors restrict the rate of tumor growth, decrease the probability of incipient tumorigenesis, or limit the emergence of particularly fast-growing clones remains unknown for even the most well-studied tumor suppressors. I will discuss the development and use of multiplexed autochthonous mouse models of human lung adenocarcinoma that integrate tumor barcoding, CRISPR/Cas9-based genome editing, and high-throughput barcode sequencing (Tuba-seq). Using these methods, the impact of large panels of putative tumor suppressor genes can be quantified in parallel. We find that many previously understudied genes have strong effects on multiple aspects of tumor growth in vivo. While some functional tumor-suppressor genes have particularly strong effects only during some but not other phases of tumorigenesis, many genes impacted multiple facets of cancer development. Tuba-seq-based studies across oncogenic contexts and with combinatorial tumor suppressor gene inactivation further highlight the context dependency of gene function during carcinogenesis. These cause-and-effect analyses uncover an unexpectedly complex taxonomy of tumor suppression. We have further employed these multiplexed and quantitative in vivo models to assess the relationship between tumor genotype and therapeutic responses at scale. We coupled Tuba-seq with robust statistical methods to enable the generation of a pharmacogenomic map of lung cancer treatment responses in vivo. We uncover a surprisingly informative map of genotype-specific therapeutic responses, which highlights the importance of tumor-suppressor genotype in driving precision treatment approaches. These blueprints of the multifaceted nature of carcinogenesis have implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches for precision cancer treatment.

Citation Format: Hongchen Cai, Chuan Li, Su Kit Chew, Maryam Yousefi, Giorgia Foggetti, Wen-Yang Lin, Zoë N. Rogers, Ian P. Winters, Christopher D. McFarland, Katherina Politi, Charlie Swanton, Dmitri A. Petrov, Monte M. Winslow. Multiplexed functional cancer genomics [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA26.
Abstract PHA01: Modeling the tissue-specific oncogenesis of mutant RAS
Authors: Moore Amanda R. , McGinnis Lisa , Malek Shiva
Published: June 2020

RAS mutations are highly prevalent in tumors, especially those of the lung, colon, skin, and pancreas. The tissues in which these tumors arise are enriched for specific RAS isoform and codon preferences. For example, mutations in KRAS are prevalent in lung, colon, and pancreas, while NRAS mutations are predominantly found in melanoma. Additionally, mutations in KRAS predominantly occur at codons 12 and NRAS mutations at codon 61. Independent of the RAS isoform, the mutated codon contributes to distinct biochemical differences, with codon 61 mutations largely viewed as more biochemically active than codon 12 mutations. Previous RAS-mutant genetically engineered mouse (GEM) models resembled the tissue specificity observed in patients. In the colon, expression of KrasG12D but not NrasG12D induced colonic hyperplasia. While in melanocytes, the expression of NrasQ61R, but not NrasG12D, led to melanoma development. Given these data, we developed RAS-mutant GEM models to identify the tissues susceptible to RAS mutations and the differences among these animal models. To achieve this, we generated four conditional knockin GEM models to directly compare Kras and Nras mutations in codons 12 and 61; G12D and Q61R. To robustly determine the effects of mutant expression across a wide range of tissues, we utilized the ubiquitous and temporally expressed Cre, Rosa26-CreERT2. Following the induction of recombination by tamoxifen treatment, we observed rapid mortality in Kras-mutant animals. KrasQ61R mice survived to a median of 13 days while KrasG12D mice survived to a median of 22 days post-tamoxifen. However, the Nras-mutant mice have extended survival. While ongoing, these survival data suggest tissues acutely sensitive to Kras-mutant expression can tolerate or are resistant to Nras-mutant expression. When comparing the two Kras conditional knockin GEM models, we found expression of KrasG12D and KrasQ61R drove hyperproliferation in both lung and colon tissues to varying degrees and different tissue types in the colon. For instance, we observe colonic hyperplasia in KrasG12D mice and polypoid hyperplasia in KrasQ61R mice. Interestingly, the hematopoietic cells were exquisitely sensitive to expression of KrasQ61R, and these animals rapidly developed acute myeloid leukemia leading to death. These data illustrate how the strength of the constitutive activation of RAS proteins drives differential tumorigenesis. We plan to further our understanding of the tissue-specific tumorigenesis of mutant-RAS proteins by comparing the Kras- and Nras-mutant GEM models.

