BACKGROUND:Lung cancer is the most common cause of cancer-related deaths. Despite recent advances in therapy, patients invariably develop resistance to standard treatments. Hence, there is an increasing need to identify newer treatment approaches to enhance the efficacy of currently used agents and improve outcomes. METHODS:An unbiased connectivity mapping analysis identified the proteasomal inhibitor ixazomib (IXZ), as a potentially effective agent against lung adenocarcinoma (LUAD). IXZ was studied for cell viability, cell cycle, migration, and apoptosis, alone or in combination with carboplatin (CBP), using human and mouse LUAD cell lines. The mechanisms were studied using a proteasome array, molecular approaches on proteasomal and autophagy pathway interventions, and in vivo lung orthotopic syngeneic mouse models. RESULTS:We identified IXZ as a potential agent that inhibits LUAD cell growth, G2/M arrest, and promotes cell death, both as a single agent and in combination with CBP. IXZ induced DNA damage and attenuated repair mechanisms in cisplatin-resistant cells, suggesting a potential therapeutic role in overcoming platinum resistance. Using the mCherry-GFP-LC3B reporter assay and pathway interventions (silencing ATG5, UBE2N, and BAG3 genes, and autophagy inhibitors 3-MA and HCQ), we found that IXZ degraded MUC5AC/integrin-β4 via the ubiquitin-mediated autophagy pathway. We also showed that IXZ destabilizes MUC5AC by blocking interaction with the deubiquitinase UCHL1. In vivo treatment studies further demonstrated that IXZ significantly decreased tumor burden by blocking the MUC5AC/UCHL1 oncogenic axis. CONCLUSIONS:IXZ effectively inhibited LUAD tumor growth and may overcome platinum resistance. These findings warrant further investigation into the clinical role of IXZ alone or in combination with CBP or other chemotherapies in patients with LUAD.

Perineural invasion (PNI) is associated with worse prognosis in various malignancies. Targeting PNI may hinder the tumor metastasis in head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC). We investigated the role of nuclear receptor subfamily 4 group A2 (NR4A2/Nurr1) mediated neuronal invasion in HNSCC and PDAC tumor progression. Aberrant expression of NR4A2 was observed in these tumors, and high levels of NR4A2 were associated with worse survival. The whole genome chromatin immunoprecipitation (ChIP) sequencing with NR4A2 antibody illustrated several genes associated with axonal guidance, suggesting its potential role in PNI. Treatment with conditioned-media (CM) collected from NR4A2-depleted cancer cells showed significantly decreased neurite outgrowths in dorsal root ganglion. Cytokine array analysis revealed several soluble factors, such as CXCL5, CCL2, IGBP2, and TIMP-2, that may be involved in neuritogenesis; these factors are decreased in CM of NR4A2-depleted cells. Further treatment with CXCL5 ligand significantly induced neuritogenesis, while the neurite outgrowth was abrogated when cotreated with CXCR2 (receptor for CXCL5) inhibitor SCH527123. Upregulation of Rac1 and phospho-AKT (S473) downstream signaling of CXCL5 was observed, and the CXCR2 inhibitor abrogated this effect in neuronal cells. Moreover, CM from CXCL5-depleted cells showed reduced neurite length. NR4A2 knockdown in UMSCC1 cells impaired tumor formation in vivo, and the xenograft tissues exhibited significant downregulation of CXCL5, providing direct in vivo evidence for the NR4A2-CXCL5 axis in tumor progression. NR4A2 is a key driver of CXCL5-mediated PNI and the NR4A2/CXCL5/CXCR2 signaling axis is a potential therapeutic target in HNSCC and PDAC.

Supplementary Figure 5. MUC5AC silencing inhibits cMET and CD44v6 expression and Astrocytes induce MUC5AC expression in breast cancer cells. A-B. Western blots showing knockdown of MUC5AC in MDA-231BR HER2 (A) and MUC5AC knockout in HCC1954BR (B) reduces expression of cMET and CD44v6. C. IHC staining for cMET and CD44v6 on brain tissue sections from mice injected with shSCR and shMUC5AC MDA-231BR HER2 cells. D. SKBR3 cells were treated with human astrocyte conditioned media for 24h and cells were lysed and subjected for MUC5AC expression. HGF induced signaling in MDA-231BR HER2 (E) and HCC1954BR (F); cells were treated with HGF (100ng/mL) for indicated times. After treatment cells were lysed and subjected for cMET and p-cMET expression using Western blot.

