Biology subjects

Ridgway, R. A.

Publications and source records attributed to Ridgway, R. A..

7 recordsLinked to original sources

bioRxiv2025

Epidermal tumour-resistant progenitors require SOX2-driven developmental reprogramming to drive tumorigenesis

The skin undergoes continuous renewal, relying on stem and progenitor cells to maintain its barrier function. Over time, multiple oncogenic and tumour suppressor events accumulate. How the skin tolerates these mutations in different populations and how cutaneous squamous cell carcinoma (cSCC) emerges from mutant clones is poorly understood. Rapid cSCC development can ensue in melanoma patients treated with BRAF inhibitors (BRAFi) through paradoxical activation of RAF signalling. To model this in mice, we induced MAPK hyperactivation in two epidermal basal populations: stem-cell-like (K14/K5+) and differentiation-committed (IVL+) cells. Remarkably rapid tumorigenesis ensued from the K14/K5+ basal population defining them as a tumour primed. In contrast, despite mutations being retained and populating the skin, IVL+ cells exhibited tumour resistance with long latency. Nevertheless, both populations can act as cSCC cells of origin. Once transformed, they share histological and transcriptomic hallmarks of epidermal transformation independently of the cell-of-origin or the oncogenic driving mutations. Critically, the pioneer factor SOX2 was uniquely upregulated in tumours arising from the resistant population and was both necessary and sufficient for their transformation. Notably, SOX2 bestow an embryonic profile to human keratinocytes and is expressed in [~]20% of human cSCC, suggesting that it could mark tumours originating from committed progenitors. HighlightsO_LIParadoxical MAPK signalling activation is a tumour promoter in cSCC C_LIO_LIK14/K5+ represent a tumour-primed population and IVL+ represents a tumour-resistant population, but both can initiate skin cancer C_LIO_LIOncogene-expressing tumour-resistant population takes over the entire skin epidermis but preserves homeostasis C_LIO_LISOX2 is sufficient to initiate cSCC from the tumour-resistant population by preventing delamination and differentiation and promoting stemness C_LI

cancer biology↗

bioRxiv2024

Viral mimicry redirects immunosuppressed colorectal tumour landscapes towards a proinflammatory and CMS1-like regenerative state

In colorectal cancer (CRC), tumours classifier as consensus molecular subtype 4 (CMS4) have the worst prognosis and derive negligible benefit from chemotherapy. We previously described how repressed interferon-related signalling is associated with increased relapse in CMS4 tumours. Although the viral mimetic poly(I:C) can reduce liver metastasis in vivo, the initial phenotypic changes that underpin its anti-metastatic response remain poorly described, particularly in the immunosuppressed CMS4 tumour microenvironment. Here we characterise lineage-specific anti-metastatic responses induced by poly(I:C), including acute macrophage polarisation and a novel CMS1-like regenerative stem cell state, which drive pro-inflammatory microenvironmental changes in CRC. These insights enabled the development of tractable biomarkers that identify an "immune-warm" patient subset most likely to respond to poly(I:C), enriched for mismatch-repair proficient (pMMR), anti-inflammatory macrophages and CMS4-like features. The viral mimetic poly(I:C) offers a tailored treatment option for CMS4 tumours, by reprogramming stem cell states and activation of an innate-adaptive anti-metastatic response.

cancer biology↗

bioRxiv2023

eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers

Dysregulated translation is a hallmark of cancer. Targeting the translational machinery represents a therapeutic avenue which is being actively explored. eIF4A inhibitors target both eIF4A1, which promotes translation as part of the eIF4F complex, and eIF4A2, which can repress translation via the CCR4-NOT complex. While high eIF4A1 expression is associated with poor patient outcome, the role of eIF4A2 in cancer remains unclear. Furthermore, the on-target toxicity of targeting specific eIF4A paralogues in healthy tissue is under-explored. We show that while loss of either paralogue is tolerated in the wild-type intestine, eIF4A1 is specifically required to support the translational demands of oncogenic Wnt signalling. Intestinal tumourigenesis is suppressed in colorectal cancer models following loss of eIF4A1 but accelerated following loss of eIF4A2, while eIF4A inhibition with eFT226 mimics loss of eIF4A1 in these models.

cancer biology↗

bioRxiv2023

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, there is still much debate over the function of wild-type KRAS in tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy of Kras in the context of an intact oncogenic Kras in colorectal cancer. We observe that in the presence of oncogenic Kras, wild-type Kras acts to restrain tumour growth. Mechanistically, deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while presence of wild-type Kras is associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-type Kras in oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-type Kras during colon tumour initiation and highlights the critical impact of wild-type Kras upon therapeutic response to MAPK and tumour progression in Kras mutant cancers. HighlightsO_LIWild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer models in vivo C_LIO_LIConcomitant loss of wild-type KRAS and activation of WNT signalling promotes mutant KRAS-driven tumour initiation. C_LIO_LIWild-type KRAS promotes resistance to MAPK inhibition in KRAS mutant tumours C_LIO_LILoss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models. C_LI

cancer biology↗

bioRxiv2023

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

With colorectal cancer (CRC) being the second most common cause of cancer-related deaths worldwide1, there is an urgent need for better diagnostic tools and new, more targeted therapies. Here we used genetically engineered mouse models (GEMMs), and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that unsupervised metabolic profiling can stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging (MSI) to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-mutant CRC, and propose one of its enzymes, i.e. adenosylhomocysteinase (AHCY), as a new therapeutic target. Collectively, we show that the profound genotype-dependent alterations in both lipid and small molecule metabolism in CRC may be exploited for tissue classification with no need for ion identification, and we applied further data analysis to expose a novel metabolic vulnerability of CRC.

cancer biology↗

bioRxiv2022

β-catenin obstructs γδ T cell immunosurveillance in colon cancer through loss of BTNL expression

WNT/{beta}-catenin signaling endows cancer cells with proliferative capacity and immune-evasive functions that impair anti-cancer immunosurveillance by conventional, cytoxtoic T cells. However, the impact of dysregulated WNT signalling on unconventional, tissue-resident T cells, specifically in colon cancer is unknown. Here, we show that cancer cells in Apc-mutant mouse models escape immunosurveillance from gut-resident intraepithelial lymphocytes (IELs) expressing {gamma}{delta} T cell receptors ({gamma}{delta}TCRs). Analysis of late-stage tumors from mice and humans revealed that {gamma}{delta}IELs are largely absent from the tumor microenvironment, and that butyrophilin-like (BTNL) molecules, which can critically regulate {gamma}{delta}IEL through direct {gamma}{delta}TCR-interactions, are also downregulated. We could attribute this to {beta}-catenin stabilization, which rapidly decreased expression of the transcription factors, HNF4A and HNF4G, that we found to bind promoter regions of Btnl genes, thereby driving their expression in normal gut epithelial cells. Indeed, inhibition of {beta}-catenin signaling restored Btnl1 gene expression and {gamma}{delta} T cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts {gamma}{delta}IEL immunosurveillance and furthers cancer progression.

cancer biology↗

bioRxiv2021

Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Increased protein synthesis supports the rapid proliferation associated with cancer. The Rpl24Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here we show that Rpl24Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in colorectal cancer, as well as other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models.

cancer biology↗