Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

Flanagan, Dustin J.; Amirkhah, Raheleh; Vincent, David F.; Gundaz, Nuray; Gentaz, Pauline; Cammareri, Patrizia; McCooey, Aoife J.; McCorry, Amy M B; Fisher, Natalie C.; Belnoue-Davis, Hayley L.; Ridgway, Rachel A.; Lohuis, Jeroen; Leach, Joshua D.G.; Jackstadt, René; Gilroy, Kathryn; Mariella, Elisa; Nixon, Colin; Clark, William; Hedley, Ann; Markert, Elke; Strathdee, Douglas; Bartholin, Laurent; Redmond, Keara L.; Kerr, Emma; Longley, Daniel B.; Ginty, Fiona; Cho, Sang‐Hee; Coleman, Helen; Loughrey, Maurice B.; Bardelli, Alberto; Maughan, T; Campbell, Andrew D.; Lawler, Mark; Leedham, Simon J.; Barry, Simon T.; Inman, Gareth J.; Rheenen, Jacco van; Dunne, Philip D.; Sansom, Owen J.

doi:10.1038/s41467-022-35134-3

Cited by 7 publications

(4 citation statements)

References 80 publications

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“…Similarly, patients with high [ 18 F]FDG and [ 18 F]FLT are more likely to have Kras mutations and therefore poor response to EGFR inhibition ( 22 ). Conversely, low [ 18 F]FDG and [ 18 F]FLT suggests alterations in TGFβ signaling, and these patients may have improved response to MEK or EGFR inhibitors ( 53 ). Ultimately, to establish the clinical significance of our findings, it is crucial to conduct further studies in patient cohorts, incorporating prospective multitracer biomarker validation.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging

Malviya,

Lannagan,

Johnson

et al. 2024

Clinical Cancer Research

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Purpose: The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression–based subtyping remain unknown. Experimental Design: In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic). Results: The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake. Conclusions: By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.

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Section: Discussionmentioning

confidence: 99%

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging

Malviya,

Lannagan,

Johnson

et al. 2024

Clinical Cancer Research

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Section: Discussionmentioning

confidence: 99%

“…This highlights the unpredictable biology of a proportion of these early CRCs. The identification of novel factors which may enable risk stratification with greater accuracy would aid in the decision-making and, indeed, certain molecular signatures have been identified which correlate with risk of distant metastases[23].Given the complexity of the decision-making it seems prudent that such cases are discussed at specialist CRC (MDT) meetings and, if possible, one focused on advanced polyps. Indeed, such an approach has been advocated by the Significant Polyp and Early Colorectal Cancer (SPECC) programme group[24].…”

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confidence: 99%

Management of malignant T1 colorectal cancer polyps: results from a 10‐year prospective observational study

Johnstone,

McSorley,

McMahon

2023

Colorectal Disease

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AimThe recurrence risk associated with residual malignant cells (bowel wall/regional nodes) following T1 colorectal cancer (CRC) polypectomy must be weighed against operative morbidity. Our aim was to describe the management and outcomes of a large prospective cohort of T1 CRCs.MethodAll T1 CRCs diagnosed between March 2007 and March 2017 at the Glasgow Royal Infirmary were included. Patients were grouped by polypectomy, rectal local excision and formal resection status. χ2 testing, multivariate binary logistic and Cox regression were performed.ResultsOf 236 patients, 90 (38.1%) underwent polypectomy only, six (2.6%) polypectomy and then rectal excision, 57 (24.2%) polypectomy and then resection, 14 (5.9%) rectal excision only and 69 (29.2%) primary resection. Polypectomy only correlated with male sex (P = 0.028), older age (P < 0.001), distal CRCs (P < 0.001) and pedunculated polyps (P < 0.001); primary resection with larger polyps (P < 0.001); polypectomy then resection with piecemeal excision (P = 0.002) and involved polypectomy margin (P < 0.001). Poor differentiation (OR 7.860, 95% CI 1.117–55.328; P = 0.038) independently predicted lymph node involvement. Submucosal venous invasion (hazard ratio [HR] 10.154, 95% CI 2.087–49.396; P = 0.004) and mucinous subtype (HR 7.779, 95% CI 1.566–38.625; P = 0.012) independently predicted recurrence. Submucosal venous invasion (HR 5.792, 95% CI 1.056–31.754; P = 0.043) predicted CRC‐specific survival. Although 64.4% of polypectomy‐only patients had margin involvement/other risk factors, none developed recurrence. Of 94 with polypectomy margin involvement, five (5.3%) had confirmed residual tumour. Overall, lymph node metastases (7.1%), recurrence (4.2%) and cancer‐specific mortality (3.0%) were rare. Cancer‐specific 5‐year survival was high: polypectomy only (100%), polypectomy and then resection (98.2%), primary resection (100%).ConclusionSurveillance may be safe for more T1 CRC polyp patients. Multidisciplinary team discussion and informed patient choice are critical.

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“…Loss of function or a buildup of acquired mutations in the major driver gene adenomatous polyposis coli (APC) is responsible for the development of CRC. 65 In the study by Baratti et al, 35 phosphatidylinositol 3-kinase catalytic subunits p110α (PIK3CA) mutations were found in 17/78 patients (25.0%), and APC mutations were found in 25/68 patients (36.7%); APC mutations were univariately related with better survival (p ¼ 0.03), and APC mutations were more prevalent in left-sided CRC. Yaeger et al 62 discovered a high enrichment of oncogenic alterations in APC and TP53 in left-sided initial tumors, and oncogenic abnormalities in APC were predictive of the survival status of CRC-PM following CRS (HR ¼ 0.57, p < 0.01).…”

Section: Apcmentioning

confidence: 99%

Impact of Molecular Status on Cytoreductive Surgery for Peritoneal Metastases from Colorectal Cancer

Zhong

Yang

Qin

et al. 2023

Clin Colon Rectal Surg

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Colorectal cancer peritoneal metastases (CRC-PM) are present in 5 to 15% of instances of CRC, and the overall survival (OS) of patients with CRC-PM is much lower than that of patients with other isolated metastatic locations. In recent years, the introduction of cytoreductive surgery (CRS) in conjunction with hyperthermic intraperitoneal chemotherapy has resulted in a significant improvement in CRC-PM patients' OS. Despite this, a significant proportion of CRS patients continue to suffer complications of grades III to V or even die during the perioperative period. Early diagnosis, optimization of patient selection criteria, and refining of individualized combination therapy are necessary for these patients. In this review, we evaluate studies examining the relationship between molecular status and CRS in CRC-PM. Our objective is to gain a comprehensive understanding of how the altered molecular status of CRC-PM impacts CRS, which could increase the likelihood of tailored therapy in the future.

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Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

Cited by 7 publications

References 80 publications

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging

Management of malignant T1 colorectal cancer polyps: results from a 10‐year prospective observational study

Impact of Molecular Status on Cytoreductive Surgery for Peritoneal Metastases from Colorectal Cancer

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