This abstract is also being presented as Poster A01.

Citation Format: Amanda R. Moore, Lisa McGinnis, Shiva Malek. Modeling the tissue-specific oncogenesis of mutant RAS [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA01.
Abstract PHA03: Coordinate translational control of KRAS signaling pathway in pancreatic adenocarcinoma
Authors: Singh Kamini , Wendel Hans-Guido
Published: June 2020

G-quadruplex (GQ) elements are conserved translational control elements that induce a requirement for RNA helicase activity for efficient mRNA translation. Computational structure analyses identify GQ elements in the 5´UTRs of mRNAs encoding KRAS and key downstream signaling molecules. KRAS is a key oncogene in pancreatic ductal adenocarcinoma (PDAC) and many other cancers, and except for the specific G12C KRAS mutation we do not have pharmacologic inhibitors. We find that KRAS and downstream signaling molecules, including PI3K, RALA, RAC2, MYC, MET, and YAP1, strictly depend on the RNA helicase eIF4A for their translation. This implies a potential utility for eIF4A/DDX2 inhibitors such as the silvestrol analogue CR31B. Indeed, CR31B shows nanomolar cell kill in vitro and in vivo efficacy across xenograft, primary PDX, and murine PDAC models. Together, our study reveals a signature of coordinate and eIF4A/DDX2 dependent oncogene translation in PDAC that is potentially accessible to therapeutic attack.

This abstract is also being presented as Poster A18.

Citation Format: Kamini Singh, Hans-Guido Wendel. Coordinate translational control of KRAS signaling pathway in pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA03.
Abstract PHA05: Strategies to improve engineering cancer-associated SNVs with base editing
Authors: Katti Alyna , Foronda Miguel , Zimmerman Jill , Diaz Bianca , Zafra Maria Paz , Goswami Sukanya , Piskounova Elena , Dow Lukas E.
Published: June 2020

Base editing (BE) is a powerful tool for engineering single-nucleotide variants (SNVs) and has been used to create targeted mutations in cell lines, organoids, and animal models. Recent development of new BE enzymes has provided an extensive toolkit for genome modification; however, unlike Cas9, which shows remarkable efficacy in creating homozygous disruptive mutations following DNA double-strand breaks (DSBs), BE is relatively inefficient and identifying and isolating edited cells for analysis has proved challenging. To enable simple identification and enrichment of base editing events, we developed a “Gene On” (GO) reporter system that indicates precise cytosine or adenine base editing in situ with high sensitivity and specificity. We validate GO using an activatable GFP and use it to measure the kinetics, efficiency, PAM specificity, and fidelity of a range of new BE variants. Further, GO is flexible and can be easily adapted to induce expression of numerous genetically encoded markers, antibiotic resistance genes, or enzymes such as Cre recombinase. With these tools, GO can be exploited to functionally link BE events at endogenous genomic loci to cellular enzymatic activities in human and mouse cell lines and organoids. We further demonstrate the application of GO in detecting in vivo BE activity using a newly generated mouse model with inducible and reversible base editor expression that will enable generation of novel cancer models in vivo. GO provides a powerful approach to increase the practicality and feasibility of implementing CRISPR BE in biomedical research.

This abstract is also being presented as Poster A45.

Citation Format: Alyna Katti, Miguel Foronda, Jill Zimmerman, Bianca Diaz, Maria Paz Zafra, Sukanya Goswami, Elena Piskounova, Lukas E. Dow. Strategies to improve engineering cancer-associated SNVs with base editing [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA05.
Abstract PHB02: Impact of genetic diversity on the growth of human-derived xenografts
Authors: Sargent Jennifer , Cartagena Roberto , Trowbridge Stephanie , Munger Steven , Hasham Muneer
Published: June 2020

