# Evolution of Cancer Metastases via Lineage Trans-Differentiation **Authors:** Yu Xiao, Wan Jin, Fangjin Chen, Kaiyu Qian, Lingao Ju, Yi Zhang PMC · DOI: 10.34133/research.1144 · Research · 2026-02-19 ## TL;DR This study reveals that cancer metastasis is driven by a process called lineage trans-differentiation, where cancer cells lose their original identity and adopt new traits, leading to more aggressive tumors. ## Contribution The paper introduces bioinformatic tools to track cancer evolution at the single-cell level and identifies lineage trans-differentiation as a novel mechanism for metastasis. ## Key findings - Cancer cells undergo de-differentiation into a fetal-like state during premetastatic evolution. - Trans-differentiation is linked to increased metastatic potential and worse patient survival. - MAPK signaling is activated during trans-differentiation and can be reversed with MAPK inhibition. ## Abstract Most cancer metastases exhibit mutational profiles similar to those of the primary tumor. However, the nongenetic mechanisms driving metastasis remain poorly understood. Here, we show that lineage trans-differentiation is a hallmark of cancer metastasis. Bioinformatic tools capable of reconstructing cancer phenotypic evolutionary trajectories at single-cell resolution were developed, revealing a progressive loss of transcriptional and epigenomic lineage fidelity in cancer cells as they evolve toward metastasis. During premetastatic evolution, cells undergo de-differentiation into a fetal-like state. The mis-expression of alternative-lineage gene programs during re-differentiation from this fetal-like state leads to the formation of trans-differentiated metastatic cells. This trans-differentiation, rather than fetal-like transcription, constitutes a key feature of metastasis in both humans and mice. In clinical samples, trans-differentiation correlates with histopathological grade, metastatic potential, and patient survival. Additionally, trans-differentiation is associated with gain of oncogenic mitogen-activated protein kinase (MAPK) signaling and can be reversed through MAPK inhibition. These findings offer a detailed account of metastatic cancer evolution driven by epigenetic reprogramming while also uncovering the molecular mechanisms underlying this process. ## Linked entities - **Chemicals:** doxorubicin (PubChem CID 31703) - **Diseases:** cancer (MONDO:0004992) - **Species:** Homo sapiens (taxon 9606), Mus musculus (taxon 10090) ## Full-text entities - **Genes:** APC (APC regulator of Wnt signaling pathway) [NCBI Gene 324] {aka BTPS2, DESMD, DP2, DP2.5, DP3, GS}, AGER (advanced glycosylation end-product specific receptor) [NCBI Gene 177] {aka RAGE, SCARJ1, sRAGE}, CDX2 (caudal type homeobox 2) [NCBI Gene 1045] {aka CDX-3, CDX2/AS, CDX3}, SFTPC (surfactant protein C) [NCBI Gene 6440] {aka BRICD6, PSP-C, SFTP2, SMDP2, SP-C}, Cd24a (CD24a antigen) [NCBI Gene 12484] {aka Cd24, HSA, Ly-52, nectadrin}, Sox9 (SRY (sex determining region Y)-box 9) [NCBI Gene 20682] {aka 2010306G03Rik, mKIAA4243, mSox9}, Hopx (HOP homeobox) [NCBI Gene 74318] {aka 1110018K11Rik, 1200015P04Rik, 2300002F06Rik, Cameo, Hdop, Hod}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, ONECUT2 (one cut homeobox 2) [NCBI Gene 9480] {aka OC-2, OC2}, Met2 (methyltransferase 2) [NCBI Gene 104165] {aka Met-2}, VIM (vimentin) [NCBI Gene 7431], GATA3 (GATA binding protein 3) [NCBI Gene 2625] {aka HDR, HDRS}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, PDPN (podoplanin) [NCBI Gene 10630] {aka AGGRUS, D2-40, GP36, GP40, Gp38, HT1A-1}, Nkx2-1 (NK2 homeobox 1) [NCBI Gene 21869] {aka Nkx2.1, T/EBP, Titf1, Ttf-1}, Tm4sf1 (transmembrane 4 superfamily member 1) [NCBI Gene 17112] {aka L6, M3s1}, Gpx3 (glutathione peroxidase 3) [NCBI Gene 14778] {aka EGPx, GPx, GSHPx-3, GSHPx-P}, Tead3 (TEA domain family member 3) [NCBI Gene 21678] {aka DTEF-1, ETFR-1, TEAD-3, TEF-5, Tcf13r2}, SOX2 (SRY-box transcription factor 2) [NCBI Gene 6657] {aka ANOP3, MCOPS3}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, ZEB1 (zinc finger E-box binding homeobox 1) [NCBI Gene 6935] {aka AREB6, BZP, DELTAEF1, FECD6, NIL2A, PPCD3}, Gata3 (GATA binding protein 3) [NCBI Gene 14462] {aka Gata-3, jal}, RB1 (RB transcriptional corepressor 1) [NCBI Gene 5925] {aka OSRC, PPP1R130, RB, p105-Rb, p110-RB1, pRb}, MEIS2 (Meis homeobox 2) [NCBI Gene 4212] {aka CPCMR, HsT18361, MRG1}, CEBPA (CCAAT enhancer binding protein alpha) [NCBI Gene 1050] {aka C/EBP-alpha, CEBP}, CLDN4 (claudin 4) [NCBI Gene 1364] {aka CPE-R, CPER, CPETR, CPETR1, WBSCR8, hCPE-R}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, PDX1 (pancreatic and duodenal homeobox 1) [NCBI Gene 3651] {aka GSF, IDX-1, IPF1, IUF1, MODY4, PAGEN1}, HNF4A (hepatocyte nuclear factor 4 alpha) [NCBI Gene 3172] {aka FRTS4, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha}, PRRX1 (paired related homeobox 1) [NCBI Gene 5396] {aka AGOTC, PHOX1, PMX1, PRX-1, PRX1}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, FOXA1 (forkhead box A1) [NCBI Gene 3169] {aka HNF3A, TCF3A}, BMP7 (bone morphogenetic protein 7) [NCBI Gene 655] {aka OP-1}, RUNX1 (RUNX family transcription factor 1) [NCBI Gene 861] {aka AML1, AML1-EVI-1, AMLCR1, CBF2alpha, CBFA2, EVI-1}, Pemt (phosphatidylethanolamine N-methyltransferase) [NCBI Gene 18618] {aka PEAMT, PEMT2, PLMT, Pempt, Pempt2}, CEBPB (CCAAT enhancer binding protein beta) [NCBI Gene 1051] {aka C/EBP-beta, IL6DBP, NF-IL6, TCF5}, SLC4A11 (solute carrier family 4 member 11) [NCBI Gene 83959] {aka BTR1, CDPD1, CHED, CHED2, NABC1, dJ794I6.2}, RET (ret proto-oncogene) [NCBI Gene 5979] {aka CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1}, APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, Bmp2 (bone morphogenetic protein 2) [NCBI Gene 12156] {aka Bmp2a}, SFTPB (surfactant protein B) [NCBI Gene 6439] {aka PSP-B, SFTB3, SFTP3, SMDP1, SP-B}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, SCGB1A1 (secretoglobin family 1A member 1) [NCBI Gene 7356] {aka CC10, CC16, CCPBP, CCSP, UGB, UP-1}, LGALS1 (galectin 1) [NCBI Gene 3956] {aka GAL1, GBP}, OSR1 (odd-skipped related transcription factor 1) [NCBI Gene 130497] {aka ODD}, HOPX (HOP homeobox) [NCBI Gene 84525] {aka CAMEO, HOD, HOP, LAGY, NECC1, OB1}, CDX1 (caudal type homeobox 1) [NCBI Gene 1044], MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, ID3 (inhibitor of DNA binding 3) [NCBI Gene 3399] {aka HEIR-1, bHLHb25}, ETV6 (ETS variant