Biology subjects

Flanagan, D. J.

Publications and source records attributed to Flanagan, D. J..

3 recordsLinked to original sources

bioRxiv2024

Type-I interferons drive the gastrointestinal inflammatory response in a mouse model of Parkinsons disease

Background and AimsParkinsons disease (PD) is an age-related neurodegenerative disorder characterised by classical motor symptoms due to a loss of dopaminergic neurons in the substantia nigra pars compacta. The type-I interferons (IFNs) are elevated in the aging brain and we have implicated them in the neuroinflammatory response in PD. With increasing evidence of gastrointestinal (GI) dysfunction in PD patients, this study explored the contribution of the type-I IFNs to the transmission of pathology from the brain to the gut in PD. MethodsYoung (10-12 weeks) and aged (40-50 weeks) wildtype and IFNAR1-/- mice received an intrastriatal injection of human alpha-synuclein (-Syn) pre-formed fibrils (PFF) (8ug) with gut tissue analysed 6-months post-injection (p.i). A mouse intestinal organoid culture model was established to further characterise the -Syn induced inflammatory response in the gut. ResultsAn intrastriatal injection of human -Syn PFFs was shown to initiate a type-I IFN-dependent neuroinflammatory response in the GI tract of wildtype mice at 6-months p.i. This response was attributed to an elevation in type-I IFN signalling in aged mice that was absent in the IFNAR1-/- mice. Mouse intestinal organoid cultures confirmed -Syn was taken up by the enteroendocrine cells (EECs) to induce a type-I IFN mediated pro-inflammatory response that was attenuated in IFNAR1-/- cultures. ConclusionThis study has confirmed the type-I IFNs modulate the -Syn PFF induced inflammatory response within the gut potentiating pathology progression along the gut-brain axis. Early intervention of this type-I IFN response may be a potential therapeutic target to limit the progression of PD.

neuroscience↗

bioRxiv2022

Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition

To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood. Here, we comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) on CRC cells. We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that renders the cells sensitive to the glutaminase 1 (GLS1) inhibitor - CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro, and importantly, reduced crypt proliferation in Apcfl/fl mice in vivo. Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.

cancer biology↗

bioRxiv2022

Molecular phenotyping of colorectal neoplasia shows dynamic and adaptive cancer stem cell population admixture

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterised by fetal transcriptional profiles. Neoplasia hijacks regenerative signalling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signalling disruption, and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis, and is influenced by cell-intrinsic, extrinsic and therapeutic selective pressures.

cancer biology↗