Biology subjects

Wong, K.-K.

Publications and source records attributed to Wong, K.-K..

At least 19 recordsLinked to original sources

bioRxiv2026

Cancer cell adaptations along a proliferation-robustness axis drive TME pro-tumor phenotypes

Tumors are highly complex dynamic ecosystems with causal relationships between cancer cells and their tumor microenvironment (TME). To disentangle these interactions, we performed long-term co-culture experiments with cancer cells evolving alongside continuously replenished fibroblasts or macrophages. This allowed us to distinguish between adaptive and physiological responses in specific cancer-TME interactions, which we then also recapitulated in patient tumors. We found that co-culture with fibroblasts induced the epithelial-mesenchymal transition in cancer cells and resulted in their increased drug tolerance, while co-culture with macrophages promoted stress, hypoxia responses and enhanced tumorigenicity. Adaptations were recurrent and partially reversible, but could not be explained by clonal selection, suggesting a dynamic non-mutational process. Moreover, adapted cancer cells elicited cell state changes in the fibroblasts and macrophages consistent with an extended phenotype mode of cancer evolution. Our findings reframe cancer-TME interactions by a systematic dissection according to sets of specific adaptations and programmed responses.

cancer biology↗

bioRxiv2026

Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRASG12C suppresses PI3Kα and leads to potent tumor inhibition

Current approved KRASG12C inhibitors covalently bind the inactive GDP-bound (OFF) form of KRASG12C. Recently, KRASG12C inhibitors that selectively bind to the GTP-bound (ON) form of both KRASG12C (ON) and (OFF) forms have been reported and entered clinical testing. In principle, KRASG12C (ON) inhibitors may be less susceptible to adaptive mechanisms that promote resistance to (OFF) inhibitors, however the specific mechanisms that differentiate the activity of (ON) versus (OFF) inhibition are not well understood. We profiled the activity of BBO-8520, a covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, in KRASG12C-mutant non-small cell lung cancer models. BBO-8520 exerted more potent and sustained inhibition of KRASG12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRASG12C (OFF)-only inhibitor. While cells treated with BBO-8520 or sotorasib both exhibited feedback reactivation of MAPK signaling driven by wild-type HRAS/NRAS isoforms, more durable suppression of KRASG12C by BBO-8520 was associated with decreased PI3K-AKT activation in vitro. Disruption of the interaction between RAS and PI3K using a novel protein:protein interaction inhibitor suppressed PI3K-AKT activation and increased the tumor response to sotorasib to a similar level as BBO-8520. Moreover, in some contexts, disruption of RAS-PI3K further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3K-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3K-AKT to improve the response to KRAS inhibitors.

cancer biology↗

bioRxiv2026

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer

The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRASG12D-selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977 in pancreatic cancer models. RNA-sequencing analyses revealed a KEAP1KO transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating a distinct mechanism of resistance. We then established a PDAC KEAP1-deficient (PKD) gene signature that was enriched in patients and preclinical models insensitive to KRAS inhibitor treatment. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the glutamine antagonist DRP-104 (sirpiglenastat) enhanced KRAS inhibitor suppression of pancreatic and lung tumors. SIGNIFICANCEKEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

cancer biology↗

bioRxiv2025

Design and Development of DNA Damage Chemical Inducers of Proximity (DD-CIP) for Targeted Cancer Therapy

Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair particularly in homologous recombination (HR)-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce "DNA Damage Chemical Inducers of Proximity" (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemical induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1 which induces the DNA damage response (DDR) and apoptosis to a range of cancer lines at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to anti-tumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical induced proximity as a strategy for modulating the DDR in cancer.

cancer biology↗

bioRxiv2025

Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB mediated inflammatory response in Triple Negative Breast Cancer

Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor five-year prognosis1. Here, we demonstrate that among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) in TNBC, induces a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-{kappa}B. TNBC cells exhibit markedly higher levels of DNA damage and canonical NF-{kappa}B activation compared to luminal breast cancer cells. Notably, NF-{kappa}B activation in this context depends on the canonical component RELA, but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contribute to NF-{kappa}B activation following POLE suppression. In vivo, POLE suppression in a murine TNBC model leads to cancer cell-intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-{kappa}B-mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC.

cancer biology↗

bioRxiv2025

Cross-species analysis identifies genotype-driven vulnerabilities in lung adenocarcinoma