The generation of human patient-derived xenograft (hPDX) models, and efficacy testing on human cell-derived xenografts (hCDX) or hPDX, are usually performed on a single mouse genetic background. Emerging evidence suggests that host genetic background underlies the variability in xenograft establishment as well as tumor response to drugs. Here we show two approaches, a genetic and a chemical one, on human-derived xenografts as proof of concept to show that xenografting can be done in genetic diverse mice and growth kinetics is different depending on the strain of the mice. The genetic approach is to use Rag1-/- mice for xenografts—Rag1-/- mice are immunodeficient and accept human cells. We found that the growth kinetics of a well-characterized hCDX is unequivocally distinct in three genetically diverse strains. The chemical approach is to use 2-deoxy glucose (2DG) to dampen the immune system in order to reduce graft rejection. We found that the growth kinetics and engraftment acceptability rates of a well-characterized hPDX were highly unique in eight genetically distinct outbred mice treated with 2DG. These findings provide proof of concept that xenografting can be conducted in genetically diverse mice. Development of these novel platforms will provide the genetic diversity necessary for the growth of any type of tumor, expanding the PDX platform to sustain cancers that have previously failed to xenograft.

This abstract is also being presented as Poster B33.

Citation Format: Jennifer Sargent, Roberto Cartagena, Stephanie Trowbridge, Steven Munger, Muneer Hasham. Impact of genetic diversity on the growth of human-derived xenografts [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHB02.
Abstract PHB05: Mechanism-based computational models to study interplay between EGFR inhibitors and KRAS mutants
Authors: Stites Edward C.
Published: June 2020

An early genotype-to-phenotype relationship in cancer personalized medicine was that KRAS mutations confer resistance to EGFR inhibitors in colorectal cancer. Confusingly, phase 3 clinical trials found that patients with the KRAS G13D mutation were an exception to this rule. That constitutively active KRAS mutants would cause resistance to EGFR inhibitors seemed intuitive, and it appeared inconsistent with known mechanisms of RAS biology for any constitutively active KRAS mutant to behave differently. We have developed a computational model that describes the biochemical mechanisms of RAS signal regulation. Simulations of this mass-action model reproduce known patterns of RAS pathway activation. The incorporation of the specific biochemical parameters for different KRAS mutants has allowed us to uncover novel, non-obvious insights into the response of KRAS G13D and KRAS G12C colorectal cancers to EGFR inhibition. For KRAS G13D, the model revealed EGFR inhibition leads to reduced wild-type HRAS and NRAS signaling in KRAS G13D cancers, but not KRAS G12D or KRAS G12V cancers. The model also revealed a critical dependence upon tumor suppressor NF1, and that the impaired binding of KRAS G13D to NF1 frees NF1 to act on wild-type RAS. Importantly, our computational predictions have been prospectively validated experimentally. Our computational model has also revealed that cotreatment of KRAS G12C colorectal cancer with EGFR and KRAS G12C inhibitors results in a depletion of the active forms of both wild-type and mutant RAS proteins, which we have also confirmed experimentally. For both KRAS G13D and KRAS G12C colorectal cancers, our work demonstrates how computational models can identify behaviors that logically follow from what is known, but which the complexity of the RAS signaling network has prevented from previously being uncovered despite extensive, empirical, experimental efforts.

This abstract is also being presented as Poster B51.

Citation Format: Edward C. Stites. Mechanism-based computational models to study interplay between EGFR inhibitors and KRAS mutants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHB05.
Abstract PR09: A systematic approach to create patient-derived models of rare tumors
Authors: Tseng Yuen-Yi , Keskula Paula , Deasy Rebecca , Hong Andrew , Chatterji Priya , Vazquez Francisca , Bass Adam , Van Hare Barbara , Sandak David , Ligon Keith , Boehm Jesse
Published: June 2020

Precision cancer medicine is based on the ability to predict the dependencies of a given tumor from its molecular makeup. Despite successes in multiple common cancers, such prediction remains challenging for the majority of rare and understudied tumors, given the absence of laboratory model systems in which to discover and/or validate therapeutic hypotheses. Here, we describe our efforts to address this challenge systematically with the ultimate goal of making it possible to learn how to predict ex vivo growth requirements for cancer samples based on technical, clinical, and genomic properties of the starting tumor material. Over the last 5 years, we have processed nearly 2,000 tumor biospecimens and created over 375 genomically confirmed patient-derived cell lines, organoids, and neurosphere cultures, with >10% of these representing rare cancers. To make this possible, we have implemented three key workflows including (1) direct-to-patient sample sourcing, (2) a tissue cryopreservation and genomic credentialing system to ensure quality prior to model creation, and (3) a systematic empirical approach to screening rich media and variations on organoid technologies ex vivo (HYBRID). We have begun performing genome-wide CRISPR viability screens in these cultures as part of our larger activities to generate a systematic laboratory-based functional map of cancer dependencies (a “Cancer Dependency Map”). The novel organoid, spheroid, and cell line models created as part of this effort are being made publicly available to the scientific community. Looking ahead, as the barriers to culturing rare tumors are overcome, we expect that preclinical functional genomics data will be useful for difficult-to-treat tumors without existing molecularly guided standard-of-care regimens.

