Biology subjects

Vendramini-Costa, D. B.

Publications and source records attributed to Vendramini-Costa, D. B..

4 recordsLinked to original sources

bioRxiv2026

Keloid transcriptomics reveal heterogeneity in fibroblast subtype enrichment, gene expression, and immune cell responses

Keloid disease (KD) is a fibroproliferative skin disorder resulting from abnormal scar formation that causes pain, itching, and decreased quality of life. While multiple KD transcriptomic studies exist, the influence of cell type composition on bulk tissue gene expression is unknown. We characterized fibroblast subtype and immune cell enrichment using bulk RNA-Seq of head and neck keloid and matched adjacent normal skin tissue (MANST) from 14 patients (10 African American and 4 European American). Cell type enrichment was calculated by single sample gene set enrichment analysis. Linear mixed-effects models were employed for 1) differential cell type enrichment across tissue, 2) tissue type-specific associations between fibroblast subtypes and immune cells, and 3) differentially expressed genes (DEGs) across tissue. Validation was conducted in an independent cohort of 8 African Americans. Three fibroblast subtypes and 14 immune cell types were differentially enriched across tissue type. Further, 17 tissue type-specific fibroblast subtype-immune cell enrichment associations were identified, with 14 exhibiting decreased association in keloid tissue relative to MANST. After adjustment for cell type enrichment, MIR31HG and NR4A2 were significant DEGs with the largest positive and negative fold-changes, respectively. By considering cell type enrichment, underlying keloid tissue-specific cell type and gene expression associations were revealed.

bioinformatics↗

bioRxiv2024

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDRs potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

cancer biology↗

bioRxiv2023

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6).

In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.

cancer biology↗

bioRxiv2021

NetrinG1+ cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress

It is projected that, in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). This fibrous stroma, known as desmoplasia, causes the collapse of local blood vessels rendering a nutrient-deprived milieu. Hence, PDAC cells are nurtured by local CAF-secreted products, which include, among others, CAF-generated small extracellular vesicles (sEVs). It is well-accepted that upon culturing functionally tumor-promoting CAFs under pathophysiological-relevant conditions (e.g., within self-produced ECM), these cells express NetrinG1 (NetG1) and sustain endosomal pools rich in active 5{beta}1-integrin; traits indicative of poor patient survival. We herein report that NetG1+ CAFs generate sEVs that rescue PDAC cells from nutrient-deprived induced apoptosis. Two unique sEVs, NetG1+ and 5{beta}1-integrin+, were uncovered. The former constitutes cargo of CAF-generated exomeres, and the latter is detected in classic exosomes. Proteomic and metabolomic analyses showed that the sEV-dependent PDAC survival is, at least in part, dictated by the cargo packaged within sEVs in a NetG1-dependent manner. Indeed, despite producing a similar number of vesicles, selected key proteins and metabolites (e.g., glutamine) were incorporated within the unique sEVs. Finally, we found that NetG1 and 5{beta}1-integrin were detected in sEVs collected from plasma of PDAC patients, while their concomitant levels were significantly lower in plasma of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF sEVs opens a new investigative avenue in tumor-stroma interactions and stroma staging detection.

cancer biology↗