Biology subjects

Franco, O. E.

Publications and source records attributed to Franco, O. E..

5 recordsLinked to original sources

bioRxiv2026

mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment.

IntroductionResistance to immunotherapy remains a major clinical challenge in TP53-mutant head and neck squamous cell carcinoma (HNSCC), a disease subset characterized by immune exclusion, high recurrence, and poor outcomes. Given the constitutive activation of PI3K/AKT/mTOR signaling in TP53-mutant HNSCC and its role in disease progression, we investigated whether the mTOR inhibition (mTORi) could overcome immune resistance and improve outcomes. MethodsWe evaluated the effects of mTOR inhibitor everolimus in TP53-mutant, anti-PD-1-resistant syngeneic HNSCC cell lines and syngeneic tumor models. Tumor microenvironment (TME) changes, including immune cell infiltration, immune checkpoint expression, and key pathways associated with immune suppression and angiogenesis were assessed to define the mechanisms underlying TME remodeling. ResultsEverolimus significantly suppressed tumor growth in syngeneic HNSCC models. At the cellular level, everolimus significantly increased intratumoral CD8+ T cell and dendritic cell (DC) infiltration while reducing the accumulation of regulatory T cells (Tregs). Mechanistically, everolimus induced a cytokine/chemokine response, marked by increased TNF-/CXCL10 expression, leading to enhanced immune infiltration. Everolimus also inhibited the HIF-1/VEGFA angiogenic axis, a central driver of immune exclusion and myeloid-derived suppressor cell (MDSC) recruitment. Furthermore, everolimus treatment attenuated PD-1/PD-L1 signaling by reducing PD-1 and PD-L1 expression, respectively, in T cells and tumor cells, thereby restoring T-cell cytotoxic competence. DiscussionThese findings demonstrate that mTORi with everolimus reverses multiple mechanisms of immune resistance in TP53-mutant HNSCC by promoting immune cell recruitment, suppressing immunosuppressive pathways, and enhancing anti-tumor T cell activity. Collectively, these results support mTORi as a mechanistically rational strategy for reprogramming immune resistance in TP53-mutant HNSCC and provide a strong preclinical rationale for combining everolimus with immune therapy in patients who are likely to fail immunotherapy.

cancer biology↗

bioRxiv2025

DGAT1 as a Racially Divergent Driver of Carcinoma-Associated Fibroblast Activation Drives Tumorigenic Pathways via ERK1/2 Signaling in Prostate Cancer.

BackgroundThe incidence of lethal prostate cancer (PCa) is disproportionately higher in African American (AA) men compared to Caucasian (Cau) men. Racial differences in lipid reprogramming have been implicated in PCa progression. Recent studies identified race-specific biological alterations in carcinoma-associated fibroblasts (CAF). Here, we demonstrate that lipid-laden CAF from AA patients (AACAF) exhibits enhanced pro-tumorigenic functions compared to CAF from Cau patients (CauCAF). MethodsDGAT1-regulated genes in fibroblasts were identified by transcriptomic profiling, and their biological consequences were evaluated in vivo. Patient-derived CAF from AA and Cau men were examined to determine their molecular response to DGAT1 inhibition during tumorigenesis. ResultsLipid droplet (LD) biogenesis analysis revealed DGAT1-dependent LD accumulation in AACAF. DGAT1 overexpression in fibroblasts enhanced fibroblast activation protein (FAP1) expression and promoted in vivo tumorigenicity of cancer cells. Transcriptome and secretome profiling identified novel DGAT1-regulated genes associated with metabolism, cell-cell signaling, motility, and angiogenesis, largely mediated through the ERK1/2 pathway. Importantly, DGAT1 inhibition in patient-derived CAF elicited racially divergent regulation of pro-tumorigenic mediators, including BDNF, VEGF, and TSP1. ConclusionsOur findings reveal elevated DGAT1 expression in AACAF as a targetable enzymatic driver that enhances fibroblast activation and supports adaptation to a lipid-rich tumor microenvironment, thereby promoting tumorigenesis.

cancer biology↗

bioRxiv2024

Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate with increased prostate volume. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define two new BPH immune subpopulations, TREM2+ and MARCO+ macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

immunology↗

bioRxiv2021

TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease

Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNF-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNF and in vitro assays confirmed that TNF stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNF-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NF{kappa}B activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNF-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNF may mechanistically drive BPH via chronic activation of the signaling axis and NF{kappa}B. TNF blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. One sentence summaryPatient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.

cell biology↗

bioRxiv2017

Stromal Reactivity Differentially Drives Tumor Cell Evolution and Prostate Cancer Progression

We implemented a hybrid multiscale model of carcinogenesis that merges data from biology and pathology on the microenvironmental regulation of prostate cancer (PCa) cell behavior. It recapitulates the biology of stromal influence in prostate cancer progression. Our data indicate that the interactions between the tumor cells and reactive stroma shape the evolutionary dynamics of PCa cells and explain overall tumor aggressiveness. We show that the degree of stromal reactivity, when coupled with the current clinical biomarkers, significantly improves PCa prognostication, both for death and recurrence, that may alter treatment decisions. We also show that stromal reactivity correlates directly with tumor growth but inversely modulates tumor evolution. This suggests that the aggressive stromal independent PCa may be an inevitable evolutionary result of poor stromal reactivity. It also suggests that purely tumor centric metrics of aggressiveness may be misleading in terms on clinical outcome.

cancer biology↗