PURPOSE:Breast cancer brain metastasis remains a significant clinical problem. Mucins have been implicated in metastasis; however, whether they are also involved in breast cancer brain metastasis remains unknown. We queried databases of patients with brain metastasis and found mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in breast cancer brain metastasis. EXPERIMENTAL DESIGN:In silico dataset analysis, RNA-sequence profiling of patient samples and cell lines, analysis of patient serum samples, and in vitro/in vivo knockdown experiments were performed to determine the function of MUC5AC in breast cancer brain metastasis. Coimmunoprecipitation was used to unravel the interactions that can be therapeutically targeted. RESULTS:Global in silico transcriptomic analysis showed that MUC5AC is significantly higher in patients with breast cancer brain metastasis. Analysis of archived breast cancer brain metastasis tissue further revealed significantly higher expression of MUC5AC in all breast cancer subtypes, and high MUC5AC expression predicted poor survival in HER2+ breast cancer brain metastasis. We validated these observations in breast cancer brain metastatic cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of patients with breast cancer brain metastasis. MUC5AC silencing in breast cancer brain metastatic cells reduced their migration and adhesion in vitro and in brain metastasis in the intracardiac injection mouse model. We found high expression of cMET and CD44v6 in breast cancer brain metastasis, which increased MUC5AC expression via hepatocyte growth factor signaling. In addition, MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes breast cancer brain metastasis via the cMET/CD44v6 axis. Inhibition of the MUC5AC/cMET/CD44v6 axis with the blood-brain barrier-permeable cMET inhibitor bozitinib (PLB1001) effectively inhibits breast cancer brain metastasis. CONCLUSIONS:Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for breast cancer brain metastasis, and blocking this axis will be a novel therapeutic approach for breast cancer brain metastasis.

Small cell lung cancer (SCLC) is a lethal lung malignancy which is associated with distant metastasis and chemoresistance. Limited targeted therapies further worsen disease outcomes. Single-cell and bulk RNA-sequencing (RNA-seq) datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression in human and murine SCLC tissues and cell lines was observed. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1 fl/fl ; TP53 fl/fl ; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of cancer cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the TME of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.

Supplementary Figure 1. Expression of MUC5AC is high in breast cancer brain metastasis. A. Heatmap showing the expression of upregulated genes in BC BrM cells as compared to primary BC cells (MDA-231BR vs MDA-231P). B. Comparison of MUC5AC expression (z-score) between BC and brain metastasis samples, using online available Gene Expression Omnibus (GEO) public datasets, probe (214385_s_at). C. Heatmap showing the expression of goblet cells marker genes in BC and breast cancer brain metastasis cell lines (MDA-231BR vs MDA-231P). Data represents upregulation of marker proteins. D. Pie chart representing H-score for MUC5AC expression in BrM tissues originating from BC (Breast cancer), LC (Lung cancer) and other cancers.

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I-deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

Background:Small cell lung cancer (SCLC) is a lethal lung malignancy and patients are often diagnosed with distant metastasis. Nearly all patients suffer from disease relapsing with inherent chemoresistance. Lack of targeted SCLC therapies further worsens disease outcomes, making it highly desirable to identify novel and effective therapeutic targets. Methods:To search for potential therapeutic targets in SCLC, we analyzed publicly available single-cell and bulk RNA-sequencing (RNA-seq) data from normal, lung adenocarcinoma, and SCLC tumor tissues. To assess the targeting potential of FOXM1, we developed various in vitro models, including DOX-On-shFOXM1 (Tet-ON) inducible stable knockdown systems. Cisplatin resistant human and murine SCLC cell lines were generated to assess the role of FOXM1 in chemotherapy resistance. Immunoblotting, immunohistochemistry (IHC), and immuno-fluorescence were used to analyze the expression of FOXM1 and target proteins. ChIP-assay was used to study protein-gene interactions. Further, multicolor flow cytometry was employed to study the effect of FOXM1 inhibition on human T cells activation and differentiation. Subcutaneous xenograft and SCLC spontaneous (RPM: RB fl/fl ;TP53 fl/fl ;LSL-MYC T58A ) mouse models were used to evaluate the efficacy of FOXM1 inhibitors. Results:Single-cell as well as bulk RNA-seq data revealed that FOXM1, an oncogenic transcription factor, is overexpressed in SCLC, and it was recapitulated in human and murine SCLC tissues and cell lines. Interestingly, chemo-resistant (CR) SCLC showed a substantially higher FOXM1 expression than naïve SCLC. Silencing FOXM1 genetically or pharmacologically by FOXM1 inhibitors revealed a marked reduction in cell viability, colony formation, migration and sphere formation in naïve and CR SCLC cells. Moreover, FOXM1 inhibition induced apoptosis and cell cycle arrest in SCLC cells. Furthermore, FOXM1 inhibition in combination with first-line platinum-based chemotherapy showed synergistic anticancer effects in both xenograft and RPM mouse models of SCLC. Our RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway, which is dysregulated in SCLC. Moreover, we found FOXM1 inhibition enhanced T cell activation and supported the differentiation of CD8 + cytotoxic T cells, and T cell-mediated killing of cancer cells. Conclusions:Our study demonstrates that FOXM1 targeting using small molecule inhibitors has the potential to be a novel therapeutic strategy to combat SCLC progression including chemotherapeutic resistance and reshaping the anti-tumor immune response.

