Biology subjects

Oliver, T. G.

Publications and source records attributed to Oliver, T. G..

9 recordsLinked to original sources

bioRxiv2025

Transmembrane Serine Protease TMPRSS11B promotes an acidified tumor microenvironment and immune suppression in lung squamous cell carcinoma

Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. To determine the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME), we evaluated the effect of Tmprss11b depletion in a syngeneic mouse model. Tmprss11b depletion significantly reduced tumor burden in immunocompetent mice and triggered an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model revealed an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13+ hillock-like cells. Ultra-pH sensitive nanoparticle imaging and metabolite analysis identified regions of acidification, elevated lactate, and enrichment of M2-like macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.

cancer biology↗

bioRxiv2025

KLF4 promotes a KRT13+ hillock-like state in squamous lung cancer

Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumour-propagating cell states in squamous tumours, the broader landscape of intra-tumoural heterogeneity within LUSC remains poorly understood. Here, we employ Sox2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover previously unrecognized levels of cell fate diversity within LUSC. Specifically, we identify a KRT13+ hillock-like population of slower-dividing tumour cells characterized by immunomodulatory gene expression signatures. The tumour hillock-like state is conserved across multiple animal and human-derived models and is present in the majority of human LUSCs as well as head and neck and esophageal squamous tumours. Our findings shed light on the cellular origins of tumour hillock-like states: lung club cells give rise to tumours with luminal hillock-like populations, while basal-like tumour-propagating cells transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, KLF4 promotes KRT13, a broadly conserved hillock-like state with enrichment of potential therapeutic targets, and resistance to platinum-based chemotherapy. Together, these results provide molecular insights into the lineage plasticity underlying intra-tumoural heterogeneity within LUSC, offering potential avenues for new therapeutic strategies.

cancer biology↗

bioRxiv2024

Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer

Summary paragraphNeuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively1,2. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes3-13. The mechanisms driving neuroendocrine-tuft tumour heterogeneity, and the origins of tuft-like cancers are unknown. Using multiple genetically-engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovers unexpected transcriptional states and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss, and ASCL1 suppression, cooperate to promote tuft-like tumours. Transcriptomics of 944 human SCLCs reveal a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate remarkable conservation between cancer states and normal basal cell injury response mechanisms14-18. Together, these data suggest that the basal cell is a plausible origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity--offering new insights for targeting lineage plasticity.

cancer biology↗

bioRxiv2024

A Lung Cancer Mouse Model Database

Lung cancer, the leading cause of cancer mortality, exhibits diverse histological subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. Here we established the Lung Cancer Mouse Model Database (LCMMDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMMs), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model. Meticulous curation and collaboration with data depositors have produced a robust and comprehensive database, enhancing the fidelity of the genetic landscape it depicts. The LCMMDB aligns 859 tumors from GEMMs with human lung cancer mutations, enabling comparative analysis and revealing a pressing need to broaden the diversity of genetic aberrations modeled in GEMMs. Accompanying this resource, we developed a web application that offers researchers intuitive tools for in-depth gene expression analysis. With standardized reprocessing of gene expression data, the LCMMDB serves as a powerful platform for cross-study comparison and lays the groundwork for future research, aiming to bridge the gap between mouse models and human lung cancer for improved translational relevance.

cancer biology↗

bioRxiv2022

Lineage plasticity in SCLC generates non-neuroendocrine cells primed for vasculogenic mimicry

IntroductionVasculogenic mimicry (VM), the process of tumor cell trans-differentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including small cell lung cancer (SCLC). In genetically engineered mouse models (GEMMs) of SCLC, NOTCH and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs. MethodsWe analysed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX and GEMMs. VM-proficient cell subpopulations in ex vivo cultures were molecularly profiled by RNA sequencing and mass spectrometry. We evaluated their 3D structure and defined collagen-integrin interactions. ResultsWe show that VM vessels are present in 23/25 CDX models and in 2 GEMMs. Perfused VM vessels support tumor growth and only Notch-active non-NE cells are VM-competent in vivo and ex vivo, expressing pseudohypoxia, blood vessel development and extracellular matrix (ECM) organization signatures. On Matrigel, VM-primed non-NE cells re-model ECM into hollow tubules in an integrin {beta}1-dependent process. ConclusionsWe identify VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take significant steps towards understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve SCLC patient outcomes in future.

cancer biology↗

bioRxiv2022

Kinase Suppressor of Ras 2 regulates small-cell lung carcinoma tumor propagating cells

Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs) in vitro and their tumor initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target. ImplicationsManipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.

cancer biology↗

bioRxiv2021

BET Bromodomain Inhibitors Target the NEUROD1-subtype SCLC by Blocking NEUROD1 Transactivation

Small cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) are identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. These master factors have not been directly druggable, and targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. SignificanceSmall cell lung cancer (SCLC) is the most aggressive form of lung malignancies, and little progress has been made to improve its outcome in the past two decades. It is now recognized that SCLC is not a single disease but has at least four molecular subtypes, and each subtype features the expression of one master transcription factor. Unfortunately, these master transcription factors are not directly druggable. Here, we identified BET bromodomain proteins as the transcriptional coactivators of NEUROD1, one of the master transcription factors in SCLC. Blocking BET bromodomain proteins with inhibitors suppresses NEUROD1-target genes and reduces tumor growth. Our results demonstrate that blocking transcriptional coactivators could be an alternative approach to targeting the master transcription factors in SCLC.

cancer biology↗

bioRxiv2021

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

Small Cell Lung Cancer (SCLC) tumors are heterogeneous mixtures of transcriptional subtypes. Understanding subtype dynamics could be key to explaining the aggressive properties that make SCLC a recalcitrant cancer. Applying archetype analysis and evolutionary theory to bulk and single-cell transcriptomics, we show that SCLC cells reside within a cell-state continuum rather than in discrete subtype clusters. Gene expression signatures and ontologies indicate each vertex of the continuum corresponds to a functional phenotype optimized for a cancer hallmark task: three neuroendocrine archetypes specialize in proliferation/survival, inflammation and immune evasion, and two non-neuroendocrine archetypes in angiogenesis and metabolic dysregulation. Single cells can trade-off between these defined tasks to increase fitness and survival. SCLC cells can easily transition from specialists that optimize a single task to generalists that fall within the continuum, suggesting that phenotypic plasticity may be a mechanism by which SCLC cells become recalcitrant to treatment and adaptable to diverse microenvironments. We show that plasticity is uncoupled from the phenotype of single cells using a novel RNA-velocity-based metric, suggesting both specialist and generalist cells have the capability of becoming destabilized and transitioning to other phenotypes. We use network simulations to identify transcription factors such as MYC that promote plasticity and resistance to treatment. Our analysis pipeline is suitable to elucidate the role of phenotypic plasticity in any cancer type, and positions SCLC as a prime candidate for treatments that target plasticity.

systems biology↗

bioRxiv2020

ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin

ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss converts tumors to a SOX9+ mesenchymal/neural-crest-stem-like state that can differentiate into RUNX2+ bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. Together, SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation.

cancer biology↗