Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers
The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-asso...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.906494/full |
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| author | Marina Domingo-Vidal Diana Whitaker-Menezes Mehri Mollaee Zhao Lin Madalina Tuluc Nancy Philp Jennifer M. Johnson Tingting Zhan Joseph Curry Ubaldo Martinez-Outschoorn |
| author_facet | Marina Domingo-Vidal Diana Whitaker-Menezes Mehri Mollaee Zhao Lin Madalina Tuluc Nancy Philp Jennifer M. Johnson Tingting Zhan Joseph Curry Ubaldo Martinez-Outschoorn |
| author_sort | Marina Domingo-Vidal |
| collection | DOAJ |
| description | The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the monocarboxylate transporter 1 (MCT1) and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of OXPHOS in carcinoma cells. It is unknown if glycolytic metabolism in CAFs is a driver of ADT cancer aggressiveness. In this study, co-cultures in vitro and co-injections in mice of ADT carcinoma cells with fibroblasts were used as experimental models to study the effects of fibroblasts on metabolic compartmentalization, oxidative stress, carcinoma cell proliferation and apoptosis, and overall tumor growth. Glycolytic metabolism in fibroblasts was modulated using the HIF-1α inhibitor BAY 87-2243, the antioxidant N-acetyl cysteine, and genetic depletion of MCT4. We found that ADT human tumors express markers of metabolic compartmentalization and that co-culture models of ADT cancers recapitulate human metabolic compartmentalization, have high levels of oxidative stress, and promote carcinoma cell proliferation and survival. In these models, BAY 87-2243 rescues IDH3α expression and NAC reduces MCT4 expression in fibroblasts, and these treatments decrease ADT carcinoma cell proliferation and increase cell death. Genetic depletion of fibroblast MCT4 decreases proliferation and survival of ADT carcinoma cells in co-culture. Moreover, co-injection of ADT carcinoma cells with fibroblasts lacking MCT4 reduces tumor growth and decreases the expression of markers of metabolic compartmentalization in tumors. In conclusion, metabolic compartmentalization with high expression of MCT4 in CAFs drives aggressiveness in ADT cancers. |
| first_indexed | 2024-04-12T13:37:07Z |
| format | Article |
| id | doaj.art-1a27894c72f64f59ae35937ec8c95bed |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T13:37:07Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-1a27894c72f64f59ae35937ec8c95bed2022-12-22T03:30:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.906494906494Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract CancersMarina Domingo-Vidal0Diana Whitaker-Menezes1Mehri Mollaee2Zhao Lin3Madalina Tuluc4Nancy Philp5Jennifer M. Johnson6Tingting Zhan7Joseph Curry8Ubaldo Martinez-Outschoorn9Sidney Kimmel Cancer Center, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesLewis Katz School of Medicine, Department of Pathology and Laboratory Medicine, Temple University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesDivision of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, United StatesSidney Kimmel Cancer Center, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United StatesThe most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the monocarboxylate transporter 1 (MCT1) and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of OXPHOS in carcinoma cells. It is unknown if glycolytic metabolism in CAFs is a driver of ADT cancer aggressiveness. In this study, co-cultures in vitro and co-injections in mice of ADT carcinoma cells with fibroblasts were used as experimental models to study the effects of fibroblasts on metabolic compartmentalization, oxidative stress, carcinoma cell proliferation and apoptosis, and overall tumor growth. Glycolytic metabolism in fibroblasts was modulated using the HIF-1α inhibitor BAY 87-2243, the antioxidant N-acetyl cysteine, and genetic depletion of MCT4. We found that ADT human tumors express markers of metabolic compartmentalization and that co-culture models of ADT cancers recapitulate human metabolic compartmentalization, have high levels of oxidative stress, and promote carcinoma cell proliferation and survival. In these models, BAY 87-2243 rescues IDH3α expression and NAC reduces MCT4 expression in fibroblasts, and these treatments decrease ADT carcinoma cell proliferation and increase cell death. Genetic depletion of fibroblast MCT4 decreases proliferation and survival of ADT carcinoma cells in co-culture. Moreover, co-injection of ADT carcinoma cells with fibroblasts lacking MCT4 reduces tumor growth and decreases the expression of markers of metabolic compartmentalization in tumors. In conclusion, metabolic compartmentalization with high expression of MCT4 in CAFs drives aggressiveness in ADT cancers.https://www.frontiersin.org/articles/10.3389/fonc.2022.906494/fullaerodigestive tract cancernon-small cell lung cancerhead and neck squamous cell carcinomacancer-associated fibroblast (CAF)metabolic compartmentalizationmonocarboxylate transporter 4 (MCT4) |
| spellingShingle | Marina Domingo-Vidal Diana Whitaker-Menezes Mehri Mollaee Zhao Lin Madalina Tuluc Nancy Philp Jennifer M. Johnson Tingting Zhan Joseph Curry Ubaldo Martinez-Outschoorn Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers Frontiers in Oncology aerodigestive tract cancer non-small cell lung cancer head and neck squamous cell carcinoma cancer-associated fibroblast (CAF) metabolic compartmentalization monocarboxylate transporter 4 (MCT4) |
| title | Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers |
| title_full | Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers |
| title_fullStr | Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers |
| title_full_unstemmed | Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers |
| title_short | Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers |
| title_sort | monocarboxylate transporter 4 in cancer associated fibroblasts is a driver of aggressiveness in aerodigestive tract cancers |
| topic | aerodigestive tract cancer non-small cell lung cancer head and neck squamous cell carcinoma cancer-associated fibroblast (CAF) metabolic compartmentalization monocarboxylate transporter 4 (MCT4) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.906494/full |
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