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Results for “cancer biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 127 records · Page 7Linked to original sources

bioRxiv2026

Genetically distinct microenvironment determines cancer survival and response to therapy in mice

Genetic uniqueness of the tumor microenvironment significantly influences cancer growth, survival, and response to therapy, independent of the cancer cells intrinsic properties or the adaptive immune system. Using genetically distinct Rag1-/- mouse models, this study shows that different strains exhibit varied tumor growth kinetics and survival outcomes when xenografted with identical leukemic and solid tumor cell lines. This study further highlights the critical role of the myeloid immune compartment and shows that disrupting both lymphoid and myeloid systems alters cancer progression. These results also reveal that the tumor microenvironment can permanently alter cancer cell phenotypes and significantly affect chemotherapy efficacy, as seen with Cisplatins varying effects across strains. These findings underscore the importance of considering genetic background in preclinical cancer models, suggesting that reliance upon a single mouse strain may lead to incomplete conclusions about cancer biology and treatment efficacy. SUMMARY STATEMENTPre-clinical xenograft mammalian models are used to study human diseases. Here we report that the genetic uniqueness of the tumor microenvironment, independent of the immune system, can determine the fate of cancer progression, survival, and therapy response.

cancer biology↗

bioRxiv2021

Relevance of Circulating Hybrid Cells as a Non-Invasive Biomarker for Myriad Solid Tumors

AbstractMetastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the ability to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease. Simple SummaryThere is an incomplete understanding of circulating neoplastic cell populations and the fundamental mechanisms that drive dissemination, immune evasion, and growth --all critical information to more effectively prevent and treat cancer progression. A novel disseminated tumor cell population, circulating hybrid cells, are detected across many cancer types and carry functional tumor-initiating properties. Additionally, circulating hybrid cells are found at significantly higher levels than conventionally defined circulating tumor cells. Our study demonstrates that neoplastic hybrid cells harbor phenotypic and genetic characteristics of tumor and immune cells, display stem features, and are a generalizable phenomenon in solid tumors. Circulating hybrid cells therefore have relevance as a novel biomarker and open a new field of study in malignancy.

cancer biology↗

bioRxiv2025

Integrative Machine Learning Reveals Potential Signature Genes Using Transcriptomics in Colon Cancer

BackgroundColon cancer is a significant health burden in the world and the second leading cause of cancer-related deaths. Despite advancements in diagnosis and treatment, identifying robust biomarkers for early detection and therapeutic targets remains imperative. Materials and methodsThis study used an integrative approach combining transcriptomics and machine learning to identify signature genes and pathways associated with colon cancer. RNA-Seq data from The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) project, comprising 485 samples (444 tumors and 41 normal tissues), were analyzed. ResultsDifferential gene expression analysis revealed 657 upregulated and 8,566 downregulated genes. Notably, EPB41L3, TSPAN7, and ABI3BP were identified as highly upregulated, while LYVE1, PLPP1, and NFE2L3 were significantly downregulated in tumor samples. Gene Set Enrichment Analysis (GSEA) identified dysregulated pathways, including E2F targets, MYC targets, and G2M checkpoints, underscoring cell cycle regulation and metabolic reprogramming alterations in colon cancer. Machine learning models-Random Forest, Neural Networks, and Logistic Regression-achieved high classification accuracy (97-99%) and near-perfect Area Under the Receiver Operating Characteristic Curve (AUC-ROC) values (approximately 1.00), validating their predictive capabilities. Key genes consistently identified across these models highlight their potential translational relevance as biomarkers. This study integrates differential expression analysis, pathway enrichment, and machine learning to uncover critical insights into colon cancer biology. ConclusionThe findings lay the groundwork for developing diagnostic and therapeutic strategies, with the identified genes and pathways serving as promising candidates for future validation and clinical applications. This approach exemplifies the potential of precision medicine to advance colon cancer research and improve patient outcomes.

cancer biology↗

bioRxiv2019

Identification of histological features to predict MUC2 expression in colon cancer tissues

