SEARCH · Search bioRxiv

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources

bioRxiv2018

Systems Biology Understanding of the Effects of Lithium on Cancer.

Lithium has many widely varying biochemical and phenomenological effects, suggesting that a systems biology approach is required to understand its action. Multiple lines of evidence point to lithium as a significant factor in development of cancer, showing that understanding lithium action is of high importance. In this paper we undertake first steps towards a systems approach by analyzing mutual enrichment between the interactomes of lithium-sensitive enzymes and the pathways associated with cancer. This work integrates information from two important databases, STRING and KEGG pathways. We find that for the majority of cancer pathways the mutual enrichment is many times greater than chance, reinforcing previous lines of evidence that lithium is an important influence on cancer.

cancer biology↗

bioRxiv2025

Beyond One-Size-Fits-All: Tumor Biology Influences Nanoparticle Behaviour in Cancer Models

Nanoparticles (NPs) are a promising tool for cancer therapy, yet few have successfully reached clinical application. Current nanomedicine development pipelines are focused on optimizing physical properties of NPs, overlooking the impact of tumor biology on their behavior. Here, we show that the same NPs exhibit distinct accumulation and penetration patterns in 3D spheroids derived from four tumor models (representative of lung, colon, breast, and cervical cancer). We uncover an inverse relationship between NP uptake and penetration: tumors with slower internalization show deeper NP diffusion. Proteomic analysis revealed that tumor-specific expression of endocytic and extracellular matrix proteins underlies this variability. Our findings challenge the prevailing one-size-fits-all approach and highlight the need to integrate tumor biology into NP design. Tailoring NPs to the unique cellular and extracellular features of each tumor type will be critical for developing more effective and clinically relevant nanotherapies.

cell biology↗

bioRxiv2022

Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity of the cell states and dynamic changes in GB. Large-scale data integration can help to uncover unexplored tumor pathobiology. Here, we resolved the composition of the tumor milieu and created a cellular map of GB ( GBmap), a curated resource that harmonizes 26 datasets gathering 240 patients and spanning over 1.1 million cells. We showcase the applications of our resource for reference mapping, transfer learning, and biological discoveries. Our results uncover the sources of pro-angiogenic signaling and the multifaceted role of mesenchymal-like cancer cells. Reconstructing the tumor architecture using spatially resolved transcriptomics unveiled a high level of well-structured neoplastic niches. The GBmap represents a framework that allows the streamlined integration and interpretation of new data and provides a platform for exploratory analysis, hypothesis generation and testing. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/505439v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@7f0d76org.highwire.dtl.DTLVardef@14cbe3borg.highwire.dtl.DTLVardef@15d1e69org.highwire.dtl.DTLVardef@77b16f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

The impact of patient biology on racial disparities in breast cancer outcome

Hormone receptor positive (HR+) breast cancer is the most common subtype of breast cancer diagnosed globally. Despite effective targeted therapies, HR+ breast cancer remains a leading cause of cancer-related death in women. Long-standing epidemiological research identifies significantly worse outcomes for Black women diagnosed with HR+ breast cancer relative to White women. While structural factors such as access to healthcare and education level contribute to this outcome disparity, it persists even in analyses where these factors are controlled. In-depth analyses of the somatic molecular biology that may underlie these outcome disparities are hampered by a lack of datasets that represent Black patient populations. Here, we generate a HR+ breast cancer patient transcriptomic dataset that overrepresents Black women and controls for access to healthcare and education level. We find that signatures relating to the tumor microenvironment, i.e. collagen deposition and prognostically unfavorable T-cell landscapes are enriched in HR+ tumors from Black women. Importantly, we find, using experimental model systems in vitro and in vivo, that race-aligned collagen deposition patterns are at least partially attributable to tumor cell-intrinsic signaling and critical for Black breast cancer metastasis. We also find that unfavorable T-cell signatures in HR+ tumors from Black women, which have previously been attributed to race and ancestry, are more strongly poverty-aligned. Using multiple independent datasets, we identify STAT4 as a potential master regulator of this poverty-associated tumor immune signature. Together, these findings provide new evidence that somatic molecular biology of breast cancer patients can be modified by multiple structural factors such as self-identified race and poverty burden to promote poor patient outcomes. Integrating an understanding of structural factors into molecular cancer research is critical for implementing truly personalized, and maximally effective, oncology systems.