While three major genetic alteration subsets, characterized by mutations in STK11, KRAS, and EGFR, are seminal in driving tumorigenesis in LUAD, their distinct effects on tumor cells and the tumor microenvironment are not fully understood. Here, we map critical oncogenic subset-specific vulnerabilities by identifying conserved cell-type-specific reprogrammings between human and mouse LUAD. Through harmonized scRNA-seq analysis of 57 human and 18 mouse specimens, we unveil that genetic alterations impose genotype-specific immune imprints on the tumor microenvironment: KRAS is associated with a transitional immune state, whereas STK11 and EGFR mutations define discrete and contrasting immune phenotypes. We find that STK11-mutant tumors exhibit complement and interferon-rich immune microenvironments while EGFR-mutant tumors harbor a naive T cell-rich phenotype accompanied by a global HLA downregulation, stress-responsive alveolar macrophages marked by MARCO. In the epithelial compartments, cross-species analysis reveals metabolic dependencies, including OGDH in EGFR- and PDE4D in STK11-mutant cells. Statement of SignificanceThis study delineates oncogenotype-specific molecular and immune imprints in lung adenocarcinoma, revealing STK11-, KRAS-, and EGFR-mutated tumors as transcriptionally and immunologically discrete ecosystems. By mapping epithelial vulnerabilities alongside immune imprints, we unveil genotype-imposed dependencies that inform the rational development of precision therapies with direct translational relevance.

cancer biology↗

bioRxiv2025

C/EBPβ-mediated PARP1 Suppression Drives Tumor Progression of Aneuploid Cells

Aneuploidy--defined as gains and losses of chromosomes--is frequently observed in cancer and has been implicated in promoting tumor progression and metastasis. However, the molecular mechanisms underlying this phenomenon remain poorly understood. By generating new models of aneuploidy, we found that aneuploidy confers remarkable resistance to reactive oxygen species (ROS)-mediated cell death. This resistance is a general consequence of aneuploidy, independent of the specific chromosomes gained or lost. Mechanistically, Poly(ADP-Ribose) Polymerase 1 (PARP1) is suppressed in aneuploid cells, which inhibits PARP1-mediated cell death after ROS (parthanatos). We validated aneuploidy-associated PARP1 suppression across 15 cell models and human tumors, with pronounced effects in metastatic tumors. Importantly, decreased PARP1 levels promote tumor metastasis while increased PARP1 suppresses it. Through a genome-wide CRISPR screen and functional validation, we identified the transcription factor CCAAT/enhancer-binding protein beta (CEBPB) as a critical mediator of PARP1 downregulation and ROS resistance in aneuploid cells. Furthermore, we found that lysosomal dysfunction serves as the upstream mediator of CEBPB activation in aneuploid cells. We propose that aneuploidy-driven CEBPB activation promotes PARP1 suppression, fostering ROS resistance and cancer progression. HighlightsO_LIAneuploidy confers resistance to oxidative stress independent of p53 status, karyotype and cell lineage through inhibition of PARP1 expression and activity C_LIO_LISuppressed PARP1 enhances metastatic potential, while PARP1 restoration suppresses metastatic spread, revealing a novel mechanism linking aneuploidy to cancer progression. C_LIO_LIPARP1 suppression compromises DNA damage repair and cell death to multiple genotoxic stressors, including reactive oxygen species, alkylating agents, and UV radiation. C_LIO_LIA genome-wide CRISPR screen and a CRISPRa screen identifies CEBPB as a critical transcription factor mediating PARP1 regulation and ROS resistance. C_LIO_LINuclear CEBPB increases significantly after aneuploidization in experimental systems and in primary human cancers. C_LI O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/670212v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1bf4edforg.highwire.dtl.DTLVardef@d3311eorg.highwire.dtl.DTLVardef@13daf25org.highwire.dtl.DTLVardef@b5e65f_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Deep Mutational Scanning Reveals EGFR Mutations Conferring Resistance to the 4th-generation EGFR tyrosine kinase inhibitor BLU-945

IntroductionOsimertinib, a covalent third-generation EGFR tyrosine kinase inhibitor (TKI) is the first-line standard of care for EGFR L858R and ex19del lung adenocarcinoma; however, tumors frequently acquire resistance through second-site mutations. Fourth-generation inhibitors designed to overcome common second-site resistance liabilities are in clinical development. MethodsWe performed deep mutational scanning (DMS) of the EGFR kinase domain in the context of an EGFR L858R driver mutation by transducing Ba/F3 cells with a saturation library of [~]17,000 EGFR L858R kinase domain variants. Ba/F3 cells expressing the DMS library were exposed to either osimertinib or BLU-945 to select for escape mutations. ResultsL718X mutations were enriched across all conditions as well as mutations private to BLU-945 treated samples including K714R, K716T, L718V, T725M, K728E, K754E/N, N771S/T, T783I, Q791L/K, G863S, S895N, K929I, and M971L. In silico pairwise comparisons of resistance profiles between each single agent condition suggested that combination treatment with osimertinib and BLU-945 would effectively suppress orthogonal resistance mechanisms, apart from L718X. A secondary DMS screen with osimertinib and BLU-945 in combination exclusively enriched for L718X mutations. L718X mutations were present in two patients treated with BLU-945 at our institution. One patient with both EGFR L858R and L718Q mutations prior to treatment was noted to have early progression. A second patient with EGFR L858R, T790M, and C797S at the time of enrollment acquired an L718V mutation at progression. ConclusionsThis study underscores the utility of comprehensive resistance profiles of single compounds, which can be used to predict the emergence of clinical resistance mutations and to devise combination treatments designed to suppress clonal escape.