This abstract is also being presented as Poster A06.

Citation Format: Yuen-Yi Tseng, Paula Keskula, Rebecca Deasy, Andrew Hong, Priya Chatterji, Francisca Vazquez, Adam Bass, Barbara Van Hare, David Sandak, Keith Ligon, Jesse Boehm. A systematic approach to create patient-derived models of rare tumors [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR09.
Abstract PR10: A versatile ES cell-based melanoma mouse modeling platform
Authors: Karreth Florian A.
Published: June 2020

The cumbersome and time-consuming process of generating new mouse strains and multiallelic experimental animals often hinders the use of genetically engineered mouse models (GEMM) in cancer research. Here, we describe the development and validation of an embryonic stem cell (ESC)-GEMM platform for rapid modeling of melanoma in mice. The platform incorporates twelve clinically relevant genotypes composed of combinations of four driver alleles (LSL-BrafV600E, LSL-NrasQ61R, PtenFlox, Cdkn2aFlox) and regulatory alleles to spatiotemporally control the perturbation of genes of interest. The ESCs produce high-contribution chimeras, which recapitulate the melanoma phenotypes of conventionally bred mice. Using the ESC-GEMM platform to modulate Pten expression in melanocytes in vivo, we highlighted the utility and advantages of gene depletion by CRISPR-Cas9, RNAi, or conditional knockout for melanoma modeling. Moreover, complementary genetic methods demonstrated the impact of Pten restoration on the prevention and maintenance of Pten-deficient melanomas. Finally, we showed that chimera-derived melanoma cell lines retain regulatory allele competency and are a powerful resource to complement ESC-GEMM chimera experiments in vitro and in syngeneic grafts in vivo. Thus, when combined with sophisticated genetic tools, the ESC-GEMM platform enables rapid, high-throughput, and versatile studies aimed at addressing outstanding questions in melanoma biology.

This abstract is also being presented as Poster B45.

Citation Format: Florian A. Karreth. A versatile ES cell-based melanoma mouse modeling platform [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR10.
Abstract PR14: A multiscale map of recurrently mutated systems in cancer
Authors: Zheng Fan , Ono Keiichiro , Silva Erica , Swaney Danielle , Kim Minkyu , Shangguan Julia , Pratt Dexter , Nan Xiaolin , Krogan Nevan , Ideker Trey
Published: June 2020

Interpreting cancer genomes requires a broad understanding of the composition and organization of cellular processes under selective pressure for mutations. Here, we integrate systematic screens for protein interaction with tumor genetic analysis to elucidate a multiscale hierarchical map of 378 protein systems recurrently altered in one or more cancer types. Diverse gene mutations converge on commonly mutated systems, from small protein complexes in specific tumor types to large molecular assemblies and organelles disrupted in most cancers. Unexpected findings include collagen structural alterations with significant prognostic value; mutations impacting the desmosome in 65% melanomas; complexes related to splicing and DNA repair; and an expanded actomyosin cluster involving PIK3CA. The map implicates 556 cancer genes, many well supported by functional assays, including canonical genes implicated in new tissues (e.g., BRCA1/2 mutations in bladder cancer). This work explains mutational heterogeneity as a collection of convergence points across scales of cell biology.

This abstract is also being presented as Poster B52.

