Oncogenic KRAS as an Architect of Mucinous Lineage Identity in Ovarian Carcinoma: Signaling Networks and Epithelial Reprogramming
Keywords:
Mucinous Ovarian Carcinoma, KRAS, Epithelial Reprogramming, Epigenetics, Tumor Microenvironment, Precision OncologyAbstract
Primary mucinous ovarian carcinoma (MOC) represents a unique biological entity that frequently exhibits resistance to standard chemotherapy. A major clinical challenge in MOC management remains accurately distinguishing primary tumors from gastrointestinal metastases. This narrative review synthesizes current evidence on how oncogenic KRAS signaling functions as a "master architect" driving lineage plasticity and shaping cellular identity in MOC. The literature indicates that KRAS/MAPK hyperactivation extends beyond driving cellular proliferation to orchestrate massive epithelial reprogramming. It actively recruits key transcription factors (such as AP-1, FOXA, and CDX2) that physically remodel chromatin and establish super-enhancers to epigenetically "lock in" a mucinous and intestinal identity. Furthermore, this state is continuously reinforced by a pro-inflammatory tumor microenvironment (via the IL-6/STAT3 axis) and specific metabolic adaptations, including enhanced glycolysis and glutaminolysis, creating a robust feed-forward loop. This mechanistic integration establishes that mucinous differentiation is not a static morphological label, but rather an actively maintained transcriptional state. Consequently, the clinical paradigm for MOC must shift toward precision oncology. This demands rigorous primary diagnostic confirmation intrinsically coupled with comprehensive molecular stratification. Future therapeutic strategies must move beyond conventional chemotherapy to exploit specific vulnerabilities within epigenetic circuits, metabolic dependencies, and targetable molecular subgroups (such as ERBB2 amplification), ultimately dismantling the resilient cellular identity of this recalcitrant tumor.
References
1. Dundr P, Bazalová B, Bártů M, Bosse T, Drozenová J, Fabian P, et al. The cytokeratin 17 expression in primary ovarian tumors has diagnostic but not prognostic significance. Virchows Archiv. 2022;481(2):201–12. doi:10.1007/s00428-022-03338-z
2. Hegazy S, Bhargava R, Roy S, Elishaev E. Synchronous Mucinous Carcinomas of Ovary and Appendix: A Case Report With Diagnostic Pitfalls and Review of Corresponding Literature. AJSP Rev Rep. 2022;27(3):103–6. doi:10.1097/PCR.0000000000000505
3. Benitz S, Steep A, Nasser MM, Preall J, Mahajan UM, McQuithey H, et al. ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma. Cancer Discov. 2024;14(11):2162–82. doi:10.1158/2159-8290.CD-24-0137
4. Przywara G, Biegańska O, Biczak E, Białoń A, Fidorowicz D, Dankowska A, et al. Recent Therapies and Biomarkers in Mucinous Ovarian Carcinoma. Cells. 2025;14(16):1232. doi:10.3390/cells14161232
5. Kawecka W, Bielak M, Urbanska K. Molecular alterations in mucinous ovarian tumors – a review. Current Issues in Pharmacy and Medical Sciences. 2024;37(3):190–4. doi:10.2478/cipms-2024-0031
6. Reyes-González JM, Quiñones-Díaz BI, Santana Y, Báez-Vega PM, Soto D, Valiyeva F, et al. Downstream Effectors of ILK in Cisplatin-Resistant Ovarian Cancer. Cancers (Basel). 2020;12(4):880. doi:10.3390/cancers12040880
7. Ackroyd SA, Goetsch L, Brown J, Houck K, Wang C, Hernandez E. Pancreaticobiliary metastasis presenting as primary mucinous ovarian neoplasm: A systematic literature review. Gynecol Oncol Rep. 2019;28:109–15. doi:10.1016/j.gore.2019.03.012