Colorectal cancer (CRC) is the third-most common form of cancer among Americans. Like normal colon tissue, CRC cells are sustained by a subpopulation of \"stem cells\" that possess the ability to self-renew and differentiate into more specialized cancer cell types. In normal colon tissue, the enterocytes, goblet cells and other epithelial cells in the mucosa region have distinct morphologies that distinguish them from the other cells in the lamina propria, muscularis mucosa, and submucosa. However, in a tumor, the morphology of the cancer cells varies dramatically. Cancer cells that express genes specific to goblet cells significantly differ in shape and size compared to their normal counterparts. Even though a large number of hematoxylin and eosin (H&E)-stained sections and the corresponding RNA sequencing (RNASeq) data from CRC are available from The Cancer Genome Atlas (TCGA), prediction of gene expression patterns from tissue histological features has not been attempted yet. In this manuscript, we identified histological features that are strongly associated with MUC2 expression patterns in a tumor. Specifically, we show that large nuclear area is associated with MUC2-high tumors (p < 0.001). This discovery provides insight into cancer biology and tumor histology and demonstrates that it may be possible to predict certain gene expressions from histological features.

cancer biology↗

bioRxiv2023

Mutational order and epistasis determine the consequences of FBXW7 mutations during colorectal cancer evolution

Somatic driver mutations, in genes such as FBXW7, have been discovered in phenotypically normal colonic tissue, however their role in cancer initiation remains elusive. Using normal and gene-edited patient-derived human colon organoids as models of early tumour evolution we observed that FBXW7-/- mutations exerted an epistatic effect on subsequent transcription depending on the mutational background of the cell. Specifically, the timing of acquiring an FBXW7-/- mutation respective to an APC mutation, led to profound phenotypic and transcriptomic differences. When FBXW7 was mutated before APC, a near-normal cell state was maintained alongside repression of the APC transcriptional response. However, when APC was mutated before FBXW7, cells acquired classical cancer-stem cell features. Single-cell RNA sequencing revealed that mutation of FBXW7 in normal tissue subtly switched cells from adult to a foetal/regenerative stem cell state. Further analysis using transposase-accessible chromatin sequencing identified this cellular plasticity was driven by changes in chromatin accessibility of transcriptional start site regions associated with TEAD, SNAI1 and AP-1 motifs, which in turn activate the foetal-like state. Taken together, we demonstrate a critical role of FBXW7 mutations in preventing colorectal cancer initiation and provide exemplar evidence for the importance of epistasis and mutational order in cancer biology.

cancer biology↗

bioRxiv2024

Weekly inhaled salmeterol xinafoate, a selective β2 adrenergic receptor agonist drug, therapeutically inhibits cancer growth and prolongs survival in vivo

Humans have spent approximately 99.5% of the 2.5 million years of evolutionary history as hunter-gatherers, which helped to evolutionarily mold our minds and bodies to the hunting and gathering lifestyle. Physical activity associated with hunting animals, gathering plants, and evading predators is essential for human survival, evolution, and prosperity. Thus, physical activity (acute stress) is mostly beneficial to the body, whereas psycho-emotional stress (chronic stress) is usually detrimental at the psychological, physiological, and pathological levels. Although physical activity exerts anticancer effects and psycho-emotional stress exhibits cancer-promoting effects, both function through the same pathway involving activation of the sympathetic nervous system, release of catecholamines, and stimulation of {beta}2 adrenergic receptor ({beta}2AR) expressed on cancer cells. Here, salmeterol xinafoate was chosen to mimic physical activity. A once-weekly administration of salmeterol xinafoate by the intraperitoneal, inhalation, or transdermal route, dose-dependently extended latency, reduced cancer incidence and growth, and prolonged survival in vivo. Remarkably, the best complete response rates were 75%, 30%, and 71.43% for the therapeutic treatment of lung cancer, breast cancer, and melanoma, respectively. Notably, the salmeterol xinafoate doses used in our experiments are comparable to those used in patients. Moreover, in endogenous {beta}2AR knockout cancer cells, the exogenous {beta}2AR mutant with impaired salmeterol xinafoate binding or downstream signaling prevented the anticancer effects of salmeterol xinafoate in vivo, demonstrating the on-target action of salmeterol xinafoate on cancer cells and the requirement of the downstream signaling pathway. Finally, we showed that treatment with salmeterol xinafoate dose-dependently decreased the self-renewal capacity of lung cancer stem cells, breast cancer stem cells, and melanoma stem cells. From the perspective of human evolution into cancer biology, our study reveals that {beta}2AR represents an ideal anticancer drug target and that salmeterol xinafoate monotherapy has strong anticancer activity.

