Biology subjects

Olex, A. L.

Publications and source records attributed to Olex, A. L..

4 recordsLinked to original sources

bioRxiv2025

Tumor cell dissemination is facilitated through regulatory T cell-driven extracellular matrix remodeling

Regulatory T (Treg) cells function to enforce peripheral tolerance and are potent suppressors of tumor immunity. In breast cancer, we have shown that Treg cells promote tumor growth by favoring alternative activation of macrophages via suppression of IFN-{gamma}. The tumor-associated extracellular matrix (ECM) is a key regulator of metastatic dissemination and is emerging as a critical regulator of tumor immunity. However, the reciprocal effects of the immune system on the ECM remain elusive. Using a combination of murine in vivo, ex vivo and bioengineering models we describe Treg cell-dependent changes in the tumor ECM that facilitate tumor cell migration and metastatic dissemination. Importantly, Treg cell-dependent matrisome signatures correlate with delayed survival advantage in human breast cancer samples, and are upregulated in tumor-associated macrophages (TAMs). Further, both IFN-{gamma} and IFN-{gamma}-sensitivity in TAMs contribute to structural and functional changes of the ECM. This work underscores a previously unrecognized role of Treg cells on the ECM that facilitates metastasis and is consistent with tissue Treg cell emergent function as critical regulators of tissue repair and cancer.

cancer biology↗

bioRxiv2024

Ethylene Receptor Gain- and Loss-of-function Mutants Reveal an ETR1-dependent Transcriptional Network in Roots

In Arabidopsis, a family of five receptors mediates ethylene responses in roots, with Ethylene Response 1 (ETR1) controlling increases in root hair proliferation and decreases in lateral root formation. To define the ETR1-dependent gene regulatory network (GRN) controlling root development, we profiled the root transcriptome from Col-0 and the etr1-3 gain-of-function and etr1-7 loss-of-function mutants in the presence and absence of ethylene or the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). We identified 4,522 differentially expressed (DE) transcripts in Col-0 roots with altered abundance in response to ethylene and/or ACC treatment, with larger magnitude changes induced by ethylene. These included 553 DE transcripts that were ETR1 dependent, defined by a lack of response to treatment with ethylene and/or ACC in ethylene-insensitive etr1-3 and constitutively altered in etr1-7 in the presence and absence of treatment relative to time-0 Col-0. Within these ETR1-dependent transcripts were ethylene biosynthesis genes and transcription factors. ACC OXIDASE 2 (ACO2) and ACO3 convert ACC to ethylene and were ETR1-dependent, and ACO-promoter-driven reporter fusions were ACC regulated in root tissues in appropriate locations to control root development, with ACO5 localized to root hairs. Abundance of ETR1-dependent transcripts that were predicted to encode transcription factors and ACOs were examined in Col-0 and an ein3eil1 mutant with and without ACC treatment, suggesting the ETR1 and EIN3/EIL1 canonical ethylene signaling pathway regulated some, but not all, of these transcriptional responses. Together, these findings reveal features of an ETR1-dependent GRN that controls both ethylene synthesis and root growth and development. One sentence summaryTranscriptional responses in etr1 LOF and GOF mutants reveal an ethylene-mediated ETR1- and EIN3 dependent gene regulatory network that modulates ethylene signaling and synthesis and root development.

plant biology↗

bioRxiv2024

Effective anti-tumor immune response against HCC is orchestrated by immune cell partnership network that functions through hepatic homeostatic pathways, not direct cytotoxicity

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear. MethodsIn a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumor inhibition upon dietary correction. ResultsCarcinogenesis begins during MAFLD, with tumor cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to turnover of liver cells but do not primarily target the tumor. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response--not merely immune activation--dictates whether tumors grow or regress, emphasizing the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming. ConclusionThese findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumor-hostile microenvironment, whereas tumor-directed approaches fail to remodel the TME. This underscores the need for tissue remodeling strategies in cancer prevention and treatment. Lay summaryOur study challenges the traditional view that the liver is purely tolerant to immune responses, revealing that it actively regulates immunity to maintain tissue health. We found that liver cancer (HCC) begins during fatty liver disease (MAFLD) but can be halted if immune cells--especially monocytes--restore tissue integrity. Instead of focusing solely on killing tumors, effective immunotherapy should harness the bodys natural ability to repair the liver, creating an environment where cancer cannot thrive. This discovery paves the way for innovative treatments that promote immune-driven tissue regeneration as a strategy for cancer prevention and therapy.

immunology↗

bioRxiv2020

Chromatin conformation capture (Hi-C) sequencing of patient-derived xenografts: analysis guidelines

Sequencing of patient-derived xenograft (PDX) mouse models allows investigation of the molecular mechanisms of human tumor samples engrafted in a mouse host. Thus, both human and mouse genetic material is sequenced. Several methods have been developed to remove mouse sequencing reads from RNA-seq or exome sequencing PDX data and improve the downstream signal. However, for more recent chromatin conformation capture technologies (Hi-C), the effect of mouse reads remains undefined. We evaluated the effect of mouse read removal on the quality of Hi-C data using in silico created PDX Hi-C data with 10% and 30% mouse reads. Additionally, we generated two experimental PDX Hi-C datasets using different library preparation strategies. We evaluated three alignment strategies (Direct, Xenome, Combined) and three processing pipelines (Juicer, HiC-Pro, HiCExplorer) on the quality of Hi-C data. Removal of mouse reads had little-to-no effect on data quality than the results obtained with Direct alignment strategy. Juicer pipeline extracted the most useful information from PDX Hi-C data. However, library preparation strategy had the largest effect on all quality metrics. Together, our study presents comprehensive guidelines on PDX Hi-C data processing.

genomics↗