Citation Format: Fan Zheng, Keiichiro Ono, Erica Silva, Danielle Swaney, Minkyu Kim, Julia Shangguan, Dexter Pratt, Xiaolin Nan, Nevan Krogan, Trey Ideker. A multiscale map of recurrently mutated systems in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR14.
Novel Insight into the in vivo Function of Mast Cell Chymase: Lessons from Knockouts and Inhibitors
Authors: Pejler Gunnar
Published: June 2020

Mast cells are now recognized as key players in diverse pathologies, but the mechanisms by which they contribute in such settings are only partially understood. Mast cells are packed with secretory granules, and when they undergo degranulation in response to activation the contents of the granules are expelled to the extracellular milieu. Chymases, neutral serine proteases, are the major constituents of the mast cell granules and are hence released in large amounts upon mast cell activation. Following their release, chymases can cleave one or several of a myriad of potential substrates, and the cleavage of many of these could potentially have a profound impact on the respective pathology. Indeed, chymases have recently been implicated in several pathological contexts, in particular through studies using chymase inhibitors and by the use of chymase-deficient animals. In many cases, chymase has been shown to account for mast cell-dependent detrimental effects in the respective conditions and is therefore emerging as a promising drug target. On the other hand, chymase has been shown to have protective roles in other pathological settings. More unexpectedly, chymase has also been shown to control certain homeostatic processes. Here, these findings are reviewed.
Extreme Levels of Platelet Count in Essential Thrombocythemia: Management and Outcome, Report of Two Cases
Authors: Abu-Tineh Mohammad , Yassin Mohamed A.
Published: June 2020

Myeloproliferative neoplasms including essential thrombocythemia (ET) is usually caused by somatic mutations in multiple genes, including the JAK2 (most frequently), CALR gene, and MPL. In rare cases, the disease is caused by other mutations such as THPO or TET2 gene; however, around 10–15% with ET might have triple-negative mutations. Here we present 2 cases of ET who were asymptomatic on diagnoses, but found to have extremely high platelet counts as never reported earlier. The management and treatment plan can be a challenging step. The objective is to draw attention to the early introduction of thrombocytapheresis in the management of such patients given its notable outcomes.
Systems Genetics for Mechanistic Discovery in Heart Diseases
Authors: Rau Christoph D. , Lusis Aldons J. , Wang Yibin
Published: June 2020

Cardiovascular diseases are the leading cause of death worldwide. Complex diseases with highly heterogenous disease progression among patient populations, cardiovascular diseases feature multifactorial contributions from both genetic and environmental stressors. Despite significant effort utilizing multiple approaches from molecular biology to genome-wide association studies, the genetic landscape of cardiovascular diseases, particularly for the nonfamilial forms of heart failure, is still poorly understood. In the past decade, systems-level approaches based on omics technologies have become an important approach for the study of complex traits in large populations. These advances create opportunities to integrate genetic variation with other biological layers to identify and prioritize candidate genes, understand pathogenic pathways, and elucidate gene-gene and gene-environment interactions. In this review, we will highlight some of the recent progress made using systems genetics approaches to uncover novel mechanisms and molecular bases of cardiovascular pathophysiological manifestations. The key technology and data analysis platforms necessary to implement systems genetics will be described, and the current major challenges and future directions will also be discussed. For complex cardiovascular diseases, such as heart failure, systems genetics represents a powerful strategy to obtain mechanistic insights and to develop individualized diagnostic and therapeutic regiments, paving the way for precision cardiovascular medicine.
Long Range Endocrine Delivery of Circulating miR-210 to Endothelium Promotes Pulmonary Hypertension
Authors: Zhao Jingsi , Florentin Jonathan , Tai Yi-Yin , Torrino Stéphanie , Ohayon Lee , Brzoska Tomasz , Tang Ying , Yang Jimin , Negi Vinny , Woodcock Chen-Shan Chen , Risbano Michael G. , Nouraie Seyed Mehdi , Sundd Prithu , Bertero Thomas , Dutta Partha , Chan Stephen Y.
Published: June 2020

Rationale:

Unproven theories abound regarding the long-range uptake and endocrine activity of extracellular blood-borne microRNAs into tissue. In pulmonary hypertension (PH), microRNA-210 (miR-210) in pulmonary endothelial cells promotes disease, but its activity as an extracellular molecule is incompletely defined.

Objective:

We investigated whether chronic and endogenous endocrine delivery of extracellular miR-210 to pulmonary vascular endothelial cells promotes PH.

