Biology subjects

Chabu, C. Y.

Publications and source records attributed to Chabu, C. Y..

6 recordsLinked to original sources

bioRxiv2026

CMTM6-Silencing Microbial Immunotherapy Reprograms PDAC Tumors and Restores T-cell Function

Despite recent advances in immunotherapy for advanced malignancies, Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to current immunotherapy due to dense fibrosis, limited antigen presentation, and myeloid-driven immune suppression. Here we report the tumor-targeting, immune remodeling, and safety profiles of the attenuated Salmonella enterica serovar Typhimurium strain CRC2631, and of iSTORM, a next-generation derivative engineered for tumor-localized CMTM6 silencing. CRC2631 preferentially colonizes orthotopic and genetically engineered PDAC tumors, with enrichment in primary lesions and metastases. Tumor-localized CRC2631 induces chemokine and adhesion programs consistent with leukocyte recruitment, increases intratumoral activated T-cell fractions, and triggers transcriptional signatures aligned with innate sensing, interferon signaling, antigen-processing and presentation, and apoptosis programs. iSTORM extends this platform by delivering CMTM6-targeting shRNA to modulate a PD-L1-stabilizing, myeloid-associated immune-evasion programs within tumor-colonized tissue. Compared with CRC2631, iSTORM increases intratumoral CD8+ T cells, shifts T-cell state toward activation with reduced exhaustion-prone features, strengthens antigen-presentation programs, and achieves deeper tumor control. A lyophilized formulation preserves immune remodeling while improving deployability. Mechanistically, glycan arrays and functional studies support mannose-rich glycan-guided tumor engagement. iSTORM toxicity studies, including systemic cytokine, hematologic, blood chemistry, and lethality demonstrate a favorable safety profile. Collectively, these findings establish iSTORM as a safe, programmable, CMTM6-silencing microbial immunotherapy platform that selectively targets and penetrate PDAC tumors to unleash anti-tumor immune activities. What is already known on this topicPDAC is highly resistant to immune checkpoint blockade because dense stroma and myeloid-dominated suppression prevent effective T-cell infiltration; attenuated Salmonella strains can selectively colonize tumors but first-generation agents showed limited efficacy and safety concerns. What this study addsThis study defines CRC2631/iSTORM as a tumor-selective microbial immunotherapy that exploits surface-exposed, mannose-rich N-glycans to colonize PDAC, delivers CMTM6 silencing, and restores CD8+ T-cell activation and tumor control in models resistant to PD-1 blockade immunotherapy. How this study might affect research, practice or policyThese findings provide a mechanistic blueprint for glycan-guided, CMTM6-targeted bacterial "living drugs," support rational combination strategies for deepening therapeutic effect, and establish a lyophilized, biocontained platform that could be developed into scalable microbial immunotherapies for PDAC and other immunologically cold solid tumors.

cancer biology↗

bioRxiv2023

A Light sheet fluorescence microscopy and machine learning-based approach to investigate drug and biomarker distribution in whole organs and tumors.

Tissue clearing and Light sheet fluorescence microscopy (LSFM) provide spatial information at a subcellular resolution in intact organs and tumors which is a significant advance over tools that limit imaging to a few representative tissue sections. The spatial distribution of drugs, targets, and biomarkers can help inform relationships between exposure at the site of action, efficacy, and safety during drug discovery. We demonstrate the use of LSFM to investigate distribution of an oncolytic virus (OV) and vasculature in xenograft tumors, as well as brain A{beta} pathology in an Alzheimers disease (AD) mouse model. Machine learning-based image analysis tools developed to segment vasculature in tumors showed that random forest and deep learning methods provided superior segmentation accuracy vs intensity-based thresholding. Sub-cellular resolution enabled detection of punctate and diffuse intracellular OV distribution profiles. LSFM investigation in the brain in a TgCRND8 AD mouse model at 6.5 months of age enabled evaluation of A{beta} plaque density in different brain regions. The utility of LSFM data to support quantitative systems pharmacology (QSP) and physiology-based pharmacokinetics (PBPK) modeling to inform drug development are also discussed. In summary, we showcase how LSFM can expand our understanding of macromolecular drug and biomarker distribution to advance drug discovery and development.

cancer biology↗

bioRxiv2021

Let-7b-5p, miR-184, and miR-22-3p: Multianalyte Plasma Biomarkers for NSCLC Diagnosis and for Predicting Resistance to Osimertinib

