Biology subjects

Soto-Pantoja, D. R.

Publications and source records attributed to Soto-Pantoja, D. R..

4 recordsLinked to original sources

bioRxiv2025

Dietary nitrate and nitrite protect against doxorubicin-induced cardiac fibrosis and oxidative protein damage in tumor-bearing mice

Anthracycline-induced cardiotoxicity remains a major limitation in cancer therapy, affecting long-term cardiovascular health in survivors. Dietary nitrate supplementation has shown cardioprotective effects in preclinical models of doxorubicin (Dox)-induced and ischemia-reperfusion injury. In this study, we evaluated the protective effects of nitrate and nitrite (NOx) supplementation in a syngeneic, tumor-bearing mouse model undergoing Dox chemotherapy (N=5 per group). NOx supplementation significantly reduced cardiac fibrosis and levels of 4-hydroxynonenal-modified proteins, a marker of oxidative stress. Tumor sizes varied, but most regressed by the final Dox dose. Importantly, NOx did not compromise the anti-tumor efficacy of Dox nor did it promote pulmonary metastasis. These findings support the potential clinical use of dietary nitrate and nitrite as adjuncts to Dox treatment to mitigate cardiotoxicity without impairing anti-cancer outcomes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/660942v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ec0e52org.highwire.dtl.DTLVardef@a03beaorg.highwire.dtl.DTLVardef@1bdb02eorg.highwire.dtl.DTLVardef@79d23e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Anti-CD47 immunotherapy as a therapeutic strategy for the treatment of breast cancer brain metastasis

The presence of cell surface protein CD47 allows cancer cells to evade innate and adaptive immune surveillance resulting in metastatic spread. CD47 binds to and activates SIRP on the surface of myeloid cells, inhibiting their phagocytic activity. On the other hand, CD47 binds the matricellular protein Thrombospondin-1, limiting T-cell activation. Thus, blocking CD47 is a potential therapeutic strategy for preventing brain metastasis. To test this hypothesis, breast cancer patient biopsies were stained with antibodies against CD47 to determine differences in protein expression. An anti-CD47 antibody was used in a syngeneic orthotopic triple-negative breast cancer model, and CD47 null mice were used in a breast cancer brain metastasis model by intracardiac injection of the E0771-Br-Luc cell line. Immunohistochemical staining of patient biopsies revealed an 89% increase in CD47 expression in metastatic brain tumors compared to normal adjacent tissue (p [≤] 0.05). Anti-CD47 treatment in mice bearing brain metastatic 4T1br3 orthotopic tumors reduced tumor volume and tumor weight by over 50% compared to control mice (p [≤] 0.05) and increased IBA1 macrophage/microglia marker 5-fold in tumors compared to control (p [≤] 0.05). Additionally, CD47 blockade increased the M1/M2 macrophage ratio in tumors 2.5-fold (p [≤] 0.05). CD47 null mice had an 89% decrease in metastatic brain burden (p [≤] 0.05) compared to control mice in a brain metastasis model. Additionally, RNA sequencing revealed several uniquely expressed genes and significantly enriched genes related to tissue development, cell death, and cell migration tumors treated with anti-CD47 antibodies. Thus, demonstrating that CD47 blockade affects cancer cell and tumor microenvironment signaling to limit metastatic spread and may be an effective therapeutic for triple-negative breast cancer brain metastasis.

cancer biology↗

bioRxiv2023

Absence of CD47 in the tumor microenvironment modulates tumor metabolism and immunosuppressive signatures limiting breast cancer progression.

The majority of breast cancers are generally considered immune-deprived tumors. This lack of immunogenicity severely hinders effectiveness of current immunotherapy approaches limiting therapeutic options to control disease. Therefore, we need new biomarkers to determine and enhance immune responses to improve the outcome of cancer patients experiencing invasive disease. Our data in matched human patient biopsies show that CD47 expression increases from primary to metastatic tumors. CD47 is an integral membrane protein that impairs antitumor immunosurveillance and influences normal tissue metabolism. However, whether CD47 plays a role in regulating tumor bioenergetics is unknown. A carcinogen-induced mouse mammary carcinogenesis model demonstrates that the absence of CD47 reduces tumor burden, which is associated with a distinct metabolic signature compared to WT tumors. Depletion of several lipid metabolites was observed in the absence of CD47, and metabolic dependency experiments suggest that anti-sense blockade of CD47 limits reliance on fatty acid oxidation as a fuel supporting cellular respiration on cancer cells. Our global metabolomics analysis also implicated the absence of CD47 in downregulation of immunosuppressive metabolites of the tryptophan and prostaglandin pathways. Spatial proteomic analysis revealed increased immune infiltrate and substantial reduction in immunosuppressive immune checkpoint proteins in the absence of CD47 with the highest reduction in intra-tumoral PD-L1 expression. Since anti-PD-L1 therapy is used in the current strategy to treat triple-negative breast cancer (TNBC), we targeted CD47 in an EMT-6 syngeneic TNBC model. The in vivo knockdown of CD47 sensitized tumors to anti-PD-L1 therapy to decrease tumor burden and increase intratumoral cytotoxic T cells. Therefore, targeting CD47 may be a suitable immunotherapeutic option to limit immunosuppression and enhance the efficacy of immune checkpoint blockade.

cancer biology↗

bioRxiv2020

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

The development of distant metastasis is the main cause of prostate cancer (CaP)-related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically anti-angiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-{beta}1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-{beta}1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-{beta}1. Similar to TSP-1 deletion, loss of platelet TGF-{beta}1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release. Within the bone microenvironment, platelet TGF-{beta}1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-{beta}1 axis regulates pre-metastatic niche formation and tumor-induced bone turnover. Targeting the platelet release of TSP-1 or TGF-{beta}1 represents a potential method to interfere with the process of CaP metastasis to bone.

cancer biology↗