Lung cancer is the leading cause of cancer-related deaths globally, with small cell lung cancer (SCLC) representing a highly aggressive subtype. The prognosis for SCLC remains dire due to early metastasis, chemoresistance, high recurrence rates, and limited therapeutic options. Despite the approval of some immunotherapeutic drugs for SCLC, their efficacy is restricted to a small subset of patients. This limited success is attributed to low expression of PD-L1 and the immune-cold tumor microenvironment in SCLC, underscoring the urgent need for new therapeutic targets. Bioinformatic analysis of SCLC datasets, focusing on immune checkpoint regulators, identified B7H3 (CD276) as a promising candidate upregulated in SCLC. This finding was confirmed in SCLC cell lines and human tissue samples. B7H3 is a cell surface protein overexpressed in multiple tumor types, functioning as both an immune modulator and an oncogenic driver. However, its role in SCLC tumorigenesis remains unclear. To investigate the functional involvement of B7H3 in SCLC, we employed CRISPR-Cas9 to knock out the B7H3 gene in SCLC cell lines. B7H3 knockout significantly reduced transwell migration and wound-healing abilities in SCLC cells. When co-cultured with T-cells, B7H3-proficient SCLC cells suppressed T cell activation, unlike their B7H3-deficient counterparts. To therapeutically target B7H3, we used the antibody-drug conjugate (ADC) m276-SL-PBD in the spontaneous SCLC mouse model RPM (Adeno-CGRP-Cre; Rb1flox/flox; TP53flox/flox; LSL-MycT58A) which significantly reduced tumor burden, metastasis, angiogenesis, and increased T cell infiltration. To further elucidate the role of B7H3 in SCLC progression, we generated a novel spontaneous mouse model, RPMC (Adeno-CGRP-Cre; Rb1flox/flox; TP53flox/flox; LSL-MycT58A; Cd276fl/fl). These mice exhibited a marked decrease in tumor burden, tumor-associated angiogenesis, and metastasis, with a significantly increased T-cell infiltration compared to controls. Transcriptomic analysis of B7H3-proficient/-deficient cells revealed NFIB among the top 50 downregulated genes following B7H3 deletion. NFIB, a key driver of SCLC metastasis, was significantly reduced in B7H3-deficient human and syngeneic (RPMC) cell lines. Metastatic tissues from RPMC mice also showed lower NFIB expression compared to the RPM model. In conclusion, this study highlights the critical role of B7H3 as well as modulation of NFIB expression in regulating SCLC progression. Our findings establish B7H3 as a promising therapeutic target and demonstrate the potential role of CD276 ADCs in overcoming the limitations of current treatments of SCLC. By advancing our understanding of B7H3’s role in promoting tumor growth, this study paves the way for designing more effective therapeutic strategies to combat SCLC. Mahek Fatima, Parvez Khan, Md Arafat Khan, Asad Ur Rehman, Laiba Anwar, Aatiya Ahmad, Jaewon Lee, Imayavaramban Lakshmanan, Anish Thomas, Dinesh Pradhan, Apar K. Ganti, Brad St Croix, Surinder K. Batra, Mohd Wasim Nasser. Unveiling the role of B7H3 in driving the tumor immune microenvironment and progression of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7234.