8. El Ghondakly RA, El Haddad SI, AbdelSalam MM, Nada OH, Farid RM, Farid LM. Immunohistochemical expression of SATB2 and PAX8 in differentiating primary from metastatic ovarian mucinous neoplasms. APMIS. 2024;132(10):706–17. doi:10.1111/apm.13449
9. Moh M, Krings G, Ates D, Aysal A, Kim GE, Rabban JT. SATB2 Expression Distinguishes Ovarian Metastases of Colorectal and Appendiceal Origin From Primary Ovarian Tumors of Mucinous or Endometrioid Type. American Journal of Surgical Pathology. 2016;40(3):419–32. doi:10.1097/PAS.0000000000000553
10. Dundr P, Bazalová B, Bártů M, Bosse T, Drozenová J, Fabian P, et al. The cytokeratin 17 expression in primary ovarian tumors has diagnostic but not prognostic significance. Virchows Archiv. 2022;481(2):201–12. doi:10.1007/s00428-022-03338-z
11. Wang F, Yang Y, Du X, Zhu X, Hu Y, Lu C, et al. Claudin18.2 as a potential therapeutic target for primary ovarian mucinous carcinomas and metastatic ovarian mucinous carcinomas from upper gastrointestinal primary tumours. BMC Cancer. 2023;23(1):44. doi:10.1186/s12885-023-10533-x
12. Van Nieuwenhuysen E, Busschaert P, Laenen A, Moerman P, Han SN, Neven P, et al. Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer. Neoplasia. 2019;21(6):582–90. doi:10.1016/j.neo.2019.03.014
13. Cheasley DA. Comprehensive genomic analysis of mucinous ovarian cancer reveals unique therapeutic vulnerabilities. Journal of Clinical Oncology. 2019;37(15_suppl):5571–5571. doi:10.1200/JCO.2019.37.15_suppl.5571
14. Moujaber T, Etemadmoghadam D, Mapagu C, Kennedy C, Chiew YE, Kan C, et al. Abstract 2584: Mutations in low-grade serous ovarian cancer and response to BRAF and MEK inhibitors. Cancer Res. 2018;78(13_Supplement):2584–2584. doi:10.1158/1538-7445.AM2018-2584
15. Jarratt A, Polidano J, Scott CL, Barker HE. Genomics of ovarian cancers and the potential of precision medicine. Ther Adv Med Oncol. 2025;17. doi:10.1177/17588359251396651
16. Kim YN, Chung YS, Park E, Lee ST, Lee JY. Human epidermal growth factor receptor-2 expression and subsequent dynamic changes in patients with ovarian cancer. Sci Rep. 2024;14(1):7992. doi:10.1038/s41598-024-57515-y
17. Knigin D, Yang BW, Matanes E, Yasmeen A, Gotlieb W. EP244/#718 Poly-(ADP-ribose)-glycohydrolase localizes to the cytoplasm following neoadjuvant chemotherapy in ovarian serous carcinoma. In: E-Posters. BMJ Publishing Group Ltd; 2022. p. A148.2-A149. doi:10.1136/ijgc-2022-igcs.335
18. Chui MH, Kang EY, Kahn RM, Chiang S, Zhou Q, Iasonos A, et al. Data from Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-grade Serous Tumors with Histologic Transformation. 2025. doi:10.1158/1078-0432.c.7928410
19. De Thaye E, Van de Vijver K, Van der Meulen J, Taminau J, Wagemans G, Denys H, et al. Establishment and characterization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma. Sci Rep. 2020;10(1):6688. doi:10.1038/s41598-020-63738-6
20. Maiorano MFP, Maiorano BA, Cormio G, Loizzi V. Mucinous Ovarian Carcinoma: Integrating Molecular Stratification into Surgical and Therapeutic Management. Biomedicines. 2025;13(5):1198. doi:10.3390/biomedicines13051198
21. Gorringe KL, Wakefield M, Hunter SM, Ryland GL, Cheasley D, Anglesio MS, et al. Abstract B08: Genomics analyses of less common epithelial ovarian cancer subtypes. Clinical Cancer Research. 2016;22(2_Supplement):B08–B08. doi:10.1158/1557-3265.OVCA15-B08
22. Knigin D, Yang BW, Matanes E, Yasmeen A, Gotlieb W. EP244/#718 Poly-(ADP-ribose)-glycohydrolase localizes to the cytoplasm following neoadjuvant chemotherapy in ovarian serous carcinoma. In: E-Posters. BMJ Publishing Group Ltd; 2022. p. A148.2-A149. doi:10.1136/ijgc-2022-igcs.335
