Biology subjects

Choi, J. E.

Publications and source records attributed to Choi, J. E..

6 recordsLinked to original sources

bioRxiv2024

PIKfyve controls dendritic cell function and tumor immunity

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-{kappa}B pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

cancer biology↗

bioRxiv2023

Clinically relevant humanized mouse models of metastatic prostate cancer to evaluate cancer therapies

There is tremendous need for improved prostate cancer (PCa) models. The mouse prostate does not spontaneously form tumors and is anatomically and developmentally different from the human prostate. Engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts represent an alternative but rely on an immunocompromised host. Accordingly, we generated PCa murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic PCa and the impact of hormonal and immunotherapies. These mice maintain multiple human cell lineages, including functional human T-cells and myeloid cells. In 22Rv1 xenografts, subcutaneous tumor size was not significantly altered across conditions; however, metastasis to secondary sites differed in castrate huNOG vs background-matched immunocompromised mice treated with enzalutamide (enza). VCaP xenograft tumors showed decreases in growth with enza and anti-Programed-Death-1 treatments in huNOG mice, and no effect was seen with treatment in NOG mice. Enza responses in huNOG and NOG mice were distinct and associated with increased T-cells within tumors of enza treated huNOG mice, and increased T-cell activation. In huNOG-EXL mice, which support human myeloid development, there was a strong population of immunosuppressive regulatory T-cells and Myeloid-Derived-Suppressor-Cells (MDSCs), and enza treatment showed no difference in metastasis. Results illustrate, to our knowledge, the first model of human PCa that metastasizes to clinically relevant locations, has an intact human immune system, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment.

cancer biology↗

bioRxiv2022

The IgH Eμ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation

Two scaffold/matrix attachment regions (5- and 3-MARsE) flank the intronic core enhancer (cE) within the immunoglobulin heavy chain locus (IgH). Besides their conservation in mice and humans, the physiological role of MARsE is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated. By analysing a mouse model devoid of MARsE, we observed an inverted substitution pattern: SHM being decreased upstream from cE and increased downstream of it. Strikingly, the SHM defect induced by MARsE-deletion was accompanied by an increase of sense transcription of the IgH V region, excluding a direct transcription-coupled effect. Interestingly, by breeding to DNA repair-deficient backgrounds, we showed that the SHM defect, observed upstream from cE in this model, was not due to a decrease in AID deamination but rather the consequence of a defect in base excision repair-associated unfaithful repair process. Our study pointed out an unexpected "fence" function of MARsE regions in limiting the error-prone repair machinery to the variable region of Ig gene loci.

immunology↗

bioRxiv2020

Synaptic correlates of associative fear memory in the lateral amygdala

Successful adaptation to the environment requires accurate responding to external threats by recalling specific memories. However, elucidating underlying neural substrates of associative fear memory was limited due to the difficulties in direct examination of extinction-induced changes of specific synapses that encode an auditory fear memory. Using dual-eGRASP (enhanced Green Fluorescent Protein Reconstitution Across Synaptic Partners), we found that synapses between engram cells or synaptic engram showed a significantly larger spine morphology at auditory cortex (AC) to lateral amygdala (LA) projections after auditory fear conditioning. Fear extinction reversed the enhanced synaptic engram spines while re-conditioning with the same tone and shock restored the size of the synaptic engram. Taken together, we suggest that the synaptic engram may represent a different state of fear memory. One Sentence SummaryAssociative fear memory enlarged the spine morphology of synapses between engram neurons in the amygdala, which was diminished by memory extinction and restored by re-conditioning, suggesting that connections between engram cells represent a different state of fear memory.

neuroscience↗

bioRxiv2020

KIAA1841, a novel SANT and BTB domain-containing protein, inhibits class switch recombination

Class switch recombination (CSR) enables B cells to produce different immunoglobulin isotypes and mount an effective immune response against pathogens. Timely resolution of CSR prevents damage due to an uncontrolled and prolonged immune response. While many positive regulators of CSR have been described, negative regulators of CSR are relatively unknown. Using a shRNA library screen in a mouse B cell line, we have identified the novel protein KIAA1841 (NM_027860) as a negative regulator of CSR. KIAA1841 is an uncharacterized protein of 82kD containing SANT and BTB domains. The BTB domain of KIAA1841 exhibited characteristic properties such as self-dimerization and interaction with co-repressor proteins. Overexpression of KIAA1841 inhibited CSR in primary mouse splenic B cells, and inhibition of CSR is dependent on the BTB domain while the SANT domain is largely dispensable. Thus, we have identified a new member of the BTB family that serves as a negative regulator of CSR.

molecular biology↗

bioRxiv2020

Merkel cell polyomavirus in Merkel cell carcinoma: Integration sites and involvement of the KMT2D tumor suppressor gene

Merkel cell carcinoma (MCC) is an uncommon, lethal cancer of the skin caused by either Merkel cell polyomavirus (MCV) or UV-linked mutations. MCV is found integrated into MCC tumor genomes, accompanied by truncation mutations that render the MCV large T antigen replication incompetent. We used the open access HPV Detector/ Cancervirus Detector tool to determine the MCV integration sites in whole exome sequencing data from 5 MCC cases, thereby adding to the limited published MCV integration site junction data. We also systematically reviewed published data on integration for MCV in the human genome, presenting a collation of 123 MCC cases and their linked chromosomal sites. We confirm that there are no highly recurrent specific sites of integration. We found that, chromosome 5 is the chromosome most frequently involved by MCV integration and that integration sites are significantly enriched for genes with binding sites for oncogenic transcription factors such as LEF1 and ZEB1, suggesting the possibility of increased open chromatin in these gene sets. Additionally, in one case we found integration involving the tumor suppressor gene KMT2D for the first time, adding to previous reports of rare MCV integration into host tumor suppressor genes in MCC.

cancer biology↗