cancer biology↗

bioRxiv2021

A suspension technique for efficient large-scale cancer organoid culturing and perturbation screens

Organoid cell culture methodologies are enabling the generation of cell models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate the genetic and histopathological diversity of patient tumours are being systematically generated, providing an opportunity to investigate novel cancer biology and therapeutic approaches. The use of organoid cultures for many applications, including genetic and chemical perturbation screens, is limited due to the technical demands and cost associated with their handling and propagation. Here we report and benchmark a suspension culture technique for cancer organoids which allows for the expansion of models to tens of millions of cells with increased efficiency in comparison to standard organoid culturing protocols. Using whole-genome DNA and RNA sequencing analyses, as well as medium-throughput drug sensitivity testing and genome-wide CRISPR-Cas9 screening, we demonstrate that cancer organoids grown as a suspension culture are genetically and phenotypically similar to their counterparts grown in standard conditions. This culture technique simplifies organoid cell culture and extends the range of organoid applications, including for routine use in large-scale perturbation screens.

cancer biology↗

bioRxiv2024

NBBC: Quantifying the Prevalence of Non-B DNA Motifs as a Marker of Non-B Burden in Cancer

Alternative DNA structures, such as Z-DNA, G-quadruplexes, and mirror repeats, have shown potential involvement in cancer etiology. NBBC (Non-B DNA Burden in Cancer) is a web-based tool designed for quantifying and analyzing non-B DNA motifs within a cancer context. Herein, we provide a step-by-step protocol for employing NBBC, starting with data input and proceeding through the quantification and normalization of non-B DNA motifs that result in calculation of non-B burden. With detailed instructions for performing various motif-centric analyses based on cancer gene signatures, including DNA damage repair and response pathways for exploring genomic stability, and sample-level gene mutation signatures, a user is able to explore non-B associative correlations within current cancer biology. We provide additional detail on input queries into NBBC, interpret the quantitative results, and apply normalization techniques to ensure accurate comparisons across different genomic regions and non-B DNA structures. NBBC offers a powerful and user-friendly interface for the cancer research community. This chapter serves as an essential, enhanced instructional guide for researchers to leverage NBBC in their cancer biomarker investigations for an understanding of the potential role of non-B DNA in contributing to them.

cancer biology↗

bioRxiv2019

Improved detection of gene fusions by applying statistical methods reveals new oncogenic RNA cancer drivers

Short AbstractThe extent to which gene fusions function as drivers of cancer remains a critical open question. Current algorithms do not sufficiently identify false-positive fusions arising during library preparation, sequencing, and alignment. Here, we introduce a new algorithm, DEEPEST, that uses statistical modeling to minimize false-positives while increasing the sensitivity of fusion detection. In 9,946 tumor RNA-sequencing datasets from The Cancer Genome Atlas (TCGA) across 33 tumor types, DEEPEST identifies 31,007 fusions, 30% more than identified by other methods, while calling ten-fold fewer false-positive fusions in non-transformed human tissues. We leverage the increased precision of DEEPEST to discover new cancer biology. For example, 888 new candidate oncogenes are identified based on over-representation in DEEPEST-Fusion calls, and 1,078 previously unreported fusions involving long intergenic noncoding RNAs partners, demonstrating a previously unappreciated prevalence and potential for function. Specific protein domains are enriched in DEEPEST calls, demonstrating a global selection for fusion functionality: kinase domains are nearly 2-fold more enriched in DEEPEST calls than expected by chance, as are domains involved in (anaerobic) metabolism and DNA binding. DEEPEST also reveals a high enrichment for fusions involving known and novel oncogenes in diseases including ovarian cancer, which has had minimal treatment advances in recent decades, finding that more than 50% of tumors harbor gene fusions predicted to be oncogenic. The statistical algorithms, population-level analytic framework, and the biological conclusions of DEEPEST call for increased attention to gene fusions as drivers of cancer and for future research into using fusions for targeted therapy.\n\nSignificanceGene fusions are tumor-specific genomic aberrations and are among the most powerful biomarkers and drug targets in translational cancer biology. The advent of RNA-Seq technologies over the past decade has provided a unique opportunity for detecting novel fusions via deploying computational algorithms on public sequencing databases. Yet, precise fusion detection algorithms are still out of reach. We develop DEEPEST, a highly specific and efficient statistical pipeline specially designed for mining massive sequencing databases, and apply it to all 33 tumor types and 10,500 samples in The Cancer Genome Atlas database. We systematically profile the landscape of detected fusions via employing classic statistical models and identify several signatures of selection for fusions in tumors.\n\nSoftware availabilityDEEPEST-Fusion workflow with a detailed readme file is available as a Github repository: https://github.com/salzmanlab/DEEPEST-Fusion. In addition to the main workflow, which is based on CWL, example input and batch scripts (for job submission on local clusters), and codes for building the SBT files and SBT querying are provided in the repository. All custom scripts used for systematic analysis of fusions are also available in the same repository.