23. Chamberlain SG, Owen D, Mott HR. Membrane extraction by calmodulin underpins the disparate signalling of RalA and RalB. BioEssays. 2022;44(6). doi:10.1002/bies.202200011
24. Seibold M, Stuehmer T, Mottok A, Scholz CJ, Chatterjee M, Leich E, et al. Activated Ral and Mutated RAS Are Independent Drivers of Multiple Myeloma Cell Survival. Blood. 2018;132(Supplement 1):3217–3217. doi:10.1182/blood-2018-99-119804
25. Aldaoud N, Erashdi M, AlKhatib S, Abdo N, Al-Mohtaseb A, Graboski-Bauer A. The utility of PAX8 and SATB2 immunohistochemical stains in distinguishing ovarian mucinous neoplasms from colonic and appendiceal mucinous neoplasm. BMC Res Notes. 2019;12(1):770. doi:10.1186/s13104-019-4816-9
26. Ates Ozdemir D, Usubutun A. PAX2, PAX8 and CDX2 Expression in Metastatic Mucinous, Primary Ovarian Mucinous and Seromucinous Tumors and Review of the Literature. Pathology & Oncology Research. 2016;22(3):593–9. doi:10.1007/s12253-016-0040-2
27. Fufa TD, Baxter LL, Wedel JC, Gildea DE, Loftus SK, Pavan WJ. MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells. Epigenetics Chromatin. 2019;12(1):50. doi:10.1186/s13072-019-0297-2
28. Matson DR, Xu J, Huffman L, Barroilhet L, Accola M, Rehrauer WM, et al. KRAS and GNAS Co-Mutation in Metastatic Low-Grade Appendiceal Mucinous Neoplasm (LAMN) to the Ovaries: A Practical Role for Next-Generation Sequencing. American Journal of Case Reports. 2017;18:558–62. doi:10.12659/AJCR.903581
29. Wang F, Li Y, Cui Y, Zhao L. Expression of CLDN18.2, CDX2, SATB2, and PAX8 in Primary and Gastrointestinal-Derived Mucinous Ovarian Carcinoma. Advances in Obstetrics and Gynecology Research. 2025;3(3):76–83. doi:10.26689/aogr.v3i3.11130
30. Niwa K, Niwa K, Isobe M, Kyogoku R, Tanaka T. Pseudomyxoma Peritonei Arising From a Mucinous Ovarian Borderline Tumor Treated With Paclitaxel, Cisplatin, and Bevacizumab: A Case Report. Cureus. 2024. doi:10.7759/cureus.67554
31. Razia S, Nakayama K, Yamashita H, Ishibashi T, Ishikawa M, Kanno K, et al. Histological and Genetic Diversity in Ovarian Mucinous Carcinomas: A Pilot Study. Current Oncology. 2023;30(4):4052–9. doi:10.3390/curroncol30040307
32. Fort G, Arnold H, Camolotto S, Tariq R, Waters A, O’Toole K, et al. Opposing lineage specifiers induce a pro-tumor hybrid-identity state in lung adenocarcinoma. 2024. doi:10.1101/2024.12.02.626384
33. Matson DR, Xu J, Huffman L, Barroilhet L, Accola M, Rehrauer WM, et al. KRAS and GNAS Co-Mutation in Metastatic Low-Grade Appendiceal Mucinous Neoplasm (LAMN) to the Ovaries: A Practical Role for Next-Generation Sequencing. American Journal of Case Reports. 2017;18:558–62. doi:10.12659/AJCR.903581
34. Saggese P, Sellitto A, Martinez CA, Giurato G, Nassa G, Rizzo F, et al. Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer. Cancers (Basel). 2020;12(12):3788. doi:10.3390/cancers12123788
35. Ruiz CF, Montal ED, Haley JA, Bott AJ, Haley JD. SREBP1 regulates mitochondrial metabolism in oncogenic KRAS expressing NSCLC. The FASEB Journal. 2020;34(8):10574–89. doi:10.1096/fj.202000052R
36. Wu X, Tao P, Zhou Q, Li J, Yu Z, Wang X, et al. IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget. 2017;8(13):20741–50. doi:10.18632/oncotarget.15119
37. Hutton JE, Wang X, Zimmerman LJ, Slebos RJC, Trenary IA, Young JD, et al. Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer. Molecular & Cellular Proteomics. 2016;15(9):2924–38. doi:10.1074/mcp.M116.058925