Low-dose computed tomography (LDCT) Non-Small Cell Lung (NSCLC) screening is associated with high false-positive rates, leading to unnecessary expensive and invasive follow ups. There is a need for minimally invasive approaches to improve the accuracy of NSCLC diagnosis. Plasma extracellular vesicle (EV) and circulating microRNA (miRNA) have been proposed as cancer screening biomarkers. However, the identification of highly sensitive and broadly predictive core miRNA signatures remains a challenge. Also, how these systemic and diverse miRNAs impact cancer drug response is not well understood. Using an integrative approach, we examined plasma EV and circulating miRNA isolated from NSCLC patients versus screening controls with a similar risk profile. We found that combining EV (Hsa-miR-184, Let-7b-5p) and circulating (Hsa-miR-22-3p) miRNAs abundance robustly discriminates between NSCLC patients and high-risk cancer-free controls. Diagnosed NSCLC patients harboring sensitizing mutations in epidermal growth factor receptor EGFR (T790M, L578R) are treated with Osimertinib, a potent tyrosine kinase inhibitor (TKI). Nearly all patients develop TKI resistance via complex mechanisms and progress. We found that Hsa-miR-22-3p, Hsa-miR-184, and Let-7b-5p functionally converge on WNT/{beta}catenin and mTOR/AKT signaling axes, known cancer therapy resistance signals. Targeting Hsa-miR-22-3p and Hsa-miR-184 desensitized EGFR-mutated (T790M, L578R) NSCLC cells to Osimertinib. These findings suggest that the expression levels of circulating hsa-miR-22-3p combined with EV hsa-miR-184 and Let-7b-5p levels potentially define a core biomarker signature for improving the accuracy of NSCLC diagnosis. Importantly, these biomarkers have the potential to enable prospective identification of patients who are at risk of responding poorly to Osimertinib alone but likely to benefit from Osimertinib/AKT blockade combination treatments.

cancer biology↗

bioRxiv2020

Cooperation between oncogenic Ras and p53 stimulates JAK/STAT non-cell autonomously to promote Ras tumor radioresistance

Oncogenic RAS mutations are associated with tumor resistance to radiation therapy. The underlying mechanisms remain unclear. Emergent cell-cell interactions in the tumor microenvironment (TME) profoundly influence therapy outcomes. The nature of these interactions and their role in Ras tumor radioresistance remain unclear. We used Drosophila oncogenic Ras tissues and human Ras cancer cell radiation models to address these questions. We discovered that cellular response to genotoxic stress cooperates with oncogenic Ras to activate JAK/STAT non-cell autonomously in the TME. JAK/STAT accelerates the growth of the less-damaged Ras tumor cells, leading to rapid tumor recurrence. Specifically, p53 is heterogeneously activated in Ras tumor tissues in response to irradiation. This mosaicism allows high p53-expressing Ras clones to stimulate JAK/STAT cytokines, which activate JAK/STAT in the nearby low p53-expressing surviving Ras clones, leading to robust tumor re-establishment. Blocking any part of this cell-cell communication loop re-sensitizes Ras tumor cells to irradiation. This finding suggests that coupling STAT inhibitors to radiotherapy might improve clinical outcomes for Ras cancer patients.

cancer biology↗

bioRxiv2020

Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model

Conventional cancer chemotherapies are not fully efficacious and do not target tumors, leading to significant treatment-related morbidities. A number of genetically attenuated cancer-targeting bacteria are being developed to safely target tumors in vivo. Here we report the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer. CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals. In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable. Moreover, tumor-targeted CRC2631 generates an anti-tumor immune response. Combination of CRC2631 with checkpoint blockade reduces metastasis burden. Collectively, these findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

cancer biology↗

bioRxiv2020

Syd/JIP3 Controls Tissue Size by Regulating Diap1 Protein Turnover Downstream of Yorkie/YAP

How organisms control organ size is not fully understood. We found that Syd/JIP3 is required for proper wing size in Drosophila. JIP3 mutations are associated with organ size defects in mammals. The underlying mechanisms are not well understood. We discovered that Syd/JIP3 inhibition results in a downregulation of the inhibitor of apoptosis protein1 (Diap1) in the Drosophila wing. Correspondingly, Syd/JIP3 deficient tissues exhibit ectopic cell death and yield smaller wings. Syd/JIP3 inhibition generated similar effects in mammalian cells, indicating a conserved mechanism. We found that Yorkie/YAP stimulates Syd/JIP3 in Drosophila and mammalian cells. Notably, Syd/JIP3 is required for the full effect of Yorkie-mediated tissue growth. Thus Syd/JIP3 regulation of Diap1 functions downstream of Yorkie/YAP to control growth. This study provides mechanistic insights into the recent and perplexing link between JIP3 mutations and organ size defects in mammals, including in humans where de novo JIP3 variants are associated with microcephaly. HighlightsO_LISyd/JIP3 is required for proper Drosophila wing size C_LIO_LISyd/JIP3 stabilizes Diap1 to inhibit cell death in Drosophila and in mammalian cells C_LIO_LIActivation of Yorkie/YAP stimulates Syd/JIP3 C_LIO_LIYorkie-mediated tissue growth is highly sensitive to Syd/JIP3 dosage C_LI

developmental biology↗