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Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment
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Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ–IL4rα and IL2rγ–IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ–IL4rα and IL2rγ–IL13rα1 receptors signal primarily via JAK1–STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. Significance: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell–intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.
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“In a KRASG12D mutation driven PDAC mice model, immune suppressive cytokines IL-4 and IL-13 and remodeling of the myeloid cell composition in TME have been demonstrated40,41.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [41]
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“The binding of IL13Ra1 to IL-13 in non-mutated cells leads to the activation of STAT-6 signaling that results in translocation to the nucleus (Dey et al., 2020).”
BackgroundGurreri, E., Genovese, G., Perelli, L., Agostini, A., Piro, G., Carbone, C., & Tortora, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119313 · Cited by 27
“However, trials with JAK1/2 inhibitors have yielded disheartening results [66].”
ResultSelf-citationZhang, H., Chen, J., Hu, X., Bai, J., & Yin, T. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10518 · Cited by 27
“Traditional orthotopic xenograft models were established by mixing cell suspension with Matrigel (BD Biosciences), and the suspension was injected into the pancreas.(30,31) Matrigel matrix is a soluble basement membrane extract isolated from Engelbreth– Holm–Swarm (EHS) mouse sarcoma rich in ECM proteins such as lamin…”
MethodHafezi, S., Saber-Ayad, M. M., & Abdel‐Rahman, W. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910219 · Cited by 28
“Subsequently, a cascade of events follows that leads to metabolic reprogramming (see Section 5) [28].”
BackgroundDice-XMBD: Deep Learning-Based Cell Segmentation for Imaging Mass Cytometry
Xiao, X., Qiao, Y., Jiao, Y., Fu, N., Yang, W., Wang, L., Yu, R., & Han, J. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.721229 · Cited by 25
“Thus, it has become a powerful tool to study tumor microenvironments and discover the underlying disease-relevant mechanisms (Brähler et al., 2018; Ali et al., 2020; Aoki et al., 2020; de Vries et al., 2020; Dey et al., 2020; Jackson et al., 2020; Zhang et al., 2020; Schwabenland et al., 2021).”
BackgroundLi, S., & Xie, K. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188698 · Cited by 27
Bandi, D. S. R., Sarvesh, S., Farran, B., Nagaraju, G. P., & El‐Rayes, B. F. (2023) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2023.06.006 · Cited by 26
Yang, S. S., Tang, W., Azizian, A., Gaedcke, J., Ohara, Y., Cawley, H., Hanna, N. N., Ghadimi, M. B., Lal, T., Sen, S., et al. (2024) · Carcinogenesis · doi:10.1093/carcin/bgae025 · Cited by 25
Self-citationNeuß, T., Chen, M.-C., Wirges, N., Usluer, S., Oellinger, R., Lier, S., Dudek, M., Madl, T., Jastroch, M., Steiger, K., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-2213 · Cited by 23
Liu, X., Yang, J., Huang, S., Hong, Y., Zhu, Y., Wang, J., Wang, Y., Liang, T., & Bai, X. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.01.023 · Cited by 27
Self-citationPrognostic Biomarker DDOST and Its Correlation With Immune Infiltrates in Hepatocellular Carcinoma
Zhu, C., Xiao, H., Jiang, X., Tong, R., & Guan, J. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2021.819520 · Cited by 24
“IL-4 produced by Th2 cells can result in the activation of several cancer-related pathways (Zhao et al., 2015; Dey et al., 2020).”
BackgroundFang, Z., Wang, W., Liu, Y., Hua, J., Liang, C., Jiang, L., Zhang, B., Shi, S., Yu, X., Meng, Q., et al. (2023) · Current Oncology · doi:10.3390/curroncol30030228 · Cited by 25
“As Th2 cytokines, IL4 and IL13 have been reported to restrain the immune response to tumor cells and promote the proliferation of KRAS-mutant cells [42].”
BackgroundIL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1
Wu, W.-J., Wang, S., Wu, C., Su, Y., Chiang, C.-Y., Lai, C.-H., Wang, T.-H., Cheng, T., Kuo, J.-Y., Hsu, T., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222112008 · Cited by 24
“In respons to these cytokines, enhanced glycolysis and glutamine metabolism su port growth of pan reatic and breast cancer cells, respectively [35,38].”
