Biology subjects

Lake, R.

Publications and source records attributed to Lake, R..

10 recordsLinked to original sources

bioRxiv2026

DVT-primed neutrophils reshape the brain microenvironment to promote brain metastasis

Brain metastasis (BrM) is a devastating complication of triple-negative breast cancer (TNBC), yet how host macroenvironmental conditions influence brain metastatic susceptibility remains poorly understood. Here, we investigated the impact of deep vein thrombosis (DVT), a common complication in patients with cancer, on TNBC brain metastasis. Analysis of a large clinical cohort identified DVT as an independent risk factor for BrM in patients with metastatic breast cancer. Using two syngeneic TNBC models, we demonstrated that DVT selectively enhanced brain metastasis without significantly affecting primary tumor growth or lung metastasis. Mechanistically, DVT increased neutrophil accumulation in the brain metastatic microenvironment, and neutrophil depletion completely abrogated the metastasis-promoting effect of DVT. Single-cell RNA sequencing of CD45+ cells in peripheral blood revealed that DVT reprogrammed circulating neutrophils toward migratory and inflammatory transcriptomic profiles characterized by neutrophil extracellular trap (NET) formation. DVT increased CXCR2 expression on circulating neutrophils and enhanced neutrophil recruitment in brain. Moreover, DVT significantly increased circulating NETs. Collectively, our findings identify DVT as a systemic driver of TNBC brain metastasis and reveal that DVT primes circulating neutrophils toward enhanced vascular recruitment and NET formation, providing a mechanistic link between cancer-associated thrombosis and brain metastatic susceptibility.

molecular biology↗

bioRxiv2026

Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.

cancer biology↗

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2026

SCD1 inhibition synergizes with TMZ to improve IDH1 MUT glioma survival of mice via lipotoxic stress

Mutations in the isocitrate dehydrogenase enzyme (IDH1) are prevalent in low-grade gliomas, such as oligodendrogliomas. Other than surgery, radiation, and chemotherapy, few options for treatment exist. The standard of care for patients currently consists of maximal safe resection, as well as the potential use of radiation and chemotherapy, typically followed by radiographic surveillance. Although significant advances have been achieved, these have not translated into meaningful improvements in overall survival, warranting the development of novel therapies. Herein, we demonstrate that the inhibition of SCD1 in vitro leads to decreased colony formation and is more specific to IDH1MUT glioma than the IDH1WT cells, We further identified MF-438 as an active inhibitor of this enzyme and showed that this inhibitor is linked with iron transport and ferroptosis. MF438 depleted oleic (C18:1) and palmitoleic acid (C16:1) levels, driving saturated phosphatidylcholine (PC) accumulation and ER stress (INSIG1, SEL1L upregulation). TS603 exhibited selective polyunsaturated phosphatidylcholine reduction with downregulation of GPX4, FTH1, and KEAP1, and upregulation of NCOA4, SLC11A2, ALDH7A1, and DPP4, consistent with ferroptosis priming via ferritinophagy-driven expansion of the labile iron pool, as confirmed by FerroOrange flow cytometry. Neutral lipid metabolism genes (LPIN1, LDLR, PNPLA3, ACSL1), intracellular lipid transport genes (TMEM41B, OSBP, STARD4), and lipid droplet organization genes (SQLE, CHKA, AUP1) were coordinately upregulated in TS603 after treatment with MF-438. MF438+TMZ activated the integrated stress response (ATF3, DDIT3, IRF1, CDKN1A, GADD45B) and synergistically suppressed TS603 neurosphere growth (p=0.0326). In vivo combination between MF-438 and TMZ showed improved survival versus the TMZ-alone group, in an IDH1-mutant oligodendroglioma model. Tissue analyses showed significant reduced Ki67 expression, a marker of cellular proliferation, in the combination treatment. Collectively, these findings suggest that targeting lipid metabolism may enhance the efficacy of standard-of-care therapy in IDH1-mutant oligodendroglioma.

Cancer Biology↗

bioRxiv2026

Cell type-centric interaction networks define spatial architecture of intrahepatic cholangiocarcinoma

Tumor spatial organization critically shapes disease progression and therapeutic response, yet remains poorly defined. Intrahepatic cholangiocarcinoma (iCCA), a rare and aggressive liver malignancy with extensive stromal and immune remodeling, provides a compelling model to study tumor architecture. We generated a single-cell spatial atlas of 1 million cells from 131 iCCA patients using 53-plex spatial proteomics. To systemically characterize tumor spatial organization, we developed a graph-based deep learning framework to define cell type-centric interaction networks, identifying 41 distinct multicellular spatial patterns. Integration of these networks revealed higher-order tumor- and immune-enriched microenvironments associated with patient outcomes. Notably, neutrophil-associated tumor-enriched and tumor-desert microenvironments delineated patient groups with opposing clinical outcomes and distinct neutrophil states. These findings were validated by single-cell spatial transcriptomic profiling of 6 million cells from 162 iCCA patients. Together, this study defines the spatial architecture of iCCA and provides a comprehensive resource for exploring tumor spatial organization.