Methods and Results:

Using
miR-210
replete (wild-type [WT]) and knockout mice, we tracked blood-borne miR-210 using bone marrow transplantation and parabiosis (conjoining of circulatory systems). With bone marrow transplantation, circulating miR-210 was derived predominantly from bone marrow. Via parabiosis during chronic hypoxia to induce miR-210 production and PH, miR-210 was undetectable in knockout-knockout mice pairs. However, in plasma and lung endothelium, but not smooth muscle or adventitia, miR-210 was observed in knockout mice of WT-knockout pairs. This was accompanied by downregulation of miR-210 targets ISCU (iron-sulfur assembly proteins)1/2 and COX10 (cytochrome c oxidase assembly protein-10), indicating endothelial import of functional miR-210. Via hemodynamic and histological indices, knockout-knockout pairs were protected from PH, whereas knockout mice in WT-knockout pairs developed PH. In particular, pulmonary vascular engraftment of miR-210–positive interstitial lung macrophages was observed in knockout mice of WT-knockout pairs. To address whether engrafted miR-210–positive myeloid or lymphoid cells contribute to paracrine miR-210 delivery, we studied miR-210 knockout mice parabiosed with miR-210 WT;
Cx3cr1
knockout mice (deficient in myeloid recruitment) or miR-210 WT;
Rag1
knockout mice (deficient in lymphocytes). In both pairs, miR-210 knockout mice still displayed miR-210 delivery and PH, thus demonstrating a pathogenic endocrine delivery of extracellular miR-210.

Conclusions:

Endogenous blood-borne transport of miR-210 into pulmonary vascular endothelial cells promotes PH, offering fundamental insight into the systemic physiology of microRNA activity. These results also describe a platform for RNA-mediated crosstalk in PH, providing an impetus for developing blood-based miR-210 technologies for diagnosis and therapy in this disease.
The Reflex Machine and the Cybernetic Brain: The Critique of Abstraction and its Application to Computationalism
Authors: Chirimuuta M.
Published: June 2020

Objections to the computational theory of cognition, inspired by twentieth century phenomenology, have tended to fixate on the embodiment and embeddedness of intelligence. In this paper I reconstruct a line of argument that focusses primarily on the abstract nature of scientific models, of which computational models of the brain are one sort. I observe that the critique of scientific abstraction was rather commonplace in the philosophy of the 1920s and 30s and that attention to it aids the reading of The Organism ([1934] 1939) by the neurologist Kurt Goldstein. With this background in place, we see that some brief but spirited criticisms of cybernetics by two later thinkers much influenced by Goldstein, Georges Canguilhem (1963) and Maurice Merleau-Ponty (1961), show continuity with the earlier discussions of abstraction in science.
Staging Touba: The Performance of Piety
Authors: Kingsbury Kate
Published: June 2020

Touba, in Senegal, is the equivalent to Mecca for Sufi Mouride Muslims, who embark on an annual pilgrimage called Le Grand Magal to celebrate the founder of their faith, Cheikh Amadou Bamba. When devotees describe their sacred city they frequently compare Touba to heaven, juxtaposing it to the materiality and chaos of other Senegalese cities, as though it was distinct from these lieux. Yet Touba shares many similarities in terms of its economic importance with other metropolises. Mourides despite presenting themselves as a united religious community, have differences of opinion and even praxis. This paper explores the imagination of Touba and the Mouride order by Mourides, positing that the sacred sites of Touba comprise a stage for the performance of piety and the generation of a particular Mouride ontology through which they see Touba, their order and the world.
Heeding the Law beyond the Law: Transgendering Alterity and the Hypernomian Perimeter of the Ethical
Authors: Wolfson Elliot R.
Published: June 2020

This essay will examine the viability of a kabbalistic ethics from the vantage point of what I have identified in previously published studies as the hypernomian foundation of the nomos, the grounding of the law in the ground that exceeds the law of the ground. Contrary to Scholem, who put the emphasis on an antinomian impulse that is in conflict with the tenets of the tradition, I argue that the hallmark of religious nihilism is the promulgation of the belief that impiety is the gesture of supreme piety. In the ensuing analysis, I will explore the subject of hypernomianism by a close analysis of what may be called in Derridean terms the law beyond the law, which he identified further as the nonjuridical ideal of justice, the gift of forgiveness, the aspect of pure mercy in relation to which it is no longer viable to distinguish guilt and innocence.
Against Metaphysical Structuralism
Authors: Busse Ralf
Published: June 2020