bioinformatics↗

bioRxiv2020

S-nitrosylated and non-nitrosylated COX2 has differential expression and distinct subcellular localization in normal and breast cancer tissue

Immunohistochemical staining in breast cancer shows both gain and loss of COX2 expression with disease risk and progression. We investigated four common COX2 antibody clones and found high specificity for purified human COX2 for three clones; however, recognition of COX2 in cell lysates was clone dependent. Biochemical characterization revealed two distinct forms of COX2, with SP21 recognizing an S-nitrosylated form and CX229 and CX294 appearing to recognize the same non-nitrosylated COX2 antigen. We found S-nitrosylated and non-nitrosylated COX2 occupy different subcellular locations in normal and breast cancer tissue, implicating distinct synthetic/trafficking pathways and function. Dual stains of ~2000 breast cancer cases show early onset breast cancer has increased expression of both forms of COX2 compared to postmenopausal cases. Our results highlight the strengths of using multiple, highly characterized antibody clones for COX2 immunohistochemical studies and raise the prospect that S-nitrosylation of COX2 may play a role in breast cancer biology.

cancer biology↗

bioRxiv2025

Pyrimethamine and a potent analogue WCDD115 inhibit NRF2 by suppressing DHFR and one-carbon metabolism

Nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2) is a critical mediator of the cellular oxidative stress response. Aberrant activation of NRF2 is common in lung and upper aerodigestive cancers, where it promotes tumor initiation and progression and confers resistance to chemotherapy, radiation therapy, and immune checkpoint inhibitors. As such, NRF2 therapeutic inhibitors are actively being sought. We previously reported that the antiparasitic drug Pyrimethamine (PYR) inhibits NRF2 in cell lines and in a NRF2-inducible genetically engineered mouse model. Here we design, synthesize, and define structure-activity relationships across a series of 25 PYR-based derivatives to reveal WCDD115 as a 22-fold more potent inhibitor of NRF2 (57nM versus 1.2{micro}M). PYR is known to inhibit plasmodial and human dihydrofolate reductase (DHFR). We found that WCDD115 inhibits hDHFR with 31-fold greater potency than PYR (144nM versus 4.49{micro}M). Metabolomics showed strong similarities between PYR, WCDD115 and methotrexate. Genetic, pharmacological and metabolic epistasis studies reveal that DHFR inactivation is required for NRF2 suppression by WCDD115 and PYR. Global and targeted proteomics revealed overlapping profiles for WCDD115, PYR and methotrexate, including suppression of NRF2 oxidative stress response and activation of TP53 and the DNA damage response. Therefore, PYR and a novel potent derivative WCDD115 are effective, indirect inhibitors of NRF2 and its antioxidant functions. These data underscore the importance of one- carbon metabolism for the NRF2 signaling pathway and support a new therapeutic strategy to suppress NRF2-driven cancer biology.

cancer biology↗

bioRxiv2024

Engineering oncogenic hotspot mutations on SF3B1 via CRISPR-directed PRECIS mutagenesis

