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1.
Cell Rep Med ; 5(2): 101376, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38228147

ABSTRACT

The bacterial genotoxin colibactin promotes colorectal cancer (CRC) tumorigenesis, but systematic assessment of its impact on DNA repair is lacking, and its effect on response to DNA-damaging chemotherapeutics is unknown. We find that CRC cell lines display differential response to colibactin on the basis of homologous recombination (HR) proficiency. Sensitivity to colibactin is induced by inhibition of ATM, which regulates DNA double-strand break repair, and blunted by HR reconstitution. Conversely, CRC cells chronically infected with colibactin develop a tolerant phenotype characterized by restored HR activity. Notably, sensitivity to colibactin correlates with response to irinotecan active metabolite SN38, in both cell lines and patient-derived organoids. Moreover, CRC cells that acquire colibactin tolerance develop cross-resistance to SN38, and a trend toward poorer response to irinotecan is observed in a retrospective cohort of CRCs harboring colibactin genomic island. Our results shed insight into colibactin activity and provide translational evidence on its chemoresistance-promoting role in CRC.


Subject(s)
Colorectal Neoplasms , Escherichia coli , Peptides , Polyketides , Humans , Irinotecan/pharmacology , Escherichia coli/genetics , Escherichia coli/metabolism , Retrospective Studies , DNA/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/microbiology
2.
Cancer Discov ; 11(7): 1644-1660, 2021 07.
Article in English | MEDLINE | ID: mdl-33820776

ABSTRACT

Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.


Subject(s)
Biomarkers, Tumor , Colorectal Neoplasms/drug therapy , Decision Support Techniques , Animals , Colorectal Neoplasms/pathology , Disease Models, Animal , Humans , Mice , Neoplasm Metastasis
3.
Int J Mol Sci ; 20(23)2019 Nov 27.
Article in English | MEDLINE | ID: mdl-31783481

ABSTRACT

Cadherins are a major family of cell-cell adhesive receptors, which are implicated in development, tissue homeostasis, and cancer. Here, we show a novel mechanism of post-translational regulation of E-cadherin in cancer cells by an intramembrane protease of the Rhomboid family, RHBDL2, which leads to the shedding of E-cadherin extracellular domain. In addition, our data indicate that RHBDL2 mediates a similar activity on VE-cadherin, which is selectively expressed by endothelial cells. We show that RHBDL2 promotes cell migration, which is consistent with its ability to interfere with the functional role of cadherins as negative regulators of motility; moreover, the two players appear to lie in the same functional pathway. Importantly, we show that RHBDL2 expression is induced by the inflammatory chemokine TNFα. The E-cadherin extracellular domain is known to be released by metalloproteases (MMPs); however, here, we provide evidence of a novel MMP-independent, TNFα inducible, E-cadherin processing mechanism that is mediated by RHBDL2. Thus, the intramembrane protease RHBDL2 is a novel regulator of cadherins promoting cell motility.


Subject(s)
Cadherins/metabolism , Metalloproteases/metabolism , Serine Endopeptidases/metabolism , Animals , COS Cells , Cell Line , Cell Line, Tumor , Cell Movement/physiology , Chemokines/metabolism , Chlorocebus aethiops , Dogs , HEK293 Cells , Humans , Inflammation/metabolism , Madin Darby Canine Kidney Cells , PC-3 Cells , Serine Proteases/metabolism , Tumor Necrosis Factor-alpha/metabolism
4.
Curr Vasc Pharmacol ; 13(2): 248-58, 2015.
Article in English | MEDLINE | ID: mdl-23927679

ABSTRACT

Warfarin inhibits vitamin-K dependent proteins involved in bone mineralization and the prevention of vascular calcification (bone Gla protein BGP, matrix Gla protein MGP). In this multicenter, cross-sectional study with 3-year follow-up, data from 387 patients on hemodialysis for ≥1 year at 18 dialysis units were analyzed. Patients on warfarin treatment for > 1 year (11.9% of the population) were compared with the remaining cohort for vertebral fractures, vascular calcifications and mortality. Vertebral fractures and vascular calcifications were sought in L-L vertebral X-rays (D5 to L4). Compared with controls, warfarin-treated male patients had more vertebral fractures (77.8 vs. 57.7%, p<0.04), but not females (42.1% vs. 48.4%, p=0.6); total BGP was significantly reduced (82.35 vs. 202 µg/L, p<0.0001), with lower levels in treated men (69.5 vs. women 117.0 µg/L, p=0.03). In multivariate logistic regression analyses, the use of warfarin was associated with increased odds of aortic (OR 2.58, p<0.001) and iliac calcifications (OR 2.86, p<0.001); identified confounders were age, atrial fibrillation, angina, PPI use and total BGP. Seventy-seven patients died during a 2.7±0.5 year follow-up. In univariate Cox regression analysis, patients on warfarin had a higher risk of all-cause mortality (HR 2.42, 95% CI 1.42-4.16, p=0.001) when compared with those untreated and data adjustment for confounders attenuated but confirmed the significant warfarin-mortality link (HR: 1.97, 95% CI: 1.02-3.84, P=0.046). In hemodialysis patients, additional studies are warranted to verify the risk/benefit ratio of warfarin, which appears to be associated with significant morbidity and increased mortality.


Subject(s)
Anticoagulants/adverse effects , Kidney Diseases/therapy , Renal Dialysis , Spinal Fractures/epidemiology , Vascular Calcification/epidemiology , Warfarin/adverse effects , Aged , Aged, 80 and over , Case-Control Studies , Cross-Sectional Studies , Female , Humans , Italy/epidemiology , Kaplan-Meier Estimate , Kidney Diseases/diagnosis , Kidney Diseases/mortality , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Prevalence , Proportional Hazards Models , Renal Dialysis/adverse effects , Renal Dialysis/mortality , Risk Factors , Sex Factors , Spinal Fractures/diagnosis , Spinal Fractures/mortality , Time Factors , Vascular Calcification/diagnosis , Vascular Calcification/mortality
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