cancer biology↗

bioRxiv2017

Quantifying Spontaneous Metastasis In A Syngeneic Mouse Melanoma Model Using Real Time PCR

Modeling metastasis in vivo with animals is a priority for both revealing mechanisms of tumor dissemination and developing therapeutic methods. While conventional intravenous injection of tumor cells provides an efficient and consistent system for studying tumor cell extravasation and colonization, studying spontaneous metastasis derived from orthotopic tumor sites has the advantage of modeling more aspects of the metastatic cascade, but is challenging as it is difficult to detect small numbers of metastatic cells. In this work, we developed an approach for quantifying spontaneous metastasis in the syngeneic mouse B16 system using real time PCR. We first transduced B16 cells with lentivirus expressing firefly luciferase Luc2 gene for bioluminescence imaging. Next, we developed a real time quantitative PCR (qPCR) method for the detection of luciferase-expressing, metastatic tumor cells in mouse lungs and other organs. To illustrate the approach, we quantified lung metastasis in both spontaneous and experimental scenarios using B16F0 and B16F10 cells in C57BL/6Ncrl and NOD-Scid Gamma (NSG) mice. We tracked B16 melanoma metastasis with both bioluminescence imaging and qPCR, which were found to be self-consistent. Using this assay, we can quantitatively detect one Luc2 positive tumor cells out of 104 tissue cells, which corresponds to a metastatic burden of 1.8x104 metastatic cells per whole mouse lung. More importantly, the qPCR method was at least a factor of 10 more sensitive in detecting metastatic cell dissemination and should be combined with bioluminescence imaging as a high-resolution, end-point method for final metastatic cell quantitation. Given the rapid growth of primary tumors in many mouse models, assays with improved sensitivity can provide better insight into biological mechanisms that underpin tumor metastasis.

cancer biology↗

bioRxiv2019

Inhibition of tumor growth by a novel engineered chimeric toxin that cleaves activated mutant and wild-type RAS

Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small molecule approaches has proven to be a major challenge. Here we describe the development of a novel pan-RAS biologic inhibitor comprised of the RAS-RAP1-specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Further, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS. Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising new approach to developing RAS therapeutics against a broad array of cancers. SignificanceRAS oncoproteins have long been considered among the most elusive drug targets in cancer research. At issue is the lack of accessible drug binding sites and the extreme affinity for its GTP substrate. Covalent inhibitors against the KRAS G12C mutant have shown early clinical promise, however, targeting the other oncogenic RAS mutants across three RAS isoforms has proven challenging. Inhibition of activated wild-type RAS in the absence of canonical RAS mutations is also highly desirable in certain tumors. Here, we demonstrate delivery of an extremely potent pan-RAS and RAP1 cleaving enzyme in therapeutic quantities to specific receptor-bearing cells in vitro and in vivo. We aim to advance this approach to engineer the first targeted pan-RAS inhibitor for cancer therapy. One Sentence SummaryEngineered chimeric toxin halts tumor growth in vivo via RAS cleavage

cancer biology↗

bioRxiv2022

Probing the Biology of Zinc Alpha2-Glycoprotein and the role it plays in cachexia

Cachexia is a metabolic disease that results in drastic weight loss and muscle wasting. 20% of total cancer patients will die due to cachexia related complications. ZAG contributes to the regulation of weight and body fat through lipid and glucose metabolism. In healthy individuals, ZAG exerts a homeostasis effect by inducing lipolysis of adipose tissue to help reduce fat storage and overall weight. ZAG is upregulated in various carcinomas and cancer patients with upregulated ZAG are observed to lose weight rapidly. The mutants of ZAG which are the 4 amino acids Tryptophan 148, Arginine 73, Phenylalanine 101, Isoleucine 76 have all been mutated to Alanine. The effect of mutants and the wild type ZAG can also be found out by conducting experiments. ZAG has a potential lipid binding site that could be imperative to the function of ZAG. A lipolysis colorimetric kit allows us to measure the ZAG variants effects on 3T3 adipose cells to determine what {beta}-adrenoreceptor signaling pathways are being utilized in its lipolytic effect. The Tryptophan-Alanine mutant showed increased lipolysis after 1h treatment than other variants. The time period is also a rate limiting step which can play major factor in lipolysis. The ultimate goal is to identify the ligand(s) and the interactions between them and ZAG. The design of a therapeutic would give patients options of treatments brought about by attenuating the weight loss. With this, it would offer a better prognosis for patients and provide them with a greater quality of life.