SF3B1 is the most recurrently mutated RNA splicing factor in cancer; However, its study has been hindered by a lack of disease-relevant cell line models. Here, we compared four genome engineering platforms to establish SF3B1mutant cell lines: CRISPR-Cas9 editing, AAV HDR editing, base editing (ABEmax, ABE8e), and prime editing (PE2, PE3, PE5Max). We showed that prime editing via PE5max achieved the most efficient SF3B1 K700E editing across a wide range of cell lines. We further refined our approach by coupling prime editing with a with a fluorescent reporter that leverages a SF3B1 mutation-responsive synthetic intron to mark prime edited cells. Calling this approach prime editing coupled intron-assisted selection (PRECIS), we then introduced the K700E hotspot mutation into two chronic lymphocytic leukemia (CLL) cell lines, HG-3 and MEC-1, and demonstrated that our PRECIS-engineered cells faithfully recapitulate the altered splicing and copy number variation (CNV) events frequently found in CLL patients with SF3B1 mutation. Our results showcase PRECIS as an efficient and generalizable method for engineering genetically faithful SF3B1 mutant models, shed new light on the role of SF3B1 mutation in cancer biology, and enables generation of novel SF3B1 mutant cell lines in any cellular context.

cancer biology↗

bioRxiv2023

The translation of a short open reading frame product within the human TUBA1B gene regulates cancer cell proliferation by importin-β

Understanding cancer biology is crucial for improving treatment strategies. This study identified TUBA1B-sORF1, a short open reading frame product alternatively translated from the human -tubulin gene (TUBA1B), which has a completely different amino acid sequence from the -tubulin 1B chain. TUBA1B-sORF1 is highly expressed in cancer cell lines and gastric carcinoma. Both methionine-initiated canonical and leucine-initiated noncanonical translations of TUBA1B-sORF1 coexist in cancer cells, and there is a transition between sORF1 and -tubulin translations, evidenced by the TUBA1B-sORF1/-tubulinlow/- subpopulation. Knocking down TUBA1B-sORF1 reduces cancer cell proliferation and tumorigenicity. TUBA1B-sORF1 facilitates protein nuclear translocation, leading to the upregulation of proliferation-promoting genes and downregulation of proliferation-inhibiting genes. Specifically, it forms a complex with importin {beta} and {beta}-catenin, promoting {beta}-catenin nuclear translocation and target gene transcription. These findings reveal that TUBA1B is a polycistronic gene translating at least two entirely different proteins: -tubulin and TUBA1B-sORF1. The variable translation between them may regulate tumorigenesis, making TUBA1B-sORF1 a promising therapeutic target and diagnostic biomarker for cancer treatment.

cancer biology↗

bioRxiv2022

A cell circuit approach to dissect fibroblast-macrophage interactions in the tumor microenvironment

The tumor microenvironment (TME) is composed of various nonmalignant cell types that interact with each other and with cancer cells, impacting all aspects of cancer biology. The TME is complex and heterogeneous, and thus simplifying systems and concepts are needed. Here we provide a tractable experimental system and powerful mathematical circuit concepts to identify the main molecular interactions that govern the composition of the TME. We focus on two major components of the TME - cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs), define their interactions and verify our predictions in mouse and human breast cancer. We measure the population dynamics starting from many initial conditions of co-cultures of macrophages and organ-derived fibroblasts from mammary, lung, and fat, and explore the effects of cancer-conditioned medium on the circuits. We define the circuits and their inferred parameters from the data using a mathematical approach, and quantitatively compare the cell circuits in each condition. We find that while the homeostatic steady-states are similar between the organs, the cancer-conditioned medium profoundly changes the circuit. Fibroblasts in all contexts depend on autocrine secretion of growth factors whereas macrophages are more dependent on external cues, including paracrine growth factors secreted from fibroblasts and cancer cells. Transcriptional profiling reveals the molecular underpinnings of the cell circuit interactions and the primacy of the fibroblast autocrine loop. The same fibroblast growth factors are shared by the co-cultures and mouse and human breast cancer. The cell circuit approach thus provides a quantitative account of cell interactions in the cancer microenvironment.

cancer biology↗

bioRxiv2016

An RNA editing/binding-independent gene regulatory mechanism of ADARs and its clinical implication in cancer

