Biology subjects

Lorens, J.

Publications and source records attributed to Lorens, J..

4 recordsLinked to original sources

bioRxiv2022

AXL-TBK1 driven nuclear AKT3 promotes metastasis

Epithelial-to-mesenchymal transition (EMT) contributes to tumor cell survival, immune evasion, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a higher likelihood of metastasis. AXL, a receptor tyrosine kinase, drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer and breast cancer. TANK-binding kinase 1 (TBK1) is central to AXL-driven EMT yet, the mechanism of how TBK1 induces EMT remains unclear. Here, we report that AXL activation stimulates TBK1 binding and phosphorylation of AKT3. TBK1 activation of AKT3 drives binding and phosphorylation of slug/snail resulting in protection from proteasomal degradation and translocation of the complex into the nucleus. We show that nuclear translocation of AKT3 is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast cancer. To advance AKT3 as a therapeutic target, an AKT3-isoform selective allosteric small molecule inhibitor, BGB214, was developed. BGB214 inhibits AKT3 nuclear translocation, EMT-TF stability, AKT3-mediated invasion of breast cancer cells and reduces tumor initiation in vivo. Our results suggest that AKT3 nuclear activity is an important feature of AXL-driven epithelial plasticity and that selective AKT3 inhibition represents a novel therapeutic avenue for treating aggressive cancer. SignificanceNuclear AKT3 activity is an important feature of AXL-TBK1 driven EMT and metastasis, thus selective AKT3 targeting represents a novel approach to treat aggressive cancer.

cancer biology↗

bioRxiv2020

C/EBPB-dependent Adaptation to Palmitic Acid Promotes Stemness in Hormone Receptor Negative Breast Cancer

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network. SignificanceCellular adaptation to obesity-induced palmitic acid drives tumor initiation through activation of a C/EBPB-dependent transcriptional network. This highlights a cell-autonomous mechanistic connection between obesity and postmenopausal hormone receptor negative breast cancer.

cancer biology↗

bioRxiv2020

AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the US, has a high metastatic rate and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, has been identified as a driver of metastasis and immune suppression in multiple cancer types. Here we use single cell RNA sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of mesenchymal tumor cells. We demonstrate that AXL-deficiency extends survival, reduces primary and metastatic burden and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression and a more active immune microenvironment compared to PDA in wild-type mice. Finally, we demonstrate that AXL-positive mesenchymal tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target for PDA patients.Competing Interest StatementRAB discloses he is a consultant for BerGenBio ASA and that he receives funding for projects distinct from the current study from BerGenBio ASA and Tolero, companies developing Axl inhibitors. JBL discloses he is an employee and stockholder of BerGenBio ASA.View Full Text

cancer biology↗

bioRxiv2019

Microenvironment-contextual cell signaling is attenuated with age

Post-menopausal women are more prone to breast cancer than younger women. The increased frequency of age-related breast cancers is likely due to interactions between acquired mutations and age-dependent epigenetic changes that affect mammary epithelial lineage fidelity. We hypothesized that the aging process fundamentally affects how human mammary epithelial cells (HMEC) respond to microenvironmental signals, resulting in increased susceptibility to oncogenic transformation. In order to measure microenvironmental cell signaling in normal finite lifespan HMEC, we applied a novel microsphere-based flow cytometry technology. The microsphere cytometry allows multiparametric single cell quantification of signaling pathway activity and lineage-specific marker expression in cells adhered to surface-functionalized microspheres that mimic specific microenvironments. Using this approach, we analyzed age-dependent changes in human mammary myoepithelial and luminal epithelial cells exposed to different ECM and growth factors. We found that ECM-mediated MAP kinase and PI3 kinase activation levels in HMEC were attenuated with age. Older luminal cells displayed higher surface integrin levels consistent with acquired basal identity, albeit with decreased integrin activation and increased Src-signaling relative to myoepithelial cells. We show that the diminished signaling magnitude in HMEC from older women correlated with reduced probability of activating oncogene-induced senescence. We propose that age-related changes in ECM-mediated epithelial cell regulation may impair protective tumor suppression mechanisms and increase breast cancer susceptibility.

cell biology↗