cancer biology↗

bioRxiv2024

Characterization of tumor heterogeneity through segmentation-free representation learning

The interaction between tumors and their microenvironment is complex and heterogeneous. Recent developments in high-dimensional multiplexed imaging have revealed the spatial organization of tumor tissues at the molecular level. However, the discovery and thorough characterization of the tumor microenvironment (TME) remains challenging due to the scale and complexity of the images. Here, we propose a self-supervised representation learning framework, CANVAS, that enables discovery of novel types of TMEs. CANVAS is a vision transformer that directly takes high-dimensional multiplexed images and is trained using self-supervised masked image modeling. In contrast to traditional spatial analysis approaches which rely on cell segmentations, CANVAS is segmentation-free, utilizes pixel-level information, and retains local morphology and biomarker distribution information. This approach allows the model to distinguish subtle morphological differences, leading to precise separation and characterization of distinct TME signatures. We applied CANVAS to a lung tumor dataset and identified and validated a monocytic signature that is associated with poor prognosis.

cancer biology↗

bioRxiv2024

Deep Quantitative Proteomics Identifies Conserved Proteome Alterations in Low and High-Grade Serous Ovarian Cancers

BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a rare and largely chemoresistant subtype of epithelial ovarian cancer. Unlike treatment for high-grade serous ovarian cancer (HGSOC), management options for LGSOC patients are limited, in part, due to a lack of deep molecular characterization of this disease. To address this limitation, we aimed to define highly conserved proteome alterations in LGSOC by performing deep quantitative proteomic analysis of tumors collected from LGSOC (n=12) and HGSOC (n=24) patients or normal fallopian tube tissues (n=12) and validating proteins within two independent proteomic datasets of LGSOC (n=25) and HGSOC (n=49) tumors. ResultsOur efforts identified 275 protein alterations conserved between LGSOC and HGSOC tumors that exhibit high quantitative correlation between discovery and validation cohorts (Spearman Rho [≥] 0.82, P < 1E-4). Conserved proteins elevated in LGSOC tumors were enriched for pathways regulating cell adhesion and defective cellular apoptosis signaling and candidates mapping as putative drug targets included 5-nucleotidase/ cluster of differentiation 73 (NT5E/CD73). We also identified MUC16 (CA125) as significantly elevated in LGSOC versus HGSOC tumors and confirmed this by immunohistochemistry analysis between three independent reviewers. We also find that MUC16 exhibits a more apical versus membrane-staining pattern in LGSOC tumors, suggesting unique regulation of MUC16 in this disease subtype. ConclusionOur efforts define highly conserved protein alterations distinguishing LGSOC from HGSOC tumors, including CD73, as well as the novel identification that MUC16 is elevated and exhibits more apical staining pattern in LGSOC tumor tissues. These findings deepen our molecular understanding of LGSOC and provide unique insights into highly conserved proteome alterations in LGSOC tumors.

cancer biology↗

bioRxiv2023

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

KRASG12C inhibitors including adagrasib and sortorasib have shown clinical promise in targeting KRASG12C-mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurring KRASG12C and STK11/LKB1 mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies of Lkb1-deficient KRASG12Cand KrasG12D lung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed {Delta}Np63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked by Krt6a upregulation. Notably, higher KRT6A expression at baseline correlated with shorter overall survival in KRAS-mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.

cancer biology↗

bioRxiv2023

Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth

Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how LKB1 mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of LKB1-mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1+ interstitial macrophages and SiglecFHi neutrophils. We discovered a novel mechanism whereby autocrine LIF signaling in Lkb1-mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling in Lkb1-mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1+ interstitial macrophages and SiglecFHi neutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment of LKB1-mutant tumors.

cancer biology↗

bioRxiv2023

Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC paralogs

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested for in vivo sensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through a MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, as MYC paralog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCESCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.

