Pennel, K. A.F. et al. (2024) JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors. Journal of Experimental and Clinical Cancer Research, 43, 64. (doi: 10.1186/s13046-024-02958-4)
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Abstract
Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.
| Item Type: | Articles |
|---|---|
| Additional Information: | The authors would like to acknowledge the CRUK centre grant (CRUK Glasgow #A25142) for funding TransSCOT work. The authors wish to acknowledge CRUK funding which enable this research (Scottish Cancer Centre CTRQQR-2021/100006) and RadNet funding (RRNPSF-JUL21/1D100010). The authors also wish to acknowledge Medical Research Council (JE, KP) (MR/ R502327) and Chief Scientific Office (CSO) Scotland funding (EPD/22/13) (KP, JE, CR). The authors would like to acknowledge a CRUK Accelerator Award (A26825) (OJS, TL), CRUK core funding (A21139) (OJS, RJ and MG) and CRUK core funding to the CRUK Scotland Institute (A31287) 795 (OJS). The authors would also like to acknowledge an International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB), and AIRC (22795). |
| Keywords: | Colorectal cancer, cellular signaling, JAK/STAT3 signal transduction, tumor microenvironment, prognosis, spatial biology, JAK inhibitors, tumor-stroma, patient-derived organoids, stratified medicine, biomarkers. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Park, Mr James and Jamieson, Professor Nigel and Lian, Dr Guang-Yu and Horgan, Professor Paul and Pennel, Miss Kathryn and Ammar, Dr Aula and Rebus, Ms Selma and Quinn, Dr Jean and Kelly, Mrs Caroline and Wood, Dr Colin and McMillan, Professor Donald and Inthagard, Jitwadee and Harkin, Mrs Andrea and Al-Badran, Ms Sara and Roseweir, Dr Antonia and legrini, assya and Steele, Dr Colin and Roxburgh, Professor Campbell and Hay, Miss Jennifer and Edwards, Professor Joanne and Chang, Professor David and Hatthakarnkul, Phimmada and Graham, Dr Janet and Sansom, Professor Owen |
| Creator Roles: | Pennel, K.Investigation, Methodology, Funding acquisition, Writing – original draft, Writing – review and editing Hatthakarnkul, P.Investigation, Writing – review and editing Wood, C.Investigation, Methodology, Writing – review and editing Lian, G.-Y.Investigation, Methodology, Writing – review and editing Al-Badran, S.Investigation Quinn, J.Supervision Inthagard, J.Investigation legrini, a.Writing – review and editing Ammar, A.Methodology Hay, J.Supervision, Resources, Writing – review and editing Rebus, S.Investigation, Supervision, Resources Chang, D.Supervision, Resources Kelly, C.Resources Harkin, A.Resources Graham, J.Resources Horgan, P.Supervision, Resources Roxburgh, C.Conceptualization, Supervision Sansom, O.Resources, Funding acquisition, Writing – review and editing McMillan, D.Conceptualization, Supervision, Writing – review and editing Steele, C.Supervision, Writing – review and editing Jamieson, N.Investigation, Methodology, Supervision, Writing – review and editing Park, J.Conceptualization, Investigation, Methodology, Supervision Roseweir, A.Conceptualization, Methodology, Supervision Edwards, J.Conceptualization, Supervision, Investigation, Resources, Methodology, Funding acquisition, Writing – original draft, Writing – review and editing |
| Authors: | Pennel, K. A.F., Hatthakarnkul, P., Wood, C. S., Lian, G.-Y., Al-Badran, S., Quinn, J. A., Legrini, A., Inthagard, J., Alexander, P. G., van Wyk, H., Kurniawan, A., Hashmi, U., Gillespie, M. A., Mills, M., Ammar, A., Hay, J., Andersen, D., Nixon, C., Rebus, S., Chang, D. K., Kelly, C., Harkin, A., Graham, J., Church, D., Tomlinson, I., Saunders, M., Iveson, T., Lannagan, T. R. M., Jackstadt, R., Maka, N., Horgan, P. G., Roxburgh, C. S. D., Sansom, O. J., McMillan, D. C., Steele, C. W., Jamieson, N. B., Park, J. H., Roseweir, A. K., and Edwards, J. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | Journal of Experimental and Clinical Cancer Research |
| Publisher: | BioMed Central |
| ISSN: | 1756-9966 |
| ISSN (Online): | 1756-9966 |
| Copyright Holders: | Copyright © The Author(s) 2024 |
| First Published: | First published in Journal of Experimental and Clinical Cancer Research 43:64 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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