Biology subjects

Jarde, T.

Publications and source records attributed to Jarde, T..

4 recordsLinked to original sources

bioRxiv2025

A spatial atlas of colorectal cancer reveals the influence of stromal niches on tumour differentiation

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related mortality. Tumour architecture is spatially heterogeneous, ranging from the necrotic core to the invasive front, accompanied by diverse stromal and immune responses that influence tumour progression and treatment outcomes. To explore the spatial organisation of the tumour microenvironment, we profiled 1000 genes in 846,469 cells in 23 normal and late-stage colorectal tumour samples. We identified nine distinct spatial niches based on their cellular composition. We show that lymphoid aggregates enriched for CCR7/SELL+ CD4 T cells displayed heightened interferon signalling, more proliferating B cells and gene expression changes indicative of an adaptive immune response. We defined granulocyte-rich regions are concomitant with inflammation-mediated stromal reprogramming and increased tumour stemness. Finally, we uncovered the impact of the tumour microenvironment by distinguishing gene expression programs that were intrinsic to cancerous epithelial cells from those mediated by niche-specific changes. Key pointsO_LIWe present a spatial atlas of colorectal cancer and normal colon alongside an R/shiny interface to interactively explore this data: https://abud-apps.abud-lab-spatial.cloud.edu.au/shiny/cosmxos/. We analysed nine CosMx slides and provide QC metrics, identify strengths and weaknesses and provide suggestions for analysis of imaging-based spatial data. C_LIO_LIWe identify and characterise nine distinct spatial niches, each with their unique gene expression profile. C_LIO_LIWe observe granulocyte infiltration associated with spatially controlled TNF and IL1 signalling from granulocytes and myeloid cells. This signalling associates with a reduction in pro-differentiation CXCL14 fibroblasts and an increase in MMP tissue-remodelling fibroblasts, ultimately reprogramming tumours toward a more foetal/stem-like (progenitor) state. We suggest IL24 as a potential regulatory factor of this response. C_LIO_LIGranulocyte chemoattractants were consistently expressed at higher levels by both cancerous epithelial cells and the tumour microenvironment (TME) relative to normal colon. C_LIO_LIWe identify colonic LAs associated with T cell infiltration, including a population of CCR7/SELL+ CD4 T cells linked to significant reprogramming of B cells. Furthermore, we show that granulocyte-driven fibroblast and myeloid reprogramming is reversed within LAs. C_LIO_LIWe show that mutated epithelial cells within tumours are uniquely marked by an FXYD5+ PIGRlow expression profile, allowing for tumour vs normal epithelial cell differential gene expression analysis. This distinction clarifies cancerous tumour-intrinsic expression changes versus those promoted by the TME. C_LI

cancer biology↗

bioRxiv2024

Ribosomal Biogenesis Hyperactivation and ErbB signalling Mediated Network Rewiring Causes Adaptive Resistance to FGFR2 Inhibition

Fibroblast Growth Factor Receptor 2 inhibition presents a promising therapeutic approach for restraining the growth and survival of cancer cells, particularly in breast tumours. However, the emergence of resistance to FGFR2 inhibitors like PD173074 highlights the importance of understanding the molecular mechanisms driving resistance and identifying effective therapeutic strategies. In this study, we employed temporal quantitative proteomics and phosphoproteomics, complemented by computational clustering, PTM-SEA analysis, and kinase activity prediction, to monitor the response of MFM223 triple negative breast cancer cells to FGFR2 inhibition. Strikingly, we observed a marked enrichment of ribosome biogenesis function modules immediately following treatment, a phenomenon not observed with other inhibitors. Additionally, we discovered that CX-5461, an RNA polymerase I inhibitor, synergistically enhanced the growth inhibition induced by PD173074, mechanistically attributed to its significant suppression of rDNA transcription stimulated by PD173074. Moreover, our phosphoproteomics dynamic profiling identified the clustering of kinases within MAPK and ErbB signalling pathways, indicative of their reactivation in response to FGFR2 inhibition. Experimentally validating this finding, we observed a notable rebound in phosphorylation levels of key kinases such as ERK1/2 and ErbB3, and demonstrated a substantial synergistic effect of PD173074 in combination with Trametinib, a MEK inhibitor, in suppressing cancer cell growth. Collectively, our findings provide critical insights into the network rewiring triggered by FGFR2 inhibition and offer a foundation for the rational design of combinatorial therapeutic strategies to overcome resistance mechanisms associated with FGFR2 inhibitors.

