Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis
Abstract Background Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating ev...
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BMC
2025-06-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-025-00400-7 |
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| author | Ann-Kathrin Daum Lisa Schlicker Marc A. Schneider Thomas Muley Ursula Klingmüller Almut Schulze Michael Thomas Petros Christopoulos Holger Sültmann |
| author_facet | Ann-Kathrin Daum Lisa Schlicker Marc A. Schneider Thomas Muley Ursula Klingmüller Almut Schulze Michael Thomas Petros Christopoulos Holger Sültmann |
| author_sort | Ann-Kathrin Daum |
| collection | DOAJ |
| description | Abstract Background Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells. Methods Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction. Results CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition. Conclusions This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes. |
| format | Article |
| id | doaj-art-13259e486c3e46a38852c292ea146fd7 |
| institution | OA Journals |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Cancer & Metabolism |
| spelling | doaj-art-13259e486c3e46a38852c292ea146fd72025-08-20T02:37:35ZengBMCCancer & Metabolism2049-30022025-06-0113112710.1186/s40170-025-00400-7Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesisAnn-Kathrin Daum0Lisa Schlicker1Marc A. Schneider2Thomas Muley3Ursula Klingmüller4Almut Schulze5Michael Thomas6Petros Christopoulos7Holger Sültmann8Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT)Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ)German Center for Lung Research (DZL), TLRC HeidelbergGerman Center for Lung Research (DZL), TLRC HeidelbergGerman Center for Lung Research (DZL), TLRC HeidelbergDivision of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ)German Center for Lung Research (DZL), TLRC HeidelbergGerman Center for Lung Research (DZL), TLRC HeidelbergDivision of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT)Abstract Background Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells. Methods Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction. Results CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition. Conclusions This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.https://doi.org/10.1186/s40170-025-00400-7Lung adenocarcinomaEML4-ALKCancer-associated fibroblastsTherapy resistanceLipid metabolism3D cell culture |
| spellingShingle | Ann-Kathrin Daum Lisa Schlicker Marc A. Schneider Thomas Muley Ursula Klingmüller Almut Schulze Michael Thomas Petros Christopoulos Holger Sültmann Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis Cancer & Metabolism Lung adenocarcinoma EML4-ALK Cancer-associated fibroblasts Therapy resistance Lipid metabolism 3D cell culture |
| title | Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis |
| title_full | Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis |
| title_fullStr | Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis |
| title_full_unstemmed | Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis |
| title_short | Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis |
| title_sort | cancer associated fibroblasts promote drug resistance in alk driven lung adenocarcinoma cells by upregulating lipid biosynthesis |
| topic | Lung adenocarcinoma EML4-ALK Cancer-associated fibroblasts Therapy resistance Lipid metabolism 3D cell culture |
| url | https://doi.org/10.1186/s40170-025-00400-7 |
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