Biology subjects

Razazan, A.

Publications and source records attributed to Razazan, A..

3 recordsLinked to original sources

bioRxiv2026

Cell Communication Network factor 4 promotes tumor-induced immunosuppression in breast cancer.

Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that is upregulated in essentially all invasive breast cancers and promotes immunosuppression in melanoma. Recent work suggests that limited anti-tumor immunity also associates with poor patient outcomes in patients with breast cancer. Motivated by increased CCN4 correlating with dampened anti-tumor immunity in primary breast cancer, we test for a direct causal link by knocking out CCN4 (CCN4 KO) in the Py230 and Py8119 mouse breast cancer models. Tumor growth is reduced when CCN4 KO breast cancer cells are implanted in immunocompetent but not in immunodeficient mice. Correspondingly in size-matched tumors, CD4+ and CD8+ T cells are significantly increased in CCN4 KO tumors while the myeloid compartment is shifted from polymorphonuclear- to monocytic-myeloid-derived suppressor cells (MDSC). This shift in the MDSC compartment is also associated with a significant reduction in splenomegaly. Among mechanisms linked to local immunosuppression, CCN4 knockout has a similar impact on the secretome of both breast cancer and melanoma cell lines. Overall, our results suggest that CCN4 promotes tumor-induced immunosuppression in the context of breast cancer and is a potential target for therapeutic combinations with immunotherapies.

cancer biology↗

bioRxiv2025

A functional comparison of two transplantable syngeneic mouse models of melanoma: B16F0 and YUMM1.7

The B16 murine melanoma cell lines are considered the gold standard for testing melanoma immunotherapies due to low treatment success rates. However, the clinical relevance of these models has been questioned due to a mutational landscape void of driver mutations typically seen in human melanomas and a tendency to form necrotic cores at high tumor volumes. Creating the YUMM1.7 line addressed these limitations by providing an additional contextually consistent model with a more clinically relevant genetic background. The combined use of both models can generate stronger studies in melanoma immunology and immunotherapy. However, to date, there have been no direct functional comparisons of the characteristics of these two models to inform the design of such studies. To address this, we conducted a series of functional experiments to characterize the kinetics of tumor growth, chemotherapeutic sensitivity, and immunogenicity of these models. We found that the B16F0 model had faster intrinsic tumor growth rates, was more susceptible to lysis by tumor-specific CD8+ T cells, and secreted higher levels of the angiogenic factors VEGF and Ang2. Meanwhile, the YUMM1.7 model was more sensitive to chemotherapeutic treatment, secreted higher levels of chemokines CCL2, CXCL1, and CX3CL1, and showed higher infiltration of lymphocyte and myeloid subsets at the same tumor size. Overall, YUMM1.7 model may be better suited for in vivo studies of mechanisms that require a wider observation window and intervention than the B16F0 model, such as immune response. However, angiogenesis and immunotherapy studies may benefit from a more in-depth comparative analyses of both models.

cancer biology↗

bioRxiv2022

Head-to-head comparison of CCN4, DNMT3A, PTPN11, and SPARC as suppressors of anti-tumor immunity

BackgroundEffective communication between innate and adaptive immunity is essential for mounting an effective antitumor immune response. Emergent cancer cells likely secrete factors that inhibit this communication. To identify such factors, we applied an in vitro workflow that coupled a functional assay with proteomics to a syngeneic mouse model of melanoma known to be resistant to immunotherapies. Collectively, these in vitro results suggested CCN4, DNMT3A, PTPN11, and SPARC as secreted factors that potentially mediate immunosuppression and could potentially become easily accessible targets for novel immunotherapies. The objective of this study was to test for consistent clinical correlates in existing human data and to verify in vivo whether knocking out tumor cell production of these secreted factors improved immune-mediated control of tumor growth. ResultsAnalyses of available human data indicate that high CCN4 expression is associated with reduced survival in primary melanoma patients. High DNMT3A, PTPN11, and SPARC expression showed no association with overall survival. In addition, scRNAseq data from patients with melanoma confirmed CCN4 is expressed by the tumor cells, as opposed to other cells in the tumor microenvironment. An experimental system was created using a CRISPR/Cas9 approach to generate knock out cell lines for each of the four genes of interest using the B16F0 mouse melanoma cell line. In a immunocompetent C57BL/6, DNMT3A, PTPN11, and SPARC knockouts had no effect on overall survival compared to mice challenged with wildtype B16F0 cells while the CCN4 knockout significantly increased survival. This increase in overall survival was lost when the CCN4 knockout cells were injected into severely immunocompromised NSG hosts, indicating that CCN4s effect on the tumor microenvironment is immune mediated. A kinetic analysis leveraging a Markov Chain Monte Carlo approach quantified the various knockouts effect on cells intrinsic growth rate. The analysis shows CCN4 is the only knockout tested that decreased the net proliferation rate in immunocompetent mice compared to wildtype cells. ConclusionsThe results suggest that CCN4 is a mediator of immunosuppression in the melanoma tumor microenvironment and a potential collateral immunotherapy target.

cancer biology↗