38. Kealey J, Düssmann H, Llorente-Folch I, Niewidok N, Salvucci M, Prehn JHM, et al. Effect of TP53 deficiency and KRAS signaling on the bioenergetics of colon cancer cells in response to different substrates: A single cell study. Front Cell Dev Biol. 2022;10. doi:10.3389/fcell.2022.893677
39. Hatipoglu A, Menon D, Levy T, Frias MA, Foster DA. Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells. PLoS One. 2022;17(10):e0276579. doi:10.1371/journal.pone.0276579
40. Suzuki T, Kishikawa T, Sato T, Takeda N, Sugiura Y, Seimiya T, et al. Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells. Cancer Gene Ther. 2022;29(5):505–18. doi:10.1038/s41417-021-00326-4
41. Mukhopadhyay S, Goswami D, Adiseshaiah PP, Burgan W, Yi M, Guerin TM, et al. Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers. Cancer Res. 2020;80(8):1630–43. doi:10.1158/0008-5472.CAN-19-1363
42. Pupo E, Avanzato D, Middonti E, Bussolino F, Lanzetti L. KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer. Front Oncol. 2019;9. doi:10.3389/fonc.2019.00848
43. Zhao H, Wu S, Li H, Duan Q, Zhang Z, Shen Q, et al. ROS/KRAS/AMPK Signaling Contributes to Gemcitabine-Induced Stem-like Cell Properties in Pancreatic Cancer. Mol Ther Oncolytics. 2019;14:299–312. doi:10.1016/j.omto.2019.07.005
44. Brunelli L, Caiola E, Marabese M, Broggini M, Pastorelli R. Comparative metabolomics profiling of isogenic KRAS wild type and mutant NSCLC cells in vitro and in vivo. Sci Rep. 2016;6(1):28398. doi:10.1038/srep28398
45. Gillis K, Orellana WA, Wilson E, Parnell TJ, Fort G, Dadzie HE, et al. FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma. 2023. doi:10.1101/2023.10.30.564775
46. Gore M, Hackshaw A, Brady WE, Penson RT, Zaino R, McCluggage WG, et al. An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor. Gynecol Oncol. 2019;153(3):541–8. doi:10.1016/j.ygyno.2019.03.256
47. Nasioudis D, Gysler S, Latif N, Ko E, Cory L, Giuntoli R, et al. Molecular profiling of mucinous ovarian carcinoma reveals actionable mutations and a unique genomic profile (1282). Gynecol Oncol. 2023;176:S176–7. doi:10.1016/j.ygyno.2023.06.188
48. Wei D, Wang L, Zuo X, Maitra A, Bresalier RS. A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer. Clinical Cancer Research. 2024;30(4):655–62. doi:10.1158/1078-0432.CCR-23-2098
49. Isermann T, Sers C, Der CJ, Papke B. KRAS inhibitors: resistance drivers and combinatorial strategies. Trends Cancer. 2025;11(2):91–116. doi:10.1016/j.trecan.2024.11.009
50. Feng J, Xiao X, Lian Z, Zhang A, Pang X. Pan-KRAS inhibition: unlocking broad-spectrum targeted therapy for KRAS-mutant cancers. Cancer Biol Med. 2026;1–7. doi:10.20892/j.issn.2095-3941.2025.0612
51. Bartl T, Cacsire Castillo-Tong D. Targeting RAS–RAF–MEK–ERK signaling in mucinous ovarian cancer: a translational evidence synthesis and clinical framework. International Journal of Gynecological Cancer. 2026;104485. doi:10.1016/j.ijgc.2026.104485
52. Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, et al. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Cancer Discov. 2018;8(2):184–95. doi:10.1158/2159-8290.CD-17-1119
53. Schram AM, Boni V, Adjei AA, Olszanski AJ, Vieito M, Francis JH, et al. A phase I, first-in-human trial of KO-947, an ERK1/2 inhibitor, in patients with advanced solid tumors. ESMO Open. 2025;10(3):104300. doi:10.1016/j.esmoop.2025.104300
54. Kalev P, Hyer ML, Gross S, Konteatis Z, Chen CC, Fletcher M, et al. MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. Cancer Cell. 2021;39(2):209-224.e11. doi:10.1016/j.ccell.2020.12.010
