Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model
Abstract Pancreatic cancer (PC) has a very low survival rate mainly due to late diagnosis and refractoriness to therapies. The latter also cause adverse effects negatively affecting the patients’ quality of life, often requiring dose reduction or discontinuation of scheduled treatments, compromising...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01397-y |
| _version_ | 1797850182096781312 |
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| author | Concetta Panebianco Federica Pisati Annacandida Villani Annapaola Andolfo Marynka Ulaszewska Edoardo Bellini Carmelapia Ferro Renato Lombardi Fabrizio Orsenigo Tiziana Pia Latiano Beatrice Belmonte Claudio Tripodo Francesco Perri Valerio Pazienza |
| author_facet | Concetta Panebianco Federica Pisati Annacandida Villani Annapaola Andolfo Marynka Ulaszewska Edoardo Bellini Carmelapia Ferro Renato Lombardi Fabrizio Orsenigo Tiziana Pia Latiano Beatrice Belmonte Claudio Tripodo Francesco Perri Valerio Pazienza |
| author_sort | Concetta Panebianco |
| collection | DOAJ |
| description | Abstract Pancreatic cancer (PC) has a very low survival rate mainly due to late diagnosis and refractoriness to therapies. The latter also cause adverse effects negatively affecting the patients’ quality of life, often requiring dose reduction or discontinuation of scheduled treatments, compromising the chances of cure. We explored the effects of a specific probiotic blend on PC mice xenografted with KRAS wild-type or KRASG12D mutated cell lines alone or together with gemcitabine+nab-paclitaxel treatment to then assess tumor volume and clinical pathological variables. Beside a semi-quantitative histopathological evaluation of murine tumor and large intestine samples, histochemical and immunohistochemical analyses were carried out to evaluate collagen deposition, proliferation index Ki67, immunological microenvironment tumor-associated, DNA damage markers and also mucin production. Blood cellular and biochemical parameters and serum metabolomics were further analyzed. 16S sequencing was performed to analyze the composition of fecal microbiota. Gemcitabine+nab-paclitaxel treatment impaired gut microbial profile in KRAS wild-type and KRASG12D mice. Counteracting gemcitabine+nab-paclitaxel- induced dysbiosis through the administration of probiotics ameliorated chemotherapy side effects and decreased cancer-associated stromatogenesis. Milder intestinal damage and improved blood count were also observed upon probiotics treatment as well as a positive effect on fecal microbiota, yielding an increase in species richness and in short chain fatty acids producing- bacteria. Mice’ serum metabolomic profiles revealed significant drops in many amino acids upon probiotics administration in KRAS wild-type mice while in animals transplanted with PANC-1 KRASG12D mutated all treated groups showed a sharp decline in serum levels of bile acids with respect to control mice. These results suggest that counteracting gemcitabine+nab-paclitaxel-induced dysbiosis ameliorates chemotherapy side effects by restoring a favorable microbiota composition. Relieving adverse effects of the chemotherapy through microbiota manipulation could be a desirable strategy in order to improve pancreatic cancer patients’ quality of life and to increase the chance of cure. |
| first_indexed | 2024-04-09T18:57:22Z |
| format | Article |
| id | doaj.art-ab5bca2f9470444ab85db057b24d980c |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-09T18:57:22Z |
| publishDate | 2023-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-ab5bca2f9470444ab85db057b24d980c2023-04-09T11:08:08ZengNature Publishing GroupCell Death Discovery2058-77162023-04-019111110.1038/s41420-023-01397-yCounteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo modelConcetta Panebianco0Federica Pisati1Annacandida Villani2Annapaola Andolfo3Marynka Ulaszewska4Edoardo Bellini5Carmelapia Ferro6Renato Lombardi7Fabrizio Orsenigo8Tiziana Pia Latiano9Beatrice Belmonte10Claudio Tripodo11Francesco Perri12Valerio Pazienza13Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della SofferenzaHistopathology Unit, Cogentech S.C.a.R.L, FIRC Institute of Molecular Oncology (IFOM)Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della SofferenzaProteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific InstituteProteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific InstituteProteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific InstituteDivision of Gastroenterology, Fondazione IRCCS Casa Sollievo della SofferenzaUnit of Pharmacy, Department of Pharmaceuticals, IRCCS Casa Sollievo della SofferenzaIFOM, FIRC Institute of Molecular OncologyOncology Unit Fondazione IRCCS Casa Sollievo della SofferenzaTumor Immunology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro”, University of PalermoHistopathology Unit, Cogentech S.C.a.R.L, FIRC Institute of Molecular Oncology (IFOM)Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della SofferenzaDivision of Gastroenterology, Fondazione IRCCS Casa Sollievo della SofferenzaAbstract Pancreatic cancer (PC) has a very low survival rate mainly due to late diagnosis and refractoriness to therapies. The latter also cause adverse effects negatively affecting the patients’ quality of life, often requiring dose reduction or discontinuation of scheduled treatments, compromising the chances of cure. We explored the effects of a specific probiotic blend on PC mice xenografted with KRAS wild-type or KRASG12D mutated cell lines alone or together with gemcitabine+nab-paclitaxel treatment to then assess tumor volume and clinical pathological variables. Beside a semi-quantitative histopathological evaluation of murine tumor and large intestine samples, histochemical and immunohistochemical analyses were carried out to evaluate collagen deposition, proliferation index Ki67, immunological microenvironment tumor-associated, DNA damage markers and also mucin production. Blood cellular and biochemical parameters and serum metabolomics were further analyzed. 16S sequencing was performed to analyze the composition of fecal microbiota. Gemcitabine+nab-paclitaxel treatment impaired gut microbial profile in KRAS wild-type and KRASG12D mice. Counteracting gemcitabine+nab-paclitaxel- induced dysbiosis through the administration of probiotics ameliorated chemotherapy side effects and decreased cancer-associated stromatogenesis. Milder intestinal damage and improved blood count were also observed upon probiotics treatment as well as a positive effect on fecal microbiota, yielding an increase in species richness and in short chain fatty acids producing- bacteria. Mice’ serum metabolomic profiles revealed significant drops in many amino acids upon probiotics administration in KRAS wild-type mice while in animals transplanted with PANC-1 KRASG12D mutated all treated groups showed a sharp decline in serum levels of bile acids with respect to control mice. These results suggest that counteracting gemcitabine+nab-paclitaxel-induced dysbiosis ameliorates chemotherapy side effects by restoring a favorable microbiota composition. Relieving adverse effects of the chemotherapy through microbiota manipulation could be a desirable strategy in order to improve pancreatic cancer patients’ quality of life and to increase the chance of cure.https://doi.org/10.1038/s41420-023-01397-y |
| spellingShingle | Concetta Panebianco Federica Pisati Annacandida Villani Annapaola Andolfo Marynka Ulaszewska Edoardo Bellini Carmelapia Ferro Renato Lombardi Fabrizio Orsenigo Tiziana Pia Latiano Beatrice Belmonte Claudio Tripodo Francesco Perri Valerio Pazienza Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model Cell Death Discovery |
| title | Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model |
| title_full | Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model |
| title_fullStr | Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model |
| title_full_unstemmed | Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model |
| title_short | Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model |
| title_sort | counteracting gemcitabine nab paclitaxel induced dysbiosis in kras wild type and krasg12d mutated pancreatic cancer in vivo model |
| url | https://doi.org/10.1038/s41420-023-01397-y |
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