cancer biology↗

bioRxiv2022

Aspirin synergizes with regorafenib to reduce growth of colorectal cancer

PurposeRegorafenib is a multi-kinase inhibitor approved for refractory metastatic colorectal cancer. Previous studies have suggested that combining kinase inhibitors with aspirin may improve patient outcomes. We aimed to determine the effects of aspirin and regorafenib combination treatment in preclinical models of colorectal cancer. Experimental DesignSW480, RKO and LIM1215 colorectal cancer cell lines were treated with aspirin and regorafenib to determine effects on proliferation and cytotoxicity. RNA sequencing and Western blotting were performed to explore underlying molecular effects. Aspirin and regorafenib combination treatment was also tested using organoids derived from three human colorectal cancer tissue specimens. For the in vivo study, SW480-derived tumors were established in athymic mice. Tumor volume was measured during treatment with aspirin and regorafenib, followed by immunohistochemical staining for markers of proliferation and apoptosis. ResultsAspirin and regorafenib synergistically inhibited proliferation of colorectal cancer cell lines and patient-derived organoids, irrespective of KRAS or BRAF mutation status. This was associated with inhibition of the PI3K-Akt-mTOR pathway and activation of the AMPK pathway. Aspirin and regorafenib effectively inhibited growth of microsatellite stable KRAS-mutant SW480-derived tumors in vivo. Immunohistochemical staining for Ki67 and cleaved caspase 3 showed that combination treatment elicited a synergistic anti-proliferative effect, in addition to a pro-apoptotic effect that was driven by regorafenib. ConclusionsAspirin and regorafenib demonstrate synergistic anti-proliferative effects in preclinical models of colorectal cancer. This suggests that combining regorafenib with aspirin may be an improved treatment strategy for patients with refractory metastatic colorectal cancer.

cancer biology↗

bioRxiv2019

SRSF3 confers selective processing of miR-17-92 cluster to promote tumorigenic properties in colorectal cancer

Almost a half of microRNAs (miRNAs) in mammalian cells are generated from polycistronic primary transcripts encoding more than one miRNA. Mature miRNAs from polycistronic clusters frequently regulate complementary sets of target mRNAs. How the processing of individual miRNAs within the clusters is controlled to give rise to distinct miRNA levels in vivo is not fully understood. Our investigation of SRSF3 (Serine-Arginine Rich Splicing Factor3) regulated noncoding RNAs in pluripotent cells identified miR-17-92 cluster as a key SRSF3 target, SRSF3 binding to the CNNC motif 17-18nt downstream of the miRNA stem loop. Here we show that SRSF3 binding site context, not merely the distance from the stem loop, within primary transcript is a critical determinant of the processing efficiency of distinct miRNAs derived from the miR-17-92 cluster. SRSF3 specifically enhanced the processing of two paralog miRNAs, miR-17 and miR-20a, targeting overlapping mRNAs including the cell cycle inhibitor CDKN1A/p21. Functional analysis demonstrated that SRSF3 inhibits CDKN1A expression and promotes cell cycle and self-renewal through the miRNA processing pathway both in normal pluripotent stem cells and cancer cells. Strikingly, analysis of colorectal cancer tumour-normal pairs demonstrated that the SRSF3-regulated miRNA processing pathway is present in a large proportion of colorectal cancer patients and distinguishes poorly differentiated high-grade tumours. Our research uncovers a critical role of SRSF3 in selective processing of miR-17-92 miRNAs, which mechanistically and functionally links SRSF3 to hallmark features of cancer.

cell biology↗