Dataset Information

Proteomic and metabolomic signatures of rectal tumor discriminate patients with different responses to preoperative radiotherapy

ABSTRACT: Background: Neoadjuvant radiotherapy (neo-RT) is widely used in locally advanced rectal cancer (LARC) as a component of radical treatment. Despite the advantages of neo-RT, which typically improves outcomes in LARC patients, the lack of reliable biomarkers that predict response and monitor the efficacy of therapy, can result in the application of unnecessary aggressive therapy affecting patientsâ€™ quality of life. Hence, the search for molecular biomarkers for assessing the radio responsiveness of this cancer represents a relevant issue. Methods: Here, we combined proteomic and metabolomic approaches to identify molecular signatures, which could discriminate LARC tumors with good and poor responses to neo-RT. Results: The integration of data on differentially accumulated proteins and metabolites made it possible to identify disrupted metabolic pathways and signaling processes connected with response to irradiation, including ketone bodies synthesis and degradation, purine metabolism, energy metabolism, degradation of fatty acid, amino acid metabolism, and focal adhesion. Moreover, we proposed multi-component panels of proteins and metabolites which could serve as a solid base to develop biomarkers for monitoring and predicting the efficacy of preoperative RT in rectal cancer patients. Conclusions: We proved that an integrated multi-omic approach presents a valid look at the analysis of the global response to cancer treatment from the perspective of metabolomic reprogramming.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Rectum, Colon

DISEASE(S): Colorectal Cancer

SUBMITTER: Anna Wojakowska

LAB HEAD: Anna Wojakowska

PROVIDER: PXD048647 | Pride | 2024-05-22

REPOSITORIES: Pride

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Proteomic and metabolomic signatures of rectal tumor discriminate patients with different responses to preoperative radiotherapy.

Wojakowska Anna A Marczak Lukasz L Zeman Marcin M Chekan Mykola M Zembala-Nożyńska Ewa E Polanski Krzysztof K Strugała Aleksander A Widlak Piotr P Pietrowska Monika M

Frontiers in oncology 20240212

<h4>Background</h4>Neoadjuvant radiotherapy (neo-RT) is widely used in locally advanced rectal cancer (LARC) as a component of radical treatment. Despite the advantages of neo-RT, which typically improves outcomes in LARC patients, the lack of reliable biomarkers that predict response and monitor the efficacy of therapy, can result in the application of unnecessary aggressive therapy affecting patients' quality of life. Hence, the search for molecular biomarkers for assessing the radio responsiv ...[more]

PMID: 38410100

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Project description:Background: Angiotensin receptorâ€“neprilysin inhibitors (ARNI) have been used in the treatment of heart failure (HF) for several years. Sacubitril/valsartan (Sac/Val) belongs to the group of ARNI and led to a reduction in mortality and pump failure. The mechanisms that mediate the beneficial effects of Sac/Val are not yet fully understood. In this study we investigated whether Sac/Val influences the two proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), in a mouse model of pressure overload-induced HF and in a human cellular model of hypertrophy. Experimental approach: Transverse aortic constriction (TAC) or sham surgery was performed in 8-week old C57BL/6N mice. 14 days after TAC or sham surgery, the animals were randomized into the following 4 groups: 1) sham/vehicle, 2) sham/Sac/Val, 3) TAC/vehicle, and 4) TAC/Sac/Val. Sac/Val (57 mg/kg body weight/day) or vehicle (200 Âµl water) was given for further 6 weeks twice a day. Cardiac function was determined weekly by echocardiography. After 8 weeks, the hearts were taken and further investigated on molecular level. Human induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs) and treated with 100 nM endothelin 1 (ET1) and 40 ÂµM Sac or 13 ÂµM Val or both 40 ÂµM Sac + 13 ÂµM Val while using DMSO as a control. Analyses were performed on transcript and protein level as well as for UPS function. Key results: TAC mice showed a continuous decline in left ventricular function starting from day 14 after surgery. Sac/Val counteracted the deterioration especially of ejection fraction and cardiac output. The HF phenotype was further confirmed by an upregulation of the fetal gene program and of genes associated with fibrosis as well as a downregulation of genes involved in Ca2+ handling in TAC mice and was partially normalized by Sac/Val treatment. Evaluation of the ALP revealed no major impact of TAC or Sac/Val on the expression of ALP key marker. Investigation of the UPS showed a higher chymotrypsin-like activity after TAC, which was normalized by Sac/Val. In hiPSC-CMs, all treatments (Sac, Val, Sac/Val) normalized mean cell area. Sac but not Val prevented ET1-induced hypertrophic gene program and reduced the ET1-induced increase in UPS activity. Gross protein ubiquitination was only lowered in Sac/Val treated cells. The proteomic footprint showed a higher overlap between control, Sac and Sac/Val treated compared to the ET1 and Val groups. Both Sac-containing groups normalized sarcomeric protein levels, while Val mostly changed levels of proteins associated with energy metabolism. Conclusion: Sac/Val improved cardiac function and reduced fibrosis and hypertrophy. Whereas Sac/Val seems to exert its protective role independently of autophagy processes, the data obtained for the UPS suggest that Sac/Val has a beneficial effect on the UPS function. In the hiPSC-CMs, Sac proved to be the component of LCZ696 that mostly prevented the negative effects of ET1 on cell area, gene expression, proteome and UPS function.

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