transcription factor 6) [NCBI Gene 2120] {aka TEL, TEL/ABL, THC5}, GPX3 (glutathione peroxidase 3) [NCBI Gene 2878] {aka GPx-P, GSHPx-3, GSHPx-P}, CLU (clusterin) [NCBI Gene 1191] {aka AAG4, APO-J, APOJ, CLI, CLU1, CLU2}, Kras (Kras proto-oncogene, GTPase) [NCBI Gene 16653] {aka K-Ras, K-Ras 2, K-ras, Ki-ras, Kras-2, Kras2}, SCGB3A1 (secretoglobin family 3A member 1) [NCBI Gene 92304] {aka HIN-1, HIN1, LU105, PnSP-2, UGRP2}, Fblim1 (filamin binding LIM protein 1) [NCBI Gene 74202] {aka 2410043F08Rik, Cal, Fblp1, Gt10, migfilin, migfilin(s)}, SNAI2 (snail family transcriptional repressor 2) [NCBI Gene 6591] {aka SLUG, SLUGH, SLUGH1, SNAIL2, WS2D}, Runx2 (runt related transcription factor 2) [NCBI Gene 12393] {aka AML3, CBF-alpha-1, Cbf, Cbfa-1, Cbfa1, LS3}, Irf7 (interferon regulatory factor 7) [NCBI Gene 54123], Dnmt1 (DNA methyltransferase 1) [NCBI Gene 13433] {aka Cxxc9, Dnmt, Dnmt1o, MCMT, MTase, Met-1}, TWIST2 (twist family bHLH transcription factor 2) [NCBI Gene 117581] {aka AMS, BBRSAY, DERMO1, FFDD3, SETLSS, bHLHa39} - **Diseases:** PRAD (MESH:D000230), G3 cancers (MESH:D009369), lung cancer (MESH:D008175), lung alveolar type 2 (MESH:D055370), Metastatic disease (MESH:D000092182), head-and-neck squamous cancer (MESH:D006258), prostate cancer (MESH:D011471), melanoma (MESH:D008545), pancreatic adenocarcinoma (MESH:D010190), PD (MESH:D010300), small cell lung carcinoma (MESH:D055752), PNET (MESH:D018358), AT2 (MESH:C567048), HNSC (MESH:D000077195), LUAD (MESH:D000077192), STAD (MESH:D013274), PE (MESH:D010996), oncogenesis (MESH:D063646), primary (MESH:D010538), teratomas (MESH:D013724), Metastasis (MESH:D009362), CRC (MESH:D015179), deficient (MESH:D007153), MEN (MESH:D008579), UMAP (MESH:C567162), brain metastases (MESH:D001932), adenosquamous carcinoma (MESH:D018196), ccRCC (MESH:D002292), GBM (MESH:D005909), BLCA (MESH:D001749), breast cancer (MESH:D001943), LGG (MESH:D008228), UVM (MESH:C536494) - **Chemicals:** xylene (MESH:D014992), streptomycin (MESH:D013307), paraffin (MESH:D010232), ethanol (MESH:D000431), H&E (MESH:D006371), crystal violet (MESH:D005840), Foxa2KO (-), hematoxylin (MESH:D006416), penicillin (MESH:D010406), eosin (MESH:D004801), formalin (MESH:D005557), SYBR Green (MESH:C098022), paraformaldehyde (MESH:C003043) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Mycoplasma (genus) [taxon 2093], Homo sapiens (human, species) [taxon 9606] - **Mutations:** G12D - **Cell lines:** A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023), AT1 — Mus musculus (Mouse), Hybridoma (CVCL_C7RB), H3122 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_5160), AT2 — Homo sapiens (Human), Telomerase immortalized cell line (CVCL_VR37), S24A — Mus musculus (Mouse), Hybridoma (CVCL_B5AU), PC9 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_B260), S21A — Mus musculus (Mouse), Transformed cell line (CVCL_K245), S26B — Homo sapiens (Human), Hybrid cell line (CVCL_B0UB) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12917112/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12917112/full.md ## References 127 references — full list in the complete paper: https://tomesphere.com/paper/PMC12917112/full.md --- Source: https://tomesphere.com/paper/PMC12917112