Radiation therapy with phenotypic medicine: towards N-of-1 personalizationChong, Li Ming; Wang, Peter; Lee, V. Vien; Vijayakumar, Smrithi; Tan, Hong Qi; Wang, Fu Qiang; Yeoh, Teri Danielle You Ying; Truong, Anh T. L.; Tan, Lester Wen Jeit; Tan, Shi Bei; Senthil Kumar, Kirthika; Hau, Eric; Vellayappan, Balamurugan A.; Blasiak, Agata; Ho, Dean
doi: 10.1038/s41416-024-02653-3pmid: 38514762
In current clinical practice, radiotherapy (RT) is prescribed as a pre-determined total dose divided over daily doses (fractions) given over several weeks. The treatment response is typically assessed months after the end of RT. However, the conventional one-dose-fits-all strategy may not achieve the desired outcome, owing to patient and tumor heterogeneity. Therefore, a treatment strategy that allows for RT dose personalization based on each individual response is preferred. Multiple strategies have been adopted to address this challenge. As an alternative to current known strategies, artificial intelligence (AI)-derived mechanism-independent small data phenotypic medicine (PM) platforms may be utilized for N-of-1 RT personalization. Unlike existing big data approaches, PM does not engage in model refining, training, and validation, and guides treatment by utilizing prospectively collected patient’s own small datasets. With PM, clinicians may guide patients’ RT dose recommendations using their responses in real-time and potentially avoid over-treatment in good responders and under-treatment in poor responders. In this paper, we discuss the potential of engaging PM to guide clinicians on upfront dose selections and ongoing adaptations during RT, as well as considerations and limitations for implementation. For practicing oncologists, clinical trialists, and researchers, PM can either be implemented as a standalone strategy or in complement with other existing RT personalizations. In addition, PM can either be used for monotherapeutic RT personalization, or in combination with other therapeutics (e.g. chemotherapy, targeted therapy). The potential of N-of-1 RT personalization with drugs will also be presented.
FGFR4-driven plasticity in breast cancer progression and resistance to therapyBraun, Marcin; Piasecka, Dominika; Sadej, Rafal; Romanska, Hanna M.
doi: 10.1038/s41416-024-02658-ypmid: 38627607
Breast cancer (BCa) is a complex and heterogeneous disease, with different intrinsic molecular subtypes that have distinct clinical outcomes and responses to therapy. Although intrinsic subtyping provides guidance for treatment decisions, it is now widely recognised that, in some cases, the switch of the BCa intrinsic subtype (which embodies cellular plasticity), may be responsible for therapy failure and disease progression. Aberrant FGFR4 signalling has been implicated in various cancers, including BCa, where it had been shown to be associated with aggressive subtypes, such as HER2-enriched BCa, and poor prognosis. More importantly, FGFR4 is also emerging as a potential driver of BCa intrinsic subtype switching, and an essential promoter of brain metastases, particularly in the HER2-positive BCa. Although the available data are still limited, the findings may have far-reaching clinical implications. Here, we provide an updated summary of the existing both pre- and clinical studies of the role of FGFR4 in BCa, with a special focus on its contribution to subtype switching during metastatic spread and/or induced by therapy. We also discuss a potential clinical benefit of targeting FGFR4 in the development of new treatment strategies.
Epithelial−mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancerJeong, Hyein; Koh, Jaemoon; Kim, Sehui; Song, Seung Geun; Lee, Soo Hyun; Jeon, Youngjoo; Lee, Chul-Hwan; Keam, Bhumsuk; Lee, Se-Hoon; Chung, Doo Hyun; Jeon, Yoon Kyung
doi: 10.1038/s41416-024-02698-4pmid: 38729997
BackgroundWe investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial−mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy.MethodsPD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed.ResultsRNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-β (TGFβ). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFβ production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration.ConclusionsTumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.
Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent mannerLee, Peter W. T.; Suwa, Tatsuya; Kobayashi, Minoru; Yang, Hui; Koseki, Lina R.; Takeuchi, Satoshi; Chow, Christalle C. T.; Yasuhara, Takaaki; Harada, Hiroshi
doi: 10.1038/s41416-024-02691-xpmid: 38740970
BackgroundCancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear.MethodsHere, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynamics and cellular motility, as a responsible factor and elucidated its mechanism of action using molecular and cellular biology techniques.ResultsHMHA1 expression was found to be induced at the transcription initiation level in a HIF-dependent manner under hypoxia. Boyden chamber invasion assay revealed that the induction of HMHA1 expression is required for the increase in invasion of hypoxic cancer cells. Reoxygenation treatment after ionising radiation in vitro that mimics dynamic changes of a microenvironment in hypoxic regions of tumour tissues after radiation therapy further enhanced HMHA1 expression and invasive potential of HMHA1 wildtype cancer cells in ROS- and HIF-dependent manners, but not of HMHA1 knockout cells.ConclusionThese results together provide insights into a potential molecular mechanism of the acquisition of invasiveness by hypoxic cancer cells after radiotherapy via the activation of the ROS/HIF/HMHA1 axis.
Nuclear factor-κB activation by transforming growth factor-β1 drives tumour microenvironment-mediated drug resistance in neuroblastomaLouault, Kévin; Blavier, Laurence; Lee, Men-Hua; Kennedy, Rebekah J.; Fernandez, G. Esteban; Pawel, Bruce R.; Asgharzadeh, Shahab; DeClerck, Yves A.
doi: 10.1038/s41416-024-02686-8pmid: 38806726
BackgroundIntrinsic and extrinsic factors in the tumour microenvironment (TME) contribute to therapeutic resistance. Here we demonstrate that transforming growth factor (TGF)-β1 produced in the TME increased drug resistance of neuroblastoma (NB) cells.MethodsHuman NB cell lines were tested in vitro for their sensitivity to Doxorubicin (DOX) and Etoposide (ETOP) in the presence of tumour-associated macrophages (TAM) and mesenchymal stromal cells/cancer-associated fibroblasts (MSC/CAF). These experiments were validated in xenotransplanted and primary tumour samples.ResultsDrug resistance was associated with an increased expression of efflux transporter and anti-apoptotic proteins. Upregulation was dependent on activation of nuclear factor (NF)-κB by TGF-β-activated kinase (TAK1) and SMAD2. Resistance was reversed upon pharmacologic and genetic inhibitions of NF-κB, and TAK1/SMAD2. Interleukin-6, leukaemia inhibitory factor and oncostatin M were upregulated by this TGF-β/TAK1/NF-κB/SMAD2 signalling pathway contributing to drug resistance via an autocrine loop activating STAT3. An analysis of xenotransplanted NB tumours revealed an increased presence of phospho (p)-NF-κB in tumours co-injected with MSC/CAF and TAM, and these tumours failed to respond to Etoposide but responded if treated with a TGF-βR1/ALK5 inhibitor. Nuclear p-NF-κB was increased in patient-derived tumours rich in TME cells.ConclusionsThe data provides a novel insight into a targetable mechanism of environment-mediated drug resistance.[graphic not available: see fulltext]