cancer biology↗

bioRxiv2023

EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas

Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell carcinomas (LSCCs). Our in vitro experiments using 2D human cancer cell lines as well as 3D murine and patient derived organoids treated with two inhibitors of the EZH2 plus interferon-{gamma} (IFN{gamma}) showed that EZH2 inhibition leads to expression of both major histocompatibility complex class I and II (MHCI/II) expression at both the mRNA and protein levels. ChIP-sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Further, we demonstrate strong tumor control in models of both autochthonous and syngeneic LSCC treated with anti-PD1 immunotherapy with EZH2 inhibition. Single-cell RNA sequencing and immune cell profiling demonstrated phenotypic changes towards more tumor suppressive phenotypes in EZH2 inhibitor treated tumors. These results indicate that this therapeutic modality could increase ICI responses in patients undergoing treatment for LSCC.

cancer biology↗

bioRxiv2023

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1-mutant lung cancer

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD+ degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD+. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)--key downstream effectors of LKB1-- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCELoss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

cancer biology↗

bioRxiv2022

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Early-stage lung adenocarcinoma is typically treated by surgical resection of the tumor. While in the majority of cases surgery can lead to cure, approximately 30% of patients progress. Despite intense efforts to map the genetic landscape of early-stage lung tumors, there has been limited success in discovering accurate biomarkers that can predict clinical outcomes. Meanwhile, the role of the tumor-adjacent tissue in cancer progression has been largely ignored. To test whether tumor-adjacent tissue can be informative of progression-free survival and to probe the underlying molecular pathways involved, we designed a multi-omic study in both tumor and matched tumor-adjacent histologically normal lung tissue from the same patient. Our study includes 143 treatment naive stage I cases with long-term patient follow-up and is, to our knowledge, the largest such study with the longest follow-up. We performed a comprehensive histologic characterization of all tumors, mapped the mutational landscape and probed the transcriptome of both tumor and adjacent normal tissue. We evaluated the predictive power of each data modality and showed that the transcriptome of tumor-adjacent histologically normal lung tissue is the only reliable predictor of clinical outcome. Unbiased discovery of co-expressed gene modules revealed that inflammatory pathways are upregulated in the tumor-adjacent tissue of patients at high risk for disease progression. Furthermore, single-cell transcriptome analysis in the tumor-adjacent lung demonstrated that progression-associated inflammatory signatures were broadly expressed by both immune and non-immune cells including mesothelial cells, alveolar type 2 cells and fibroblasts, CD1 dendritic cells and MAST cells. Collectively, our studies suggest that molecular profiling of tumor-adjacent tissue can identify patients that are at high risk for disease progression.

bioinformatics↗

bioRxiv2021

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance

Lung cancer treatment has benefited greatly from the development of effective immune-based therapies. However, these strategies still fail in a large subset of patients. Tumor-intrinsic mutations can drive immune evasion via recruiting immunosuppressive populations or suppressing anti-tumor immune responses. KEAP1 is one of the most frequently mutated genes in lung adenocarcinoma patients and is associated with poor prognosis and inferior response to all therapies, including checkpoint blockade. Here, we established a novel antigenic lung cancer model and showed that Keap1-mutant tumors promote dramatic remodeling of the tumor immune microenvironment. Combining single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. Importantly, analysis of KEAP1 mutant patient tumors revealed analogous decrease in dendritic cell and T cell infiltration. Our study provides new insight into the role of KEAP1 mutations in promoting immune evasion and suggests a path to novel immune-based therapeutic strategies for KEAP1 mutant lung cancer. Statement of significanceThis study establishes that tumor-intrinsic KEAP1 mutations contribute to immune evasion through suppression of dendritic cell and T cell responses, explaining the observed resistance to immunotherapy of KEAP1 mutant tumors. These results highlight the importance of stratifying patients based on KEAP1 status and paves the way for novel therapeutic strategies.

cancer biology↗

bioRxiv2021

Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis

Small cell lung cancer (SCLC) is a recalcitrant cancer featured with high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using Rb1L/L/Trp53L/L mouse model, we identify the NCAMhiCD44lo/- subpopulation as SCLC metastasizing cell (SMC), which is progressively transitioned from non-metastasizing NCAMloCD44hi cell (Non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal an important role of SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by SWI/SNF complex during SCLC malignant progression, and its knockdown promotes SMC transition and metastasis. Importantly, ectopic TAZ expression reversely drives SMC-to-Non-SMC transition and alleviates metastasis. Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis, and immunostaining data show a positive correlation between TAZ and patient prognosis. These data uncover high SCLC plasticity and identify TAZ as key molecular switch in orchestrating SCLC phenotypic transition and metastasis.

cancer biology↗