cancer biology↗

bioRxiv2023

Bone Morphogenetic Protein (BMP) signaling upregulates expression of the E protein repressors, ID1 and ID3, in pancreatitis and pancreatic ductal adenocarcinoma

Identification of biological modulators of pancreatic ductal adenocarcinoma (PDAC) initiation and progression is of critical importance as it remains one of the deadliest cancers. We have previously shown that ID1 and ID3 are highly expressed in human PDAC and function to repress expression of E47 target genes involved in acinar cell differentiation and quiescence. Here, mining of large bulk RNA-seq and single cell RNA-seq (scRNA-seq) datasets has associated high expression of ID1 and ID3 with poor PDAC patient survival. We show that upregulated expression of ID1 and ID3 in human PDAC cells occurs in response to canonical BMP signaling through pSMAD1/5/9. Conversely, treatment with Noggin, an endogenous BMP antagonist, or with DMH1 and LDN193189, small molecule inhibitors of BMP receptors, reduced expression of ID1, ID3 and cell cycle control genes. Based on our RNA-seq and immunohistochemical analyses, upregulation of BMP signaling to ID1 and ID3 is an early event that occurs in human pancreatic intraepithelial neoplasia (PanIN) and murine models of pre-neoplastic lesions induced by mutant Kras. Strikingly, the same result was observed in a murine model of pancreatitis induced by the cholecystokinin (CCK) analog caerulein. Moreover, we show that caerulein is sufficient to induce BMP signaling and expression of ID1 and ID3 in a cell-autonomous manner in non-transformed rodent exocrine pancreas cells. Together, the data suggest that canonical BMP signaling upregulates expression of ID1 and ID3 early in pancreas pathogenesis and that pancreatic cancer cells remain addicted to this important signaling circuit as the disease progresses. Future exploration of druggable targets within this pathway could be of therapeutic benefit in the treatment of pancreatitis and PDAC.

cancer biology↗

bioRxiv2019

APC2 is Critical for Ovarian WNT Signalling Control, Fertility and Tumour Suppression

Canonical WNT signalling plays a critical role in the regulation of ovarian development; mis-regulation of this key pathway in the adult ovary is associated with subfertility and tumourigenesis. The roles of Adenomatous polyposis coli 2 (APC2), a little-studied WNT signalling pathway regulator, in ovarian homeostasis, fertility and tumourigenesis have not previously been explored. Here, we demonstrate for the first time using constitutive APC2-knockout (Apc2-/-) mice, essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. APC2-deficiency resulted in activation of ovarian WNT signalling and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which could not be rescued by administration of gonadotrophins. Defects in steroidogenesis and follicular vascularity contributed to the subfertility phenotype. Tumour incidence was assessed in aged APC2-deficient mice, which also carried a hypomorphic Apc allele. APC2-deficiency in these mice resulted in predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and a histologic pattern and molecular signature seen in human adult GCTs. Hence, APC2 has an important tumour-suppressor activity within ovarian granulosa cells, most likely due to its role in regulating WNT-signalling. Importantly, given that the APC2-deficient tumours recapitulate the molecular signature and histological features of human adult GCTs, this APC2-deficient mouse has excellent potential as a pre-clinical model to study ovarian tumour biology and for therapeutic testing.

cancer biology↗

bioRxiv2020

Highly multiplexed quantitative phosphosite assay for biology and preclinical studies

Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug-treatment in cells and tissues but are presently lacking. Here we present SigPath, a targeted mass spectrometry (MS) assay that measures 284 phosphosites in 200 phosphoproteins of biological interest. SigPath probes a broad swath of signaling biology with high throughput and quantitative precision. We applied the assay to investigate changes in phospho-signaling in drug-treated cancer cell lines, breast cancer preclinical models and human medulloblastoma tumors. In addition to validating previous findings, SigPath detected and quantified a large number of differentially regulated phosphosites newly associated with disease models and human tumors at baseline or with drug perturbation. Our results highlight the potential of SigPath to monitor phosphoproteomic signaling events and to nominate mechanistic hypotheses regarding oncogenesis, response and resistance to therapy.

cancer biology↗

bioRxiv2023

Senescent cells and macrophages cooperate through a multikinase signaling network to promote intestinal transformation in Drosophila.