BackgroundChen, P., Ning, Y., Li, H., Su, J.-G., Shen, J.-B., Feng, Q.-C., Jiang, S., Shi, P.-D., & Guo, R.-S. (2023) · Cellular Oncology · doi:10.1007/s13402-023-00852-3 · Cited by 23
“Many factors contribute to the enhancement of glycolysis, including oncogenic Kras mutation [29], tumor-associated mutant p53 [30], HIF signaling, c-Myc [7 ], specific transcription factors [31], TAMs [32 ], and cancer-associated fibroblasts [ 33].”
Metabolic Constrains Rule Metastasis Progression
Roda, N., Gambino, V., & Giorgio, M. (2020) · Cells · doi:10.3390/cells9092081 · Cited by 22
“Moreover, two independent works on pancreatic cancer have shown the role of MYC in promoting both glycolysis upregulation [55] and protein anabolism [46].”
BackgroundShedding Light on the Role of Neurotransmitters in the Microenvironment of Pancreatic Cancer
Liang, Y., Li, H., Gan, Y., & Tu, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.688953 · Cited by 22
Zhang, W., Qi, L., Liu, Z., He, S., Wang, C., Wu, Y., Han, L., Liu, Z., Fu, Z., Tu, C., et al. (2023) · MedComm · doi:10.1002/mco2.317 · Cited by 20
Yang, Q., Bariani, M. V., Falahati, A., Khosh, A., Lastra, R. R., Siblini, H., Boyer, T., & Al-Hendy, A. A. (2022) · Cells · doi:10.3390/cells11142160 · Cited by 19
“MYC is known to cooperate with KRAS in driving many cancers and contributes to many cancer hallmarks [53].”
BackgroundFAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer
Davidson, C., Taggart, D., Sims, A. H., Lonergan, D. W., Canel, M., & Serrels, A. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01966-5 · Cited by 20
“Both murine and human PDAC tumours are extensively infiltrated with a variety of immune cells that not only contribute to establishing a highly immuno-suppressive tumour microenvironment (TME)[4, 7–12] but also promote PDAC development and progression via hematopoietic-to-epithelial cell signalling [13, 14].”
Hershey, B. J., Barozzi, S., Orsenigo, F., Pompei, S., Iannelli, F., Kamrad, S., Matafora, V., Pisati, F., Calabrese, L., Fragale, G., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh4184 · Cited by 20
Schreyer, D., Neoptolemos, J. P., Barry, S. T., & Bailey, P. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.795735 · Cited by 19
Dutta, P., Castro-Pando, S., Mascaró, M., Riquelme, E. M., Zoltan, M. A., Zacharias, N. M., Gammon, S. T., Piwnica-Worms, D. R., Pagel, M. D., Sen, S., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103722 · Cited by 19
“It has been reported that genetic mutations, along with the unique tumor microenvironment in PDAC, are susceptible to metabolic plasticity [17].”
BackgroundSelf-citationZhang, F., Wang, B., Wu, M., Zhang, L., & Ji, M. Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1509173 · Cited by 20
Sun, M., Xie, M., Zhang, T., Wang, Y., Huang, W., & Xia, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.739768 · Cited by 18
Self-citationZhang, Z., & Zhang, H. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.2015321 · Cited by 18
“Activation of Myc and promotion of glycolysis occurred mainly through JAK1–STAT6 signaling [37].”
BackgroundImmuno-oncology-microbiome axis of gastrointestinal malignancy
Lin, Q., Guan, S.-W., & Yu, H. (2023) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v15.i5.757 · Cited by 20
Fujisawa, T., Shimamura, T., Goto, K., Nakagawa, R., Muroyama, R., Ino, Y., Horiuchi, H., Endo, I., Maeda, S., Harihara, Y., et al. (2020) · Cancers · doi:10.3390/cancers12051294 · Cited by 18
“A recent study demonstrated that an interaction between mutant-KRAS signaling in cancer cells and IL-13Rα1 from the tumor micro-environment in preneoplastic lesions and PDAC, which suggests that KRAS drives the expression of cytokine receptors, which in turn are activated by cytokines produced predominantly by infiltr…”
BackgroundLeBleu, V. S., Smaglo, B. G., Mahadevan, K. K., Kirtley, M. L., McAndrews, K. M., Mendt, M. C., Yang, S., Maldonado, A. S., Sugimoto, H., Salvatierra, M. E., et al. (2025) · medRxiv · doi:10.1101/2025.03.03.25322827 · Cited by 18
Self-citationA Novel ZNF304/miR-183-5p/FOXO4 Pathway Regulates Cell Proliferation in Clear Cell Renal Carcinoma
Ren, L., Zeng, B., Zhu, M., Zhao, A., Shi, B., Zhang, H., Wang, D., Gu, J., & Yang, Z. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.710525 · Cited by 17
Zhang, J. H., Darman, L., Hassan, M. S., von Holzen, U. W., & Awasthi, N. (2023) · Oncology Reports · doi:10.3892/or.2023.8643 · Cited by 19
“…that rapamycin was specifically effective on KRAS ‑mutant PDAC tumors that have loss of PTEN (median survival in controls, gemcitabine, rapamycin and gemcitabine plus rapamycin was 10, 14, 56 and 32 days, respectively), while KRAS ‑mutant tumors with mutant p53 (KPC) did not respond (39).”