AbstractPurpose: Breast cancer brain metastasis remains a significant clinical problem. Mucins have been implicated in metastasis; however, whether they are also involved in breast cancer brain metastasis remains unknown. We queried databases of patients with brain metastasis and found mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in breast cancer brain metastasis. Experimental Design: In silico dataset analysis, RNA-sequence profiling of patient samples and cell lines, analysis of patient serum samples, and in vitro/in vivo knockdown experiments were performed to determine the function of MUC5AC in breast cancer brain metastasis. Coimmunoprecipitation was used to unravel the interactions that can be therapeutically targeted. Results: Global in silico transcriptomic analysis showed that MUC5AC is significantly higher in patients with breast cancer brain metastasis. Analysis of archived breast cancer brain metastasis tissue further revealed significantly higher expression of MUC5AC in all breast cancer subtypes, and high MUC5AC expression predicted poor survival in HER2+ breast cancer brain metastasis. We validated these observations in breast cancer brain metastatic cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of patients with breast cancer brain metastasis. MUC5AC silencing in breast cancer brain metastatic cells reduced their migration and adhesion in vitro and in brain metastasis in the intracardiac injection mouse model. We found high expression of cMET and CD44v6 in breast cancer brain metastasis, which increased MUC5AC expression via hepatocyte growth factor signaling. In addition, MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes breast cancer brain metastasis via the cMET/CD44v6 axis. Inhibition of the MUC5AC/cMET/CD44v6 axis with the blood–brain barrier–permeable cMET inhibitor bozitinib (PLB1001) effectively inhibits breast cancer brain metastasis. Conclusions: Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for breast cancer brain metastasis, and blocking this axis will be a novel therapeutic approach for breast cancer brain metastasis.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) cancer and is one of the most lethal types of solid tumors. Although platinum-based therapy forms the backbone of systemic therapy for SCLC, resistance, and recurrence occur rapidly, and most patients die within a year of diagnosis. Despite the approval of immune checkpoint inhibitors for SCLC, the survival benefit of these combinations in an unselected patient population is modest. The majority of SCLCs (∼70-75%) are initiated from pulmonary NE cells; therefore, exploiting NE drivers/modulators is crucial for developing effective therapeutic strategies. To identify novel therapeutic molecules, we performed unbiased RNA-seq expression analysis of NE modulators in SCLC gene expression datasets. Our data showed an atypical expression profile of dopamine receptor D2 (DRD2) in various cell lines of SCLC belonging to NE, non-neuroendocrine, brain metastatic (BrM), and chemotherapy-resistant phenotypes. DRD2 is a G-protein coupled receptor that governs multiple physiological functions, including modulation of the synthesis, storage, and secretion of dopamine (DA); and seems to play a role in neuropsychiatric disorders, brain tumors, and promotes oncogenesis. We studied the role of DRD2 in cell lines representing multiple subtypes of SCLC and tumor tissues compared to their matched normal controls. DRD2 expression was also high in murine SCLC cell lines derived from RPM (Rb1flox/flox; TP53flox/flox; LSL-MycT58A), a spontaneous SCLC mouse model. High expression both in murine and human cell lines derived from brain metastatic lesions (BrM), suggests that DRD2 expression may play an essential role in brain metastasis. Additionally, a substantially high expression of DRD2 was observed in chemotherapy- and immunotherapy-resistant cell lines derived from SCLC patient-derived xenografts. To assess the therapeutic potential of DRD2, we utilized ONC206, a highly specific, orally bioavailable, and blood-brain barrier penetrating DRD2 antagonist. ONC206 treatment attenuated SCLC growth and metastasis, including brain metastasis both in preclinical in vitro and in vivo models. Integrated gene expression studies coupled with pathway analysis showed that DRD2 inhibition reduces SCLC growth and metastasis by inhibiting the cholesterol biosynthesis pathway. Altogether, our study provides strong preclinical rationale for targeting DRD2 via dopamine antagonism to attenuate SCLC growth and metastasis. Parvez Khan, Aatiya Ahmad, Md Arafat Khan, Mahek Fatima, Asad Ur Rehman, Laiba Anwar, Sanib Chaudhary, Imayavaramban Lakshmanan, Anish Thomas, Surinder K. Batra, Varun V. Prabhu, Apar K. Ganti, Mohd Wasim Nasser. Dopamine receptor D2 and dopamine antagonism modulate the progression of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4747.

