Biology subjects

Drouillard, D.

Publications and source records attributed to Drouillard, D..

3 recordsLinked to original sources

bioRxiv2026

Mutant KRAS promotes NF-kB driven CCL20 chemokine expression in pancreatic ductal adenocarcinoma

The chemokine CCL20 is implicated in inflammation and cancer but has proven challenging to target therapeutically. In this study, we precisely define what cells produce CCL20 in pancreatic inflammation and cancer. Through analysis of single cell RNA data, mutation and copy number signatures, gene methylation, and in vitro studies, we show that CCL20 and other NF-{kappa}B driven chemokine production is largely dependent on oncogenic KRAS in the malignant pancreas. Blockade of CCL20-CCR6 signaling in vivo using a novel partial agonist inhibitor, CCL20LD, increased recruitment of antigen presenting cells without significantly impinging tumor growth. Lastly, resistance to pan-RAS or allele-specific KRAS inhibitors decreased CCL20-dependent immune recruitment in culture. These results suggest that oncogenic KRAS activates NF-{kappa}B signaling in human pancreas cancer, resulting in pharmacologically reversible changes to chemokine production that may participate in immune suppression or immune evasion within the pancreas cancer microenvironment.

cancer biology↗

bioRxiv2024

CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization

Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors that mobilize AML cells into the bloodstream have failed to improve patient survival, likely reflecting persistent chemokine receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the naturally occurring oligomer of CXCL12. CXCL12-LD, in contrast to wild-type or locked monomer variants, was unable to induce chemotaxis in AML cells. CXCL12-LD binding to CXCR4 decreased G protein, {beta}-arrestin, and intracellular calcium mobilization signaling pathways, and indicated the locked dimer is a partial agonist of CXCR4. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wildtype and monomeric CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in survival, proliferation, and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist can avoid pharmacodynamic tolerance and may identify new avenues to better target G protein coupled receptors.

cancer biology↗

bioRxiv2019

Beta 1 Integrin Signaling Mediates Pancreatic Ductal Adenocarcinoma Resistance to MEK Inhibition

Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. The high mortality rate can be attributed to multiple factors, including late diagnosis and lack of effective therapies. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer using primary mouse and human 3D organoid cultures. We optimized the culture of pancreatic tumor organoids that utilized Matrigel as a basement membrane mimetic, facilitating polarized growth. Pancreatic tumor organoids recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the organoids with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin {beta}1, a mediator of extracellular matrix contact, and found that combined MEK and integrin {beta}1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.

cancer biology↗