Inductive Metaphysics (IM) combines an anti-aprioristic emphasis on an empirical and scientific basis for metaphysics with an insistence on a specifically philosophical abductive theory-building. Since the latter specifically philosophical work is not empirical itself, it may in a liberal sense be called apriori. This paper highlights this apriori dimension within IM by a case study on Structuralism, the view that fundamental reality consists of a network of relations (and properties), which a number of philosophers consider to be suggested by modern physics. Focussing on Dasgupta’s algebraic Generalism, the author argues that Structuralism suffers from a severe entailment problem, because the relations-spanning apparatus must stand for metaphysically fundamental forms. Schaffer’s contention that there are no entailment problems is rejected. Advocates of IM are well advised to take seriously their own insistence on metaphysical abduction and not to one-sidedly emphasise the empirical input: the elaboration of exact metaphysical theories and the apriori evaluation of their inherent tenability is a constituent of IM no less important than the consideration of scientific input. More traditional ways of metaphysical reasoning inevitably survive as an essential dimension within IM.
Tetractys
Authors: Izdebska Anna
Published: June 2020

Tetractys was a Greek technical term, specific to the Pythagorean tradition, that the late antique neoplatonist philosophers considered to be the central notion of Pythagorean metaphysics. As the Greek philosophical heritage started to be translated into Arabic, this term also made its way into the new language, resulting in a number of different translations. This paper explores the ways in which the term tetractys was expressed in Arabic and then explained to the medieval islamicate readers. By comparing the ways in which specific authors and intellectual circles coped with a technical term that no longer assumed the philosophical significance it had had in Late Antiquity, I show the vagaries of the Greco-Arabic translation movement. The changing renderings and understandings of this term offers a great opportunity to understand the different factors that influenced the course of translating the Greek heritage into the Arabic world.
Trimelopter crispolanatum (Asparagaceae, Scilloideae), a new species from Namaqualand, South Africa

Authors: MARTÍNEZ-AZORÍN MARIO , CRESPO MANUEL B. , ALONSO-VARGAS MARÍA ÁNGELES , PINTER MICHAEL
Published: June 2020

Hyacinthaceae subfam. Ornithogaloideae (= tribe Ornithogaleae of Aparagaceae sensu APG 2009, 2016, Chase et al. 2009) includes about 300 species of bulbous plants mainly distributed throughout Europe, Africa and south-west Asia. The latest comprehensive study in Ornithogaloideae (Martínez-Azorín et al. 2011) demonstrates the existence of 19 monophyletic genera which are characterised by a clear syndrome of morphological characters related to biogeographic patterns.
Parapercis annamalai sp. nov., a new sandperch from southwestern India (Family Pinguipedidiae)
Authors: YOSUVA MARIASINGARAYAN , HO HSUAN-CHING , JEYAPRAGASH DANARAJ , SARAVANAKUAMR AYYAPPAN
Published: June 2020

A new sandperch is described from 3 specimens from off Parangipettai, southeastern India. It can be separated from its congeners in having a combination of dorsal-fin rays V, 21‒22; anal-fin rays I, 17‒18; pectoral-fin rays 17‒18; pored lateral-line scales 53‒54; median predorsal scales 7; transverse scale rows 4/13; gill rakers on 1st gill arch 15‒17; single row of stout teeth on vomer; no teeth on palatine; 3 pairs of enlarged canines at front of lower jaw; opercle uniformly dark brownish; blade-like patch on cheek, the patch orange dorsally and reddish ventrally, fading entirely in preservative; dorsal fins light grayish with 2 rows of spots; a whitish longitudinal band just above lateral axis of body; dorsal surface of body with 8 irregular blackish saddles and lower half with 7 reddish bars and black dots on upper half of each bar; lower half of anal fin reddish; caudal fin grayish with upper and lower portion darker and vertical rows of orange dots on yellowish bands. The new species is most similar to Parapercis somaliensis and Parapercis kentingensis morphologically and genetically, but differs in coloration, serrations on the opercle, and body proportions. The establishment of the new species is also supported by DNA barcoding analysis.
Distinctive Nanogels as High-Efficiency Transdermal Carriers for Skin Wound Healing
Authors: Uk Son Seong , Jang Soojin , Choi Yuna , Park Mirae , Son Hye Young , Huh Yong-Min , Yeom Soo-Jin , Ham Moon Sun , Lee Do Kyung , Kim Han-Na , Jin Yeung-Bae , Kang Taejoon , Jung Juyeon , Lim Eun-Kyung
Published: June 2020