Adenosine-to-inosine (A-to-I) editing, catalysed by Adenosine DeAminases acting on double-stranded RNA (dsRNA) (ADAR), occurs predominantly in the 3 untranslated regions (3UTRs). Here we uncover an unanticipated link between ADARs (ADAR1 and ADAR2) and the expression of target genes undergoing extensive 3UTR editing. Using METTL7A (Methyltransferase Like 7A), a novel tumor suppressor as an exemplary target gene, we demonstrate that its expression could be repressed by ADARs beyond their RNA editing and dsRNA binding functions. ADARs interact with Dicer to augment the processing of pre-miR-27a to mature miR-27a. Consequently, mature miR-27a targets the METTL7A 3UTR to repress its expression level. In sum, our study unveils that the extensive 3UTR editing is merely a footprint of ADAR binding, and is dispensable for the regulation of at least a subset of target genes. Instead, ADARs contribute to cancer progression by regulating cancer-related gene expression through their non-canonical functions independent of RNA editing and dsRNA binding. The functional significance of ADARs is much more diverse than previously appreciated and this gene regulatory function of ADARs is most likely to be of higher importance than the best-studied editing function. This novel non-editing side of ADARs opens another door to target cancer. This study is timely and represents a major break-through in the field of ADAR gene regulation and cancer biology.

Cancer Biology↗

bioRxiv2021

CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that expression of voltage gated calcium channels (VGCC) is increased in cancer, particularly the CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients regardless of TMPRSS2:ERG status. Corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. The expression was found to be a shortened 170kDA CaV1.3 isoform associated which failed to mediate calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This in turn drove both proliferation and survival of long-term ADT CRPC cells. Overall, this study demonstrates for the first time in PCa that increased SOCE through a novel CaV1.3 mechanism which represents a novel oncogenic switch that contributes to ADT resistance and promotes CRPC biology. Highlighting aberrant intracellular calcium in CRPC as a potential area for therapeutic development to improve patient outcomes.

cancer biology↗

bioRxiv2022

Sensitive Spatiotemporal Tracking of Spontaneous Metastasis in Deep Tissues via a Genetically-Encoded Magnetic Resonance Imaging Reporter

Metastasis remains a poorly understood aspect of cancer biology and the leading cause of cancer-related death, yet most preclinical cancer studies do not examine metastasis, focusing solely on the primary tumor. One major factor contributing to this paradox is a gap in available tools for accurate spatiotemporal measurements of metastatic spread in vivo. Our objective was to develop an imaging reporter system that offers sensitive three-dimensional detection of cancer cells at high resolutions in live mice. We utilized organic anion-transporting polypeptide lb3 (oatp1b3) as a magnetic resonance imaging (MRI) reporter gene to this end, and systematically optimized its framework for in vivo tracking of viable cancer cells in a spontaneous metastasis model. We were able to image metastasis on oatp1b3-MRI at the single lymph node level and continued to track its progression over time as cancer cells spread to multiple lymph nodes and different organ systems in single animals. While initial single lesions were successfully imaged in parallel via bioluminescence, later metastases were obscured by light scatter from the initial node. Importantly, we demonstrate and validate that 100-m isotropic resolution MR images could detect micrometastases in lung tissue estimated to contain fewer than 103 cancer cells. In summary, oatp1b3-MRI enables precise determination of lesion size and location over time and offers a path towards deep-tissue tracking of any oatp1b3-engineered cell type with combined high resolution, high sensitivity, 3D spatial information, and surrounding anatomical context.

bioengineering↗

bioRxiv2020

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma

ZBP1 is an inducible, non-constitutively expressed cellular nucleic acid sensor that triggers type I interferon (IFN) responses via phosphorylation and activation of the transcription factor (TF) IRF3 by TBK1. However, the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively and constitutively expressed in late B cell development and it is required for optimal T cell-dependent humoral immune responses. In the plasma cell (PC) cancer multiple myeloma, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. Notably, rather than IFN type I response genes, IRF3 directly activates, in part through co-operation with the PC lineage-defining TF IRF4, cell cycle genes thus promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. These data expand our knowledge of the role of cellular immune sensors in cancer biology.

cancer biology↗