BackgroundSelf-citationMcAndrews, K. M., Paradiso, F., Stalnecker, C. A., Selvanesan, B. C., Thege, F. I., Peng, D. H., Diaz, B. A. M., Sugimoto, H., Patel, S. I., Mahadevan, K. K., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adt5511 · Cited by 17
Self-citationLoss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer
Shi, J., Shen, X., Kang, Q., Yang, X., Denzinger, M., Kornmann, M., & Traub, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073659 · Cited by 15
“In the loading-control corrected expression of STAT6, STAT3, ERK and PI3K were comparable to control cells.”
BackgroundResultInfluentialConquering oncogenic KRAS and its bypass mechanisms
Hou, P., & Wang, Y. (2022) · Theranostics · doi:10.7150/thno.71260 · Cited by 18
Self-citationRationale for MYC imaging and targeting in pancreatic cancer
Schneider, G., Wirth, M., Keller, U. B., & Saur, D. (2021) · EJNMMI Research · doi:10.1186/s13550-021-00843-1 · Cited by 15
“Furthermore, JAK1-STAT6-MYCmediated increase in expression of enolase 1 and hexokinase (HK2)—enzymes involved in glycolysis— is promoted by IL4 and IL13 cytokines present in the TME, revealing the complex modalities of signals integrated by MYC [37].”
Background
Metadata
- Authors
- Dey, P., Li, J., Zhang, J., Chaurasiya, S., Strom, A., Wang, H., Liao, W.-T., Cavallaro, F., Denz, P., Bernard, V., Yen, E.-Y., Genovese, G., Gulhati, P., Liu, J., Chakravarti, D., Deng, P., Zhang, T., Carbone, F., Chang, Q., Ying, H., Shang, X., Spring, D. J., Ghosh, B., Putluri, N., Maitra, A., Wang, Y. A., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Houston (US)
- 3Center for Nuclear Receptor and Cell Signaling, University of Houston, Houston, Texas.
- 1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Roswell Park Comprehensive Cancer Center (US)
- Baylor College of Medicine (US)
- Corresponding author
- DePinho, Ronald A.
- ORCID
- Dey, Prasenjit
- Li, Jun
- Zhang, Jianhua
- Chaurasiya, Surendra
- Wang, Huamin
- Liao, Wen-Ting
- Cavallaro, Frederick
- Denz, Parker
- Bernard, Vincent
- Yen, Er-Yen
- Genovese, Giannicola
- Gulhati, Pat
- Liu, Jielin
- Chakravarti, Deepavali
- Deng, Pingna
- Zhang, Tingxin
- Carbone, Federica
- Chang, Qing
- Ying, Haoqiang
- Shang, Xiaoying
- Spring, Denise J.
- Putluri, Nagireddy
- Maitra, Anirban
- Wang, Y. Alan
- DePinho, Ronald A.
- Venue
- Cancer Discovery
- Published
- 2020-04-01
- Volume
- 10
- Issue
- 4
- Pages
- 608-625
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W3006227213
- Cited by
- 213
- References
- 65
- Citations by year
- 2026: 30 · 2025: 33 · 2024: 33 · 2023: 33 · 2022: 40 · 2021: 36 · 2020: 8
- FWCI
- 10.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MD Anderson (P30CA16672)
- Baylor College of Medicine (P30CA125123)
- CPRIT (RP170005, RP140106170067, 170067)
- NCI (P01 CA117969, R01 CA225955)
- DOD (W81XWH-14-1-0429, K99/R00, 1K99 CA218891-01A1, U24 CA224020, R01 CA218004, R01 CA304969)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, oncogenic KRAS, tumor microenvironment, metabolic reprogramming, glycolysis, c-Myc, STAT6, IL-4, IL-13, Th2 cells, paracrine signaling, tumor stroma
- MeSH terms
- Animals, Humans, Oncogenes, Pancreatic Neoplasms, Transfection, Cytokines, Proto-Oncogene Proteins p21(ras), Mice, Tumor Microenvironment, Cellular Reprogramming
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