MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification o...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/16/3/604 |
| _version_ | 1797318967883202560 |
|---|---|
| author | Müge Erdem Kyung Hwan Lee Markus Hardt Joseph L. Regan Dennis Kobelt Wolfgang Walther Margarita Mokrizkij Christian Regenbrecht Ulrike Stein |
| author_facet | Müge Erdem Kyung Hwan Lee Markus Hardt Joseph L. Regan Dennis Kobelt Wolfgang Walther Margarita Mokrizkij Christian Regenbrecht Ulrike Stein |
| author_sort | Müge Erdem |
| collection | DOAJ |
| description | Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation. |
| first_indexed | 2024-03-08T04:00:02Z |
| format | Article |
| id | doaj.art-d570f3c3729044b6b88d973dc01264cd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T04:00:02Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d570f3c3729044b6b88d973dc01264cd2024-02-09T15:09:16ZengMDPI AGCancers2072-66942024-01-0116360410.3390/cancers16030604MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal CancerMüge Erdem0Kyung Hwan Lee1Markus Hardt2Joseph L. Regan3Dennis Kobelt4Wolfgang Walther5Margarita Mokrizkij6Christian Regenbrecht7Ulrike Stein8Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyBayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, GermanyExperimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyCELLphenomics GmbH, 13125 Berlin, GermanyExperimental and Clinical Research Center, Charité—Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Translational Oncology of Solid Tumors Research Group, 13125 Berlin, GermanyColorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.https://www.mdpi.com/2072-6694/16/3/604MACC1LGR5transcriptional regulationstemness |
| spellingShingle | Müge Erdem Kyung Hwan Lee Markus Hardt Joseph L. Regan Dennis Kobelt Wolfgang Walther Margarita Mokrizkij Christian Regenbrecht Ulrike Stein MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer Cancers MACC1 LGR5 transcriptional regulation stemness |
| title | MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer |
| title_full | MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer |
| title_fullStr | MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer |
| title_full_unstemmed | MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer |
| title_short | MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer |
| title_sort | macc1 regulates lgr5 to promote cancer stem cell properties in colorectal cancer |
| topic | MACC1 LGR5 transcriptional regulation stemness |
| url | https://www.mdpi.com/2072-6694/16/3/604 |
| work_keys_str_mv | AT mugeerdem macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT kyunghwanlee macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT markushardt macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT josephlregan macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT denniskobelt macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT wolfgangwalther macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT margaritamokrizkij macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT christianregenbrecht macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer AT ulrikestein macc1regulateslgr5topromotecancerstemcellpropertiesincolorectalcancer |