cancer biology↗

bioRxiv2026

Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) remains lethal as adaptive resistance to standard-of-care therapy develops, often driven by AR splice variants alongside transcriptional and translational reprogramming. To identify strategies capable of overcoming these mechanisms, we performed an unbiased high-throughput screen of 2,480 mechanistically annotated compounds across advanced prostate cancer models. Exportin-1 (XPO1)-mediated nuclear export emerged as a critical dependency, and matrix-based combination screening uncovered robust synergy between inhibitors of XPO1 and the translation initiation factor EIF4A1. Dual inhibition induced coordinated disruption of oncogenic protein networks, including AR/AR-V7, triggering apoptosis and suppressing cell-cycle and metabolic programs. These effects extended to genetically diverse patient-derived organoids and in vivo xenografts at low doses, approximately 8-fold (Eltanexor) and 12-fold (Zotatifin) below established human single-agent regimens. Together, these findings reveal concurrent control of nuclear export and protein translation as a therapeutic vulnerability in mCRPC, providing a strong rationale for clinical evaluation of XPO1-EIF4A1 co-inhibition to overcome AR-driven resistance. STATEMENT OF SIGNIFICANCEUnbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.

cancer biology↗

bioRxiv2024

Microenvironment Shapes Cell State, Plasticity, and Heterogeneity of Small Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Together, our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.

cancer biology↗

bioRxiv2022

A cancer stem cell population underlies a multi-lineage phenotype and drug resistance in prostate cancer

PurposeTo resist lineage-dependent therapies such as androgen receptor inhibition in prostate cancer, cancer cells often adopt a stem-like state resulting in lineage-plasticity and phenotypic heterogeneity. We assessed the dynamics of lineage determination and cellular subpopulation expansion in treatment-resistant adenocarcinoma, amphicrine, and small cell neuroendocrine castrate resistant prostate cancers (CRPCs). Experimental DesignWe developed CRPC patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model harboring epigenetic driver mutations, ARID1A and ARID1B, and displaying a range of luminal and neuroendocrine phenotypes. We used single-cell RNA-seq, barcode lineage-tracing, single-cell ATAC-seq, and RNA-FISH to delineate the subpopulation structure of the heterogeneous organoids and define the lineage hierarchy, determine potential transcriptional regulators of amphicrine lineage-plasticity, and identify subpopulation-specific molecular targets for therapeutic intervention. ResultsTranscriptionally similar stem/progenitor cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent stem/progenitor cells that produced mainly quiescent differentiated amphicrine progeny. Amphicrine cells were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures. By contrast, adenocarcinoma CRPC had a less defined hierarchy, as progeny originated from stem/progenitor cells and self-renewing differentiated luminal cells. NEPC was composed almost exclusively of self-renewing stem/progenitor cells. Amphicrine stem cells demonstrated concurrent transcription factor activities associated with stem/progenitor, luminal epithelial and mesenchymal lineages. Finally, the amphicrine stem/progenitor subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. ConclusionsThese data illuminate distinct origins and dynamics of subtype-specific CRPC plasticity in addition to demonstrating a strategy for targeting differentiation-competent stem cells. Translational RelevanceFor advanced prostate cancer, therapeutic resistance to androgen signaling suppression increasingly involves the development of lineage plasticity. The cellular states of transition and subpopulation heterogeneity that underlie lineage-plasticity are not well understood, which is an ongoing challenge to the design of effective treatments. Using patient-derived organoid models of various CRPC lineage subtypes, we observed distinct patterns with respect to stem/progenitor activity and associated growth phenotypes. The simultaneous expression of AR-driven and neuroendocrine identities, so-called amphicrine tumors, are thought to be an early dedifferentiation stage in plasticity-mediated resistance. We observed in an epigenetically-driven, amphicrine model of CRPC that a rare but necessary bipotent stem/progenitor population is suppressed by AURKA inhibitors, leading to tumor regression, while ARPC demonstrates both self-renewing differentiated luminal cells and stem/progenitors. These data suggest that AURKA inhibition may block the amplification of a resistance dedifferentiation pathway and should be considered in combination with AR signaling inhibitors for ARPC with characteristics of lineage plasticity.

cancer biology↗

bioRxiv2019

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity

Localized prostate cancer develops very slowly in most men, with the androgen receptor (AR) and MYC transcription factors amongst the most well-characterized drivers of prostate tumorigenesis. Canonically, MYC up-regulation in luminal prostate cancer cells functions to oppose the terminally differentiating effects of AR. However, the effects of MYC up-regulation are pleiotropic and inconsistent with a poorly proliferative phenotype. Here we show that increased MYC expression and activity are associated with the down-regulation of MEIS1, a HOX-family transcription factor. Using RNA-seq to profile a series of human prostate cancer specimens laser capture microdissected on the basis of MYC immunohistochemistry, MYC activity and MEIS1 expression were inversely correlated. Knockdown of MYC expression in prostate cancer cells increased expression of MEIS1 and increased occupancy of MYC at the MEIS1 locus. Finally, we show in laser capture microdissected human prostate cancer samples and the prostate TCGA cohort that MEIS1 expression is inversely proportional to AR activity as well as HOXB13, a known interacting protein of both AR and MEIS1. Collectively, our data demonstrate that elevated MYC in a subset of primary prostate cancers functions in a negative role in regulating MEIS1 expression, and that this down-regulation may contribute to MYC-driven development and progression.

cancer biology↗

bioRxiv2019

Low abundance of circulating tumor DNA in localized prostate cancer

Despite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease prior to treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease. We applied ultra-low pass whole genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases. We also performed similar analyses on patients with metastatic prostate cancer. In all cases of localized disease, even in clinically high-risk patients who subsequently recurred, we did not detect ctDNA by either method in plasma acquired before surgery or before recurrence. In contrast, ctDNA was detected from patients with metastatic disease. Our findings demonstrate clear differences between localized and advanced prostate cancer with respect to the dissemination and detectability of ctDNA. Because allele-specific alterations in ctDNA are below the threshold for detection in localized prostate cancer, other approaches to identify cell-free nucleic acids of tumor origin may demonstrate better specificity for aggressive disease.

genomics↗