The IL6/JAK/STAT3 pathway as a therapeutic target for histological subtypes of colorectal cancer

Summary: pages 3-4. Graphical abstract: page 5

Does Downhill Running Alter Monocyte Susceptibility to Apoptosis?

Introduction/purpose: Recovery from muscle damage involves a type of programmed cell death known as apoptosis. Damage Associated Molecular Patterns (DAMPs) are released after muscle damage and may cause premature apoptosis in monocytes infiltrating the damaged site. This may alter the time course of events towards recovery. Therefore, the purpose of this study was to investigate if downhill running causes a change in the susceptibility of monocytes to apoptosis. Methods: Participants (5 male, 6 female) completed a downhill running protocol consisting of 6-5 minute bouts at a speed of 6-9mph on a -15% grade treadmill. Venous blood samples were collected immediately pre-exercise (PRE), in addition to 4 -h, 24 -h and 48 -h post-exercise. Creatine kinase (CK) was measured to give an indication of muscle damage. Monocytes were analyzed by flow cytometry for expression of multicaspase and annexin v reagent was used to detect changes in the plasma membrane. A MILLIPLEX MAP human early apoptosis magnetic bead 7-plex kit (EMD Millipore, Billerica, MA) was used to assess the relative concentration of phosphorylated protein kinase B (Akt), Bcl-2 associated death promoter (BAD), B cell lymphoma-2 (Bcl-2), active caspase-8, active caspase-9, c jun N terminal kinase (JNK) and tumor protein p53 by Luminex multiplex assay. Results: CK peaked at 24- h. Monocytes showed greater expression of multicaspase at 24 –h and 48 -h than at PRE. Bcl-2, p53 and caspase-8 were all significantly greater at 24 –h than at PRE. Conclusion: Downhill running did alter the apoptotic response of monocytes and therefore may be important in the recovery process from muscle damage

Signal interaction between the tumour and inflammatory cells in patients with gastrointestinal cancer: implications for treatment

Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention

Trailblazers in Cancer Research : The Next Generation – The British Association of Cancer Research Early Career Conference

ACKNOWLEDGEMENTS We thank Mrs Janet Alexander and Ms Barbora Gaborova for their invaluable help with this conference's organisation, marketing, and administration.Peer reviewe

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes

Neoadjuvant radiotherapy is commonly used as standard treatment for rectal cancer. However, response rates are variable and survival outcomes remain poor, highlighting the need to develop new therapeutic strategies. Research is focused on identifying novel methods for sensitizing rectal tumours to radiotherapy to enhance responses and improve patient outcomes. This can be achieved through harnessing tumour promoting effects of radiation or preventing development of radio-resistance in cancer cells. Many of the approaches being investigated involve targeting the recently published new dimensions of cancer hallmarks. This review article will discuss key radiation and targeted therapy combination strategies being investigated in the rectal cancer setting, with a focus on exploitation of mechanisms which target the hallmarks of cancer

Trailblazers in cancer research: the next generation – the British Association of Cancer Research early-career conference

The inaugural ‘British Association of Cancer Research (BACR) Early Career Conference, Trailblazers in Cancer Research 2023’, was a 2-day meeting held in Manchester, UK. Recognising the disruption caused by the COVID-19 pandemic to early-career researchers (ECRs), the BACR executive committee organised an in-person conference to address the lack of network and training opportunities during this time. The conference brought together PhD students and post-doctoral researchers from across the UK and beyond, who shared their outstanding contributions to cancer research. The meeting incorporated several cutting-edge cancer themes, including ‘Cancer Cell Signalling and The Tumour Microenvironment’; ‘Emerging Approaches in Cancer Treatment’; ‘Cancer Omics and Lifestyle’, and ‘Nutrition and Cancer’. Alongside showcasing world-class cancer research, the meeting included a career-focused session which allowed industrial and non-academic speakers to provide vital insight into alternative career paths aside from the familiar ‘academic’ route. Importantly, the conference also introduced delegates to Patient Public Involvement in cancer research, an area of limited experience for many. Overall, the BACR Trailblazers Conference was hugely successful and presented an excellent platform for collaboration and networking among ECRs in cancer research

WNT signalling promotes NF-κB activation and drug resistance in KRAS-mutant colorectal cancer [pre-print]

