Cancers最新文献

{"title":"Correction: Schöbel et al. Non-Cisplatin Concurrent Systemic Therapy with Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Network Meta-Analysis of Randomized Clinical Trials. <i>Cancers</i> 2026, <i>18</i>, 1599.","authors":"Katharina Sophie Schöbel, Anne-Josephin Schoele, Georg Wurschi, Klaus Pietschmann, Maximilian Römer","doi":"10.3390/cancers18213466","DOIUrl":"10.3390/cancers18213466","url":null,"abstract":"<p><p>There was an error in the original publication [...].</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 21","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13727366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149318415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Stereotactic Body Radiation Therapy: Expanding Clinical Applications and Improving Treatment Precision.","authors":"Michael D Chuong, Sam Beddar","doi":"10.3390/cancers18203402","DOIUrl":"10.3390/cancers18203402","url":null,"abstract":"<p><p>Stereotactic body radiation therapy (SBRT), also referred to as stereotactic ablative radiotherapy (SABR), was pioneered at the Karolinska Institute in Sweden in the early 1990s, extending the principles of intracranial stereotactic radiosurgery (SRS) to extracranial tumors [...].</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salvage Surgery with Intraoperative Electron Radiation Therapy for Recurrent or Persistent Head and Neck Cancer After Prior Radiotherapy.","authors":"Ahmed N Elguindy, Sujith Baliga, Brett G Klamer, Allison Palmiero, Khaled N Dibs, Andrew Koempel, Emile Gogineni, David Konieczkowski, Darrion L Mitchell, Nolan Seim, Kyle VanKoevering, Catherine Haring, Lauren Miller, Stephen Y Kang, Amit Agrawal, Enver Ozer, James W Rocco, Ricardo L Carrau, Matthew Old, Marcelo Bonomi, Priyanka Bhateja, Arnab Chakravarti, John Grecula, Dukagjin M Blakaj","doi":"10.3390/cancers18203399","DOIUrl":"10.3390/cancers18203399","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Locoregionally recurrent or persistent head and neck cancer (rpHNC) after prior radiotherapy carries a poor prognosis, and optimal salvage strategies remain uncertain. We evaluated survival, patterns of failure, and 90-day postoperative complications after salvage surgery combined with intraoperative electron radiation therapy (IOERT). <b>Methods:</b> We retrospectively identified 127 previously irradiated patients treated with salvage surgery and IOERT between 1999 and 2023. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and locoregional failure (LRF) and distant failure were estimated using Aalen-Johansen cumulative incidence with death as a competing event. Associations were evaluated one predictor at a time in age- and sex-adjusted Cox (OS, DFS) and Fine-Gray (LRF) models without multiplicity adjustment, and they are exploratory. <b>Results:</b> With a median follow-up of 70 months, median overall survival (OS) was 20.5 months (95% CI, 14.6-40.2), with 1-, 2-, and 3-year OS rates of 63%, 48%, and 43%, respectively. Median disease-free survival (DFS) was 8.8 months. Positive surgical margins and extranodal extension (ENE) were associated with worse OS in separate age- and sex-adjusted models. The 1-, 2-, and 3-year cumulative incidences of LRF were 34.3%, 44.7%, and 49.8%, respectively. The corresponding cumulative incidences of distant failure were 21.6%, 24.0%, and 26.7%, respectively. Thirty-seven patients had a documented distant failure, of whom 27 (73%) experienced distant failure within one year. Available records documented three deaths within 90 days (3/127, 2.4%). <b>Conclusions:</b> Among rpHNC patients treated with this IOERT-containing multimodality salvage strategy, median OS was 20.5 months. Because the study lacked a salvage-surgery-only comparator, postoperative treatments were selectively administered, and complication reporting was incomplete, neither the efficacy nor the comparative safety of IOERT can be determined from these data.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal Hematopoiesis Across the Cancer Treatment Continuum: A Scoping Review of Clonal Selection, Evolution, and Clinical Outcomes.","authors":"Abdullah M AlShahrani","doi":"10.3390/cancers18203398","DOIUrl":"10.3390/cancers18203398","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Clonal hematopoiesis (CH) is characterized by the proliferation of blood cell clones that possess acquired genetic modifications. While therapy-related CH refers to CH detected in the setting of prior or current treatment in cancer populations, therapy-selected CH demands demonstration that treatment preferentially expanded or maintained an extant clone; therapy-induced CH requires evidence of de novo treatment-associated mutation supported by serial sampling and mutational-signature analyses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To map evidence distinguishing therapy-related, therapy-selected and therapy-induced CH across cancer treatment, including clonal dynamics, genomic features, clinical outcomes and surveillance gaps.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidance, PubMed/MEDLINE, Embase, Scopus, Web of Science Core Collection, Cochrane Library and Google Scholar were searched from inception through 1 June 2026, and updated on 15 September 2026. Primary evidence mapping was limited to original human studies. Reviews and conceptual sources were used only for context or reference tracking and were ineligible for the primary evidence map. Narrative synthesis was employed as critical variation existed in sequencing platforms, variant allele frequency thresholds, timepoints of sampling, filtering strategies, and outcome definitions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of 684 records identified, 213 duplicates were removed and 471 records were screened. Across both pathways, 121 full texts were assessed, 87 excluded and 34 primary reports mapped; contextual citations were outside the included set. Contextual references were used for definitions and interpretation and were excluded from the included-report count. Six domains were deductively established and inductively refined during charting: terminology; therapy-associated mechanisms of clonal selection/expansion; genomic architecture; longitudinal clonal dynamics; clinical consequences; and study design and methodological heterogeneity. Treatment-associated selection or expansion of pre-existing TP53 and PPM1D clones was the most consistently reported mechanism of therapy-related CH, while CHEK2 was inconsistently detected. Pediatric cohorts and mutational-signature analyses also supported de novo mutagenesis with therapy in select contexts. Progression to therapy-related myeloid neoplasm was the most consistent outcome across studies; however, cytopenia, CAR-T-therapy-associated toxicity, cardiovascular events and mortality were inconsistently reported.