Cellular senescence is a conserved biological process essential for embryonic development, tissue remodeling, repair, and a key regulator of aging. Senescence also plays a crucial role in cancer, though this role can be tumor-suppressive or tumor-promoting, depending on the genetic context and the microenvironment. The highly heterogeneous, dynamic, and context-dependent nature of senescence-associated features and the relatively small numbers of senescent cells in tissues makes in vivo mechanistic studies of senescence challenging. As a result, which senescence-associated features are observed in which disease contexts and how they contribute to disease phenotypes remain largely unknown. Similarly, the specific mechanisms by which various senescence-inducing signals are integrated in vivo to induce senescence and why some cells become senescent while their immediate neighbors do not are unclear. Here, we identify a small number of cells that exhibit multiple features of senescence in a genetically complex model of intestinal transformation we recently established in the developing Drosophila larval hindgut epithelium. We demonstrate that these cells emerge in response to concurrent activation of AKT, JNK, and DNA damage response pathways within transformed tissue. Eliminating senescent cells, genetically or by treatment with senolytic compounds, reduces overgrowth and improves survival. We find that this tumor-promoting role is mediated by Drosophila macrophages recruited to the transformed tissue by senescent cells, which results in non-autonomous activation of JNK signaling within the transformed epithelium. These findings emphasize complex cell-cell interactions underlying epithelial transformation and identify senescent cell-macrophage interactions as a potential druggable node in cancer. One sentence summary: Interactions between transformed senescent cells and macrophages drive tumorigenesis.

cancer biology↗

bioRxiv2025

Spatial dissection of ADC/RPT targets defines therapeutic opportunities inrhabdoid tumors

Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP, CXCR4, and IL13RA2 and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC, and eMRT). Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features. These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target discovery in pediatric cancer.

cancer biology↗

bioRxiv2025

An LC-MS/MS method for the quantification of tobacco-specific carcinogen protein adducts.

4-(Methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its major metabolite 4-(methylnitrosamino)-l-(3-pyri-dine)-l-butanol (NNAL) are tobacco-specific lung carcinogens. Methods have been developed to quantify NNK- and NNAL-specific DNA adducts in pre-clinical samples but are less feasible to translation due to limited access to target tissues for sufficient DNA. NNAL-specific DNA or protein adducts have never been detected in clinical samples, which are critical to support the physiological relevance of NNAL bioactivation and carcinogenesis. We reported a sensitive and specific LC-MS/MS method to quantify hydrolyzed NNAL adduct, 1-(3-pyridinyl)-1,4-butanediol (PBD). The method was applicable to variety of biological samples, to assess tobacco exposure and estimate NNAL bioactivation.

cancer biology↗

bioRxiv2026

Differential Transcript Usage Reveals Isoform-Level Remodeling of Tumor Biology in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is characterized by transcriptional reprogramming driven by hypoxia signaling, metabolic rewiring, and immune modulation. While gene-level analyses have defined key features of ccRCC biology, they do not capture isoform-level variation arising from alternative splicing. Differential transcript usage (DTU) represents an additional regulatory layer that may influence protein function, pathway activity, and clinical outcomes, yet its role in ccRCC biology and prognosis remains incompletely understood. We assessed differential expression in 127 ccRCC tumors and 33 normal-adjacent tissues from the Dartmouth Cancer Center cohort, with external validation in 94 CPTAC tumors, adjusting for cell-type proportions. DTU was identified using DRIMSeq/stageR, followed by limmavoom modeling with clinical and tumor microenvironment covariates. Transcript-based consensus clustering defined tumor subgroups, and Cox proportional hazards modeling integrated transcript-level features with clinical variables. In tumor versus normal comparisons, 1,170 transcripts exhibited significant differential usage, mapping to canonical ccRCC pathways with distinct patterns across functional and non-functional transcript classes. Consensus clustering based on transcript us-age identified two subgroups with distinct angiogenic profiles and significant survival differences. Cluster-level analysis revealed DTU in genes involved in cytoskeletal organization (ACTB), immune processes (B2M), extracellular matrix organization (FN1, APLP2), and iron metabolism (FTH1) with protein domain alterations, including the loss of actin-associated domains in ACTB and immunoglobulin-like domains in B2M. Prognostic modeling identified twelve transcripts consistently retained across bootstraps, improving risk stratification over clinical variables alone. External validation confirmed overlapping prognostic transcripts, including FGFR1 and NUCB1. Isoform-level features may serve as biomarkers and therapeutic targets in ccRCC. Statement of significanceTranscript-level analysis uncovers potential regulatory pathways in ccRCC missed by gene-level approaches, revealing isoform-specific alterations that define survival sub-groups and offer potential biomarkers and therapeutic targets.

