Microsatellite instability and chemosensitivity in solid tumours

Cherri, Sara; Oneda, Ester; Noventa, Silvia; Melocchi, Laura; Zaniboni, Alberto

doi:10.1177/17588359221099347

Cited by 11 publications

(8 citation statements)

References 170 publications

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“…Furthermore, we analyzed the expression of XBP1 and ATF6 on protein levels in a small cohort of surgically resected human CRC using flow cytometry ( n = 7), compared to clinical characteristics (summarized in Table S1). Three cases were diagnosed with high microsatellite instability (MSI-high), indicating mismatch-repair deficiency, a known predictor of chemotherapy response (Cherri et al, 2022). Interestingly, ATF6 positivity in tumors was significantly associated with MSI-high status, while ATF6 levels in adjacent normal colon and XBP1 in tumors remained essentially unchanged (Fig.…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress signaling actively contributes to therapy resistance in colorectal cancer

Sasaki,

Sato,

Wilhelm

et al. 2024

Preprint

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Purpose: We investigated the involvement of endoplasmic reticulum (ER) stress signaling in cancer cell responses to chemo- and radiotherapy, focusing on three main ER stress mediators, the transcription factors ATF4, XBP1 and ATF6. Methods: Public cancer genome datasets were assessed for alterations in ER stress mediators. Surgically resected colorectal cancer tissues were tested by flow cytometry and used to generate patient-derived organoids. Human cell lines and organoids were characterized under oxaliplatin treatment, alone or combined with pharmacological inhibitors of the three ER stress branches, or X-ray irradiation, for cytotoxicity, activation of ER stress and proteome changes. To monitor ER stress in real time, stable HEK293 kidney epithelial cell lines were established expressing ATF4, XBP1, or ATF6, fused with a fluorophore. Results: Genomic amplification of ATF6, but not ATF4 or XBP1, was frequent in solid tumor entities like breast, lung and colorectal cancer and significantly associated with reduced disease-free survival. In colorectal cancer, increased ATF6 was associated with genetic instability. Basal ER stress mediator expression was correlated to chemoresistance in colorectal cancer cell lines, and generally high in cancer cells compared to HEK293 cells. With proteomics and live HEK293-based reporter lines, we noted that oxaliplatin treatment induced ER stress in a remarkably different way from the canonical ER stress inducer thapsigargin. Moreover, modulation of ER stress signaling by exogenous expression of the stress mediators positively affects chemoresistance, and pharmacological inhibition of ATF6 sensitizes ER-stressed HCT116 colorectal cancer cells to chemotherapy. Of note, cellular stress responses was strongly dependent on the individual transcription factor: XBP1-driven response appeared multi-functional, involved in ribosome biogenesis stress and associated with oxaliplatin resistance. ATF6-dependent stress signaling was involved in DNA damage repair, and was essential for radioresistance. Moreover, chemoresistance in HCT116 cancer cells was impaired by pharmacological ATF6 inhibition. Conclusion: Activation of the ER stress signaling may be critically involved in acquired chemo- and radioresistance. Due to their apparent cytoprotective roles, ATF6 and XBP1 could be attractive predictive biomarkers and putative therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress signaling actively contributes to therapy resistance in colorectal cancer

Sasaki,

Sato,

Wilhelm

et al. 2024

Preprint

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“…Several cohort analyses in different types of cancer, including gastric cancer, have provided consistent evidence that MSI-H/dMMR is associated with better long-term outcome, resistance to chemotherapy, and responsiveness to ICI [66].…”

Section: Microsatellite Instability (Msi)mentioning

confidence: 88%

Optimizing the Choice for Adjuvant Chemotherapy in Gastric Cancer

Grassadonia

Luca

Carletti

et al. 2022

Cancers

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Advances in the management of gastric cancer have improved patient survival in the last decade. Nonetheless, the number of patients relapsing and dying after a diagnosis of localized gastric cancer is still too high, even in early stages (10% in stage I). Adjuvant systemic chemotherapy has been proven to significantly improve outcomes. In the present article we have critically reviewed the clinical trials that guide the current clinical practice in the adjuvant treatment of patients affected by resectable gastric cancer, focusing on the different approaches worldwide, i.e., adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. We also delineate the clinical–pathological characteristics that are commonly taken into account to identify patients at a higher risk of recurrence and requiring adjuvant chemotherapy, and also describe novel biomarkers and therapeutic agents that might allow personalization of the treatment.

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“…Evaluating the expression of the MMR proteins by immunohistochemistry (IHC) on histological tissue sections has been regarded as a valid surrogate to identify tumors with a higher probability of instability. The two methods also involved a discordance because MSI also resulted from other mechanisms (Cherri et al, 2022). The two methods are inappropriate for the cancers with low incidence of MSI and MMR dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome

Liu²,

Zheng³

et al. 2023

Front. Genet.

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Background: Lung squamous cell carcinoma (LUSC) shares less typical onco-drivers and target resistance, but a high overall mutation rate and marked genomic complexity. Mismatch repair (MMR) deficiency leads to microsatellite instability (MSI) and genomic instability. MSI is not an ideal option for prognosis of LUSC, whereas its function deserves exploration.Method: MSI status was classified by MMR proteins using unsupervised clustering in the TCGA–LUSC dataset. The MSI score of each sample was determined by gene set variation analysis. Intersections of the differential expression genes and differential methylation probes were classified into functional modules by weighted gene co-expression network analysis. Least absolute shrinkage and selection operator regression and stepwise gene selection were performed for model downscaling.Results: Compared with the MSI-low (MSI-L) phenotype, MSI-high (MSI-H) displayed higher genomic instability. The MSI score was decreased from MSI-H to normal samples (MSI-H > MSI-L > normal). A total of 843 genes activated by hypomethylation and 430 genes silenced by hypermethylation in MSI-H tumors were classified into six functional modules. CCDC68, LYSMD1, RPS7, and CDK20 were used to construct MSI-related prognostic risk score (MSI-pRS). Low MSI-pRS was a protective prognostic factor in all cohorts (HR = 0.46, 0.47, 0.37; p-value = 7.57e-06, 0.009, 0.021). The model contains tumor stage, age, and MSI-pRS that showed good discrimination and calibration. Decision curve analyses indicated that microsatellite instability-related prognostic risk score added extra value to the prognosis. A low MSI-pRS was negatively correlated with genomic instability. LUSC with low MSI-pRS was associated with increased genomic instability and cold immunophenotype.Conclusion: MSI-pRS is a promising prognostic biomarker in LUSC as the substitute of MSI. Moreover, we first declared that LYSMD1 contributed to genomic instability of LUSC. Our findings provided new insights in the biomarker finder of LUSC.

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Microsatellite instability and chemosensitivity in solid tumours

Cited by 11 publications

References 170 publications

Endoplasmic reticulum stress signaling actively contributes to therapy resistance in colorectal cancer

Endoplasmic reticulum stress signaling actively contributes to therapy resistance in colorectal cancer

Optimizing the Choice for Adjuvant Chemotherapy in Gastric Cancer

Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome

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