Approximately 40% of colorectal cancer (CRC) cases are characterized by KRAS mutations, rendering them insensitive to most CRC therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities ("RAP"). Here, we demonstrate that elevated WNT activity upregulates canonical (NF-κB) signalling in both and human RAS mutant tumours. This upregulation required Toll-1 and Toll-9 and resulted in reduced efficacy of RAS pathway targeted drugs such as the MEK inhibitor trametinib. Inhibiting WNT activity pharmacologically significantly suppressed trametinib resistance in RAP tumours and more genetically complex RAP-containing 'patient avatar' models. WNT/MEK drug inhibitor combinations were further improved by targeting brm, shg, ago rhoGAPp190 and upf1, highlighting these genes as candidate biomarkers for patients sensitive to this duel approach. These findings shed light on how genetic complexity impacts drug resistance and proposes a therapeutic strategy to reverse this resistance

High expression of STAT3 within the tumour-associated stroma predicts poor outcome in breast cancer patients

Introduction: Triple-negative breast cancer (TNBC) patients have the poorest clinical outcomes compared to other molecular subtypes of breast cancer. IL6/JAK/STAT3 signalling is upregulated in breast cancer; however, there is limited evidence for its role in TNBC. This study aimed to assess the expression of IL6/JAK/STAT3 in TNBC as a prognostic biomarker. Methods: Tissue microarrays consisting of breast cancer specimens from a retrospective cohort (n = 850) were stained for IL6R, JAK1, JAK2 and STAT3 via immunohistochemistry. Staining intensity was assessed by weighted histoscore and analysed for association with survival/clinical characteristics. In a subset of patients (n = 14) bulk transcriptional profiling was performed using TempO-Seq. Nanostring GeoMx® digital spatial profiling was utilised to establish the differential spatial gene expression in high STAT3 tumours. Results: In TNBC patients, high expression of stromal STAT3 was associated with reduced cancer-specific survival (HR = 2.202, 95% CI: 1.148–4.224, log rank p = 0.018). TNBC patients with high stromal STAT3 had reduced CD4+ T-cell infiltrates within the tumour (p = 0.001) and higher tumour budding (p = 0.003). Gene set enrichment analysis (GSEA) of bulk RNA sequencing showed high stromal STAT3 tumours were characterised by enrichment of IFNγ, upregulation of KRAS signalling and inflammatory signalling Hallmark pathways. GeoMx™ spatial profiling showed high stromal STAT3 samples. Pan cytokeratin (panCK)-negative regions were enriched for CD27 (p < 0.001), CD3 (p < 0.05) and CD8 (p < 0.001). In panCK-positive regions, high stromal STAT3 regions had higher expression of VEGFA (p < 0.05). Conclusion: High expression of IL6/JAK/STAT3 proteins was associated with poor prognosis and characterised by distinct underlying biology in TNBC

Reduced Inflammatory and muscle damage biomarkers following oral supplementation with bioavailable curcumin

This article seeks to determine the effects of oral curcumin supplementation on muscle and activities of daily living soreness, creatine kinase, and inflammatory cytokines following exercise-induced muscle damage

Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer

Colorectal cancer (CRC) is a heterogenous malignancy and research is focused on identifying novel ways to subtype patients. In this study, a novel classification system, tumour microenvironment score (TMS), was devised based on Klintrup–Mäkinen grade (KMG), tumour stroma percentage (TSP), and tumour budding. TMS was performed using a haematoxylin and eosin (H&E)-stained section from retrospective CRC discovery and validation cohorts (n = 1,030, n = 787). TMS0 patients had high KMG, TMS1 were low for KMG, TSP, and budding, TMS2 were high for budding, or TSP and TMS3 were high for TSP and budding. Scores were assessed for association with survival and clinicopathological characteristics. Mutational landscaping and Templated Oligo-Sequencing (TempO-Seq) profiling were performed to establish differences in the underlying biology of TMS. TMS was independently prognostic in both cohorts (p < 0.001, p < 0.001), with TMS3 predictive of the shortest survival times. TMS3 was associated with adverse clinical features including sidedness, local and distant recurrence, higher T stage, higher N stage, and presence of margin involvement. Gene set enrichment analysis of TempO-Seq data showed higher expression of genes associated with hallmarks of cancer pathways including epithelial to mesenchymal transition (p < 0.001), IL2 STAT5 signalling (p = 0.007), and angiogenesis (p = 0.017) in TMS3. Additionally, enrichment of immunosuppressive immune signatures was associated with TMS3 classification. In conclusion, TMS represents a novel and clinically relevant method for subtyping CRC patients from a single H&E-stained tumour section