cancer biology↗

bioRxiv2020

A novel role of MNT as a negative regulator of REL and the NF-κB pathway

MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and c-REL (REL), the oncogenic member of the REL/NF-{kappa}B family. REL is involved in important biological processes and it is found altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with I{kappa}B and translocates to the nucleus when the NF-{kappa}B pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-{kappa}B pathway. Meanwhile, MNT overexpression results in the repression of I{kappa}B, a bona-fide REL target. Indeed, both MNT and REL bind to the I{kappa}B gene at a region mapping in the first exon, suggesting its regulation as a MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-{kappa}B pathway by two different mechanisms: 1) retention of REL in the cytoplasm by MNT protein interaction and 2) MNT-driven repression of REL-target genes through a MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and the NF-{kappa}B pathways, two of the most prominent pathways involved in cancer.

cancer biology↗

bioRxiv2025

IMMUNIA: A Multi-LLM Reasoning Agent for Immunoregulatory Surfaceome Discovery

Biomarker discovery for immunotherapy often requires reasoning across complex immune contexts. We present IMMUNIA, a multi-large-language-model (multi-LLM) reasoning agent designed to identify immunoregulatory surfaceome genes through interpretable, biologically grounded analysis. The term IMMUNIA originates from the fusion of Immune and Noeia (the Greek concept of perception and understanding), defining an AI system that perceives, reasons, and interprets the immune landscape with human-like cognition. IMMUNIA integrates structured prompting, contextual scoring across immunotherapy, inflammation, and NF-{kappa}B signaling, and consensus reasoning across GPT-4o, GPT-5, and Gemini 2.5 Pro. Benchmarking with positive (HLA) and negative (contactin) controls confirmed model consistency and contextual discrimination. Consensus evaluation prioritized IL1R1, BSG, CD276, ALCAM, B2M, PTPRS, VCAN, and MXRA5 as high-confidence candidates. Among these, PTPRS, VCAN, and MXRA5 emerged as previously unrecognized stromal immune checkpoint-like regulators, shaping tumor-immune crosstalk via phosphatase, ECM, and cytokine signaling networks. IMMUNIA thus establishes a reasoning-centric AI paradigm that bridges computational inference with biological plausibility, offering a scalable approach for precision immunotherapy biomarker discovery.

cancer biology↗

bioRxiv2018

Imprint of parity and age at first birth on the genomic landscape of subsequent breast cancer

BackgroundAlthough parity and age at first birth are among the most known extrinsic factors that modulates breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. In this study, we investigate the imprint of parity and age at first birth on the pattern of somatic mutations, somatic copy number alterations (SCNAs), transcriptomic profiles, and tumor infiltrating lymphocytes (TILs) levels of subsequent breast cancer.\n\nMethodsA total of 313 patients with primary breast cancer with available whole genome and RNA sequencing data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first birth as a cut-off value. PABC was defined as patients diagnosed up to 10 years postpartum.\n\nResultsGenomic alterations of breast cancer are associated with age at first birth but not parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7% Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; Padj = 0.010) and MYC amplification (28% vs. 7% Padj = 0.008), and a lower prevalence of mutational signature 2. PABC were associated with increased TILs infiltration (Padj = 0.0495).\n\nConclusionsThese findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. With the rapid development of precision oncology, this work advocates that reproductive history should not be underestimated in future clinical studies of breast cancer.

cancer biology↗

bioRxiv2018

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response.\n\nSIGNIFICANCEThe cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.

cancer biology↗