We propose that nanogels (HLGs) prepared by simply blending an epidermal growth factor (EGF)-loaded hyaluronan (HA)-based nanoformulation and poloxamers can be efficient transdermal drug carriers. In particular, due to the thermogelling behavior of poloxamer, when the HLGs, which are
liquid at room temperature, are applied to the skin's surface, they form a gel at skin temperature. First, lipid-based nanoformulations (EGF-LNs) were fabricated by the lipid thin film method and then chemically conjugated with HA on the surface of the films to prepare EGF-loaded HA-based
nanoformulations (EGF-HLNs). Both EGF-LNs and EGF-HLNs exhibited a uniform size and spherical lamellar structure. The EGF-HLN was added to a poloxamer solution to form EGF-HLG, which is a liquid at room temperature and a gel at skin temperature. HLGs have been shown to be able to deliver and
permeate EGF well into the skin using both in vitro and in vivo systems, thus serving as an effective transdermal delivery system. In addition, it has been confirmed that this system could be a possible implantable drug carrier. Therefore, HLGs, which are uncomplicated and easily
prepared, are expected to be easily used not only in the pharmaceutical field but also in the cosmetic field.
Radiotherapy Enhancement for Human Pancreatic Carcinoma Using a Peptide-Gold Nanoparticle Hybrid
Authors: Dong Wenyu , Cai Zhi , Pang Jing , Wang Jingjing , Tang Ningyuan , Zhang Weiran , Wang Feng , Xie Zhuoying , Lin Fengming , Chang Xiaoai , Qian Bin , Zhang Yaqin , Lei Ting , Han Xiao
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is radioresistant. Due to their strong X-ray absorption capacity, gold nanoparticles (AuNPs) have been used as radiosensitizers for cancer therapeutics. Herein, we describe a novel conjugate complex consisting of a peptide for targeting plectin-1
(PTP) specifically expressed on the PDAC cell membrane and AuNPs, termed AuNP-PTP, to be used for PDAC radiotherapy in vitro and in vivo. Previous studies revealed that compared with unmodified AuNPs, AuNP-PTP along with relevant low-energy X-ray irradiation of 6 MV at a dose
of 2 Gy (RF) increased the targeting efficiency and induced apoptosis in treated PANC-1 cells and tumours. Importantly, extensive histopathological examination did not reveal evidence of acute or chronic injury in mice due to AuNPs or AuNP-PTP for up to six weeks despite the presence of X-ray
exposure. The delicate AuNP-PTP hybrid provides a novel strategy to enhance radiotherapy efficiency in PDAC treatment.
Visual Comparator: An Interactive Tool for Dynamic Spatiotemporal Comparative Visualizations
Authors: Cherukuru Nihanth W. , Scheitlin Tim
Published: June 2020

Visualizations enable us to detect patterns, time-evolving features, and trends in complex datasets that might not be obvious by looking at the raw data. The visual exploration process often requires comparisons between multiple visualizations, either from the same dataset or a different one, to identify relationships and patterns. This visualization process, referred to as comparative visualization, is valuable for analyzing multivariate, multispectral, or multidimensional data. The existing tools that facilitate visual comparisons do this by three means: juxtaposition (placing visuals side by side), superposition (overlaying visuals), and explicit encoding (visualizing a derived quantity corresponding to the relationship being studied). While superposition is ideal for static, geospatial datasets, where spatialization is a key component of the data, the spatiotemporal nature of Earth science datasets presents a challenge with comparative visualizations. Visual Comparator is an interactive, cross-platform (desktops, kiosks, and web), open-source application, developed to address this shortcoming. The application is used to superimpose and compare up to three synchronized, animated visualizations, and a transition between the visualizations is provided through a slider-based interface. This form of visualization has the advantage of drawing the viewers’ attention to changes between the datasets, enabling comparisons of scale, and reducing the clutter caused by having multiple variables in one visual. This article provides an overview of the project, a brief review of literature pertaining to human perception research and comparative visualizations, and a guide to accessing this application.