Supplementary Figure 6. PLB1001 inhibit cMET and CD44v6 expression. A. Representative IHC images showing MUC5AC expression in G5-3 PDXs B. Representative fluorescence microscopy images showing GFP+ in G5-3 PDXs C. Representative IHC images showing expression of MUC5AC, cMET, CD44v6 and cleaved caspase3 in G5-3 PDX treated with vehicle or PLB1001 (50mg/kg).

Small cell lung cancer (SCLC) is a lethal lung malignancy, which is associated with distant metastasis and chemoresistance. Due to the limited availability of targeted therapies, identifying a potential therapeutic target is a pressing unmet need in SCLC. Single-cell and bulk-transcriptomic datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression was observed in human and murine SCLC tissues and cell lines. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1fl/fl; TP53 fl/fl; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of SCLC cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the tumor microenvironment (TME) of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.

Non-small cell lung carcinoma (NSCLC) exhibits a heightened propensity for brain metastasis, posing a significant clinical challenge. Mucin 5ac (MUC5AC) plays a pivotal role in the development of lung adenocarcinoma (LUAD); however, its role in causing brain metastases remains unknown. In this study, we aimed to investigate the contribution of MUC5AC to brain metastasis in patients with LUAD utilizing various brain metastasis models. Our findings revealed a substantial increase in the MUC5AC level in LUAD brain metastases (LUAD-BrM) samples and brain-tropic cell lines compared to primary samples or parental control cell lines. Intriguingly, depletion of MUC5AC in brain-tropic cells led to significant reductions in intracranial metastasis and tumor growth, and improved survival following intracardiac injection, in contrast to the observations in the control groups. Proteomic analysis revealed that mechanistically, MUC5AC depletion resulted in decreased expression of metastasis-associated molecules. There were increases in epithelial-to-mesenchymal transition, tumor invasiveness, and metastasis phenotypes in tumors with high MUC5AC expression. Furthermore, immunoprecipitation and proteomic analysis revealed a novel interaction of MUC5AC with Annexin A2 (ANXA2), which activated downstream matrix metalloproteases and facilitated extracellular matrix degradation to promote metastasis. Disrupting MUC5AC-ANXA2 signaling with a peptide inhibitor effectively abrogated the metastatic process. Additionally, treatment of tumor cells with an astrocyte-conditioned medium or the chemokine CCL2 resulted in upregulation of MUC5AC expression and enhanced brain colonization. In summary, our study demonstrates that the MUC5AC/ANXA2 signaling axis promotes brain metastasis, suggesting a potential therapeutic paradigm for LUAD patients with high MUC5AC expression. Lung cancer frequently moves to the brain, but why is unclear. Scientists have found that a protein, MUC5AC, is crucial in this. The research, led by Sanjib Chaudhary and team, discovered that MUC5AC works with another protein, ANXA2, to help lung cancer cells move to the brain. They also found that astrocytes (a type of brain cell), release a substance that boosts the presence of MUC5AC in lung cancer cells. This research was a lab experiment using lung cancer cells and mice. They found that lowering MUC5AC in lung cancer cells greatly reduced their movement to the brain in mice. This suggests that focusing on MUC5AC could help stop lung cancer from moving to the brain. Future studies will need to confirm these results and look into possible treatments.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers. ch5E6 binds and interferes with MUC16-associated oncogenesis, suppresses the downstream signaling pFAK(Y397)/p-p70S6K(T389)/N-cadherin axis and exert antiproliferative effects in cancer cells, 3D organoids, and tumor xenografts of both PC and NSCLC. The robust clinical correlations observed between MUC16 and N-cadherin in patient tumors and metastatic samples imply ch5E6 potential in targeting a complex and significantly occurring phenomenon of epithelial to mesenchymal transition (EMT) associated with disease aggressiveness. Our study supports evaluating ch5E6 with standard-of-care drugs, to potentially augment treatment outcomes in malignancies inflicted with MUC16-associated poor prognosis.

Supplementary Figure from MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2-Associated Cell Adhesion

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