Biology subjects

Bartlett, A. Q.

Publications and source records attributed to Bartlett, A. Q..

6 recordsLinked to original sources

bioRxiv2025

Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles

Pancreatic ductal adenocarcinoma (PDAC) tumors contain chaotic vasculature that limits immune surveillance and promotes early events in the metastatic cascade. However, current antiangiogenic therapies have failed in PDAC, and thus, it remains important to uncover mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein HuR (ELAVL1) plays an important role re-shaping the tumor microenvironment (TME) by regulating the stability and translation of cytokine encoding transcripts. Herein, we demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. We found that HuR knockout (KO) tumors have impaired growth in an immunocompetent mouse model, and that administering purified wildtype (WT) EVs can increase tumor growth. Further, we observed that PDAC EVs contain HuR-dependent mRNA and protein cargoes relating to endothelial cell function and angiogenesis. Treatment of endothelial cells with HuR WT EVs strongly increased the expression of genes involved in barrier function and endothelial cell development, and directly increased their migratory and tube forming functions. In an immunocompetent orthotopic mouse model of PDAC, we showed that HuR increases endothelial cell presence and sprouting, while decreasing ICAM-1 expression. Importantly, we found utilizing a genetic EV reporter, that decreased ICAM-1 within WT tumors occurs in endothelial cells that have imported PDAC EVs, suggesting that this signaling axis is directly modulating endothelial cell behavior in vivo. Collectively, our data reveal a new role of HuR in EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.

cancer biology↗

bioRxiv2025

mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR (ELAVL1), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth due to a novel role of HuR inducing T-cell suppression. Importantly, we found that HuR depletion in tumors enhanced both T cell number and activation states and diminished myeloid phenotypes by comprehensive spatial profiling of the PDAC TME. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, and inhibition of mTOR activity rescued the impaired function of local T cells. Translating these findings, we demonstrated that HuR depletion sensitized PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. For the first time, we show that HuR facilitates tumor immune suppression in PDAC by inhibiting T cell infiltration and function and implicate targeting HuR as a potential therapeutic strategy in combination with immunotherapy. SIGNIFICANCEThis study identified a novel mechanism that HuR supports pancreatic tumor growth by restricting T cell infiltration, promoting immune evasion. Our work supports targeting strategies against HuR in PDAC with the goal of enhancing PDAC sensitivity to immune-based cancer therapies, such as checkpoint blockade and T cell transfer.

cancer biology↗

bioRxiv2024

Pancreatic cancer cells overexpressing interleukin 6 induce T-cell-mediated tumor clearance and durable anti-tumor immune response

Background & AimsTumor immune resistance is recognized as a contributor to low survivorship in pancreatic ductal adenocarcinoma (PDAC). The inflammatory cytokine interleukin-6 (IL-6) promotes polarization of CD4 T cell populations away from immune tolerance, and induces differentiation of cytotoxic CD8 T cells. This work aims to test whether IL-6 could stimulate an anti-tumor response in PDAC MethodsWe overexpressed IL-6 in multiple KrasG12D/+, Tp53R172H/+, Pdx1-Cre (KPC) cell lines, which were orthotopically implanted in mice (OT-PDACIL6). We followed mouse survival and measured tumor growth, tumor histology, and plasma IL-6 at 5 and 10 days after tumor implantation. We measured tumor immune cell infiltration via flow cytometry and histology. We used antibody-based T cell depletion and secondary tumor implantation rechallenge to test the dependency of the durable immune reaction on T cells. We use lipid nanoparticle (LNP)-based delivery of IL-6 mRNA to the pancreas as an orthogonal approach for testing the effect of elevated IL-6 in the tumor microenvironment on anti-tumor T cell invasion. ResultsImproved survival occurred in all instances of OT-PDACIL6, with one cell line (KxPxCx) reproducibly resulting in long-term recurrence-free survival. With KxPxCx cells, circulating IL-6 was 100-fold higher in OT-KxPxCxIL6 than in OT-KxPxCxparental mice. Flow cytometry revealed increased T cells and NK cells, and decreased T regulatory cells, and we observed significantly increased lymphoid aggregates in OT-KXPXCXIL6 as compared to OT--KxPxCxparental tumors. Antibody-based CD4+ and CD8+ T cell depletion prevented tumor clearance and completely abolished the survival advantage in OT-KxPxCxIL6 mice. The anti-tumor immune response to OT-KxPxCxIL6 rendered mice immune to re-challenge with OT-KxPxCxparental tumors. LNP delivery of IL-6 to the pancreas elevated systemic IL-6 levels [~]50 fold, lowered tumor burden, and increased anti-tumor T cell phenotypes. ConclusionsLocally high IL-6 concentrations potently enhance the T cell-mediated anti-tumor response to PDAC. SYNOPSISInterleukin-6 induces rapid and durable T cell-driven immune clearance of pancreatic ductal adenocarcinoma. The anti-tumor immune microenvironment is hallmarked by increased lymphoid aggregate formation, increased CD4 T cell abundance, and decreased Treg abundance.

cancer biology↗

bioRxiv2024

Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis

Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an influx of immune suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver pre-metastatic niches. This work identifies features of reproductive control of liver biology that sets a foundation for better understanding the potential role of the liver in maternal health.

cancer biology↗

bioRxiv2022

IL-6/STAT3 signaling drives early-stage pancreatic cancer cachexia via suppressed ketogenesis

Cancer cachexia is highly prevalent in patients with pancreatic ductal adenocarcinoma (PDAC). Although advanced cachexia is associated with inflammatory signaling, the early events driving wasting are poorly defined. Using an orthotopic mouse model of PDAC, we find that early cachexia is defined by a pronounced vulnerability to undernutrition, characterized by increased skeletal muscle wasting. PDAC suppresses lipid beta oxidation and impairs ketogenesis in the liver, which coordinates the adaptive response to nutritional scarcity. When PDAC mice are fed ketogenic diet, this effect is reversed, and muscle mass is preserved. Furthermore, physiologic levels of ketones are sufficient to protect myotubes against PDAC-associated wasting. Interleukin-6 (IL-6) drives liver metabolic reprogramming, and hepatocyte-specific loss of Signal Transducer and Activator of Transcription 3 (STAT3) is sufficient to prevent PDAC-associated muscle loss. Together, these studies define a key role for the liver in cachexia development and directly link skeletal muscle homeostasis to hepatic lipid oxidation.

cancer biology↗

bioRxiv2021

Pregnancy and weaning regulate human maternal liver size and function

BACKGROUNDDuring pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a pro-metastatic niche. These data suggest a mechanism for increased liver metastasis in postpartum breast cancer patients. OBJECTIVESInvestigate if the human liver changes in size and function during pregnancy and weaning. METHODSAbdominal imaging was obtained in healthy women at early and late pregnancy, and post-wean. During pregnancy time points, endogenous glucose production was measured and fasting blood taken to measure bile acids. RESULTSIndependent of weight gain, most womens livers increased in size with pregnancy, returning to baseline post-wean. Putative roles for bile acids in liver growth were observed in pregnant women and rodents. CONCLUSIONSThe human liver is regulated by reproductive state with growth during pregnancy and volume loss post-wean. These findings may have broad implications for sex-specific liver diseases and cancer.

physiology↗