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Current evidence supports a spectrum of mechanisms ranging from selection of pre-existing clones to therapy-induced de novo mutation. Existing literature cannot support universal CH screening recommendations or guide treatment decisions. Prospective serial analyses harmoni","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Significance of Amino Acid Transporters in Endometrial Cancer.","authors":"Mikołaj Piotr Zaborowski, Łukasz Ciecierski, Piotr Tyburski, Magdalena Nadolna, Marta Brygida Szczygieł, Jędrzej Sikora, Mateusz Szot, Stefan Malewski, Marcin Iwanicki, Kinga Piątek-Bajan, Jarosław Lewandowski, Cezary Miedziarek, Michał Potograbski, Nikodem Horst, Ewa Nowak-Markwitz","doi":"10.3390/cancers18203404","DOIUrl":"10.3390/cancers18203404","url":null,"abstract":"<p><p><b>Background:</b> Identification of high-risk patients with endometrial cancer (EC) remains challenging despite advances in molecular profiling. <b>Methods:</b> We comprehensively analyzed the RNA expression of 18 amino acid transporters (AATs) in 373 EC samples from The Cancer Genome Atlas (TCGA). <b>Results:</b> Our clustering analysis based on AAT expression identified a patient group with a significantly worse prognosis. Sideroflexin family (SFXN1, SFXN5), glutamine (SLC38A1, SLC38A3), glycine (SLC6A9) transporters, and the heavy-chain subunit of heteromeric AATs (SLC3A2) were elevated in poorly differentiated tumors. In contrast, the transporter of small neutral amino acids (SLC1A4) and proline/imino-acid transporter (SLC6A20) were enriched in lower-grade disease. SFXN1 and SLC38A1 were also higher in advanced (III/IV) FIGO stages. AAT expression differed across molecular subtypes, with SFXN5, SLC38A1, SLC38A3, and SLC3A2 associated with the copy-number-high profile. In survival analysis, we demonstrated that SLC38A3, SFXN4, and SLC3A2 were associated with shorter disease-free survival, and SLC38A1, SLC38A3, and SFXN1 with worse overall survival, whereas SLC1A4, SLC6A20, and the taurine transporter (SLC6A6) were related to favorable outcomes. <b>Conclusions:</b> These findings highlight AAT expression as a potential marker of EC aggressiveness and prognosis and suggest that integrating metabolic features with molecular classification may improve risk stratification and identify potential therapeutic targets.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13703075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optic Nerve Sheath Meningiomas: A Narrative Review of Clinical Features, Imaging Advances, and Current Management.","authors":"Nima Sadeghi, Kamil Laban, Peerooz Saeed","doi":"10.3390/cancers18203405","DOIUrl":"10.3390/cancers18203405","url":null,"abstract":"<p><p>Optic nerve sheath meningioma (ONSM) is a rare orbital tumor that can pose a significant threat to visual function due to its close relationship with the optic nerve and surrounding vascular structures. Early and accurate diagnosis is essential to preserve vision and guide individualized management. The objective of this narrative review is to provide a comprehensive overview of the current evidence on the clinical presentation, diagnostic evaluation, imaging characteristics, and management of ONSM, with a particular focus on recent advances in imaging techniques and their implications for clinical decision-making. This review synthesizes current knowledge on clinical presentation, diagnostic workup, and evolving treatment strategies for ONSM, with particular emphasis on advanced imaging modalities. Magnetic resonance imaging remains the cornerstone of diagnosis, yet functional imaging, especially somatostatin receptor--based techniques such as 68GaDOTATATE PET/CT have shown potential as a useful adjunct in the diagnostic evaluation of ONSM, especially for assessing tumor characteristics, extent, and treatment planning in selected cases. We discuss the emerging role of DOTATATE imaging in differentiating ONSM from other optic nerve and orbital pathologies, as well as its potential application in monitoring therapeutic response. We also highlight contemporary management approaches, including fractionated radiotherapy and the selective role of surgical intervention, underscoring the importance of multidisciplinary decision-making in optimizing visual outcomes. Emerging molecular insights from meningioma research may inform future therapeutic strategies for ONSM; however, clinical evidence specific to ONSM remains limited.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Challenges in Triple-Negative Breast Cancer (TNBC): Current Treatment Options, Their Limitations, and Emerging Perspectives.","authors":"Rubismita Deka, Thiyam Ramsing Singh","doi":"10.3390/cancers18203403","DOIUrl":"10.3390/cancers18203403","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is characterised by the absence of expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Compared with other breast cancer subtypes, TNBC is generally associated with a more aggressive clinical course, in part because of its marked molecular heterogeneity. Consequently, the availability of effective targeted therapies remains limited. Chemotherapy continues to be a major component of treatment, although its clinical benefit may be constrained by toxicity and the development of drug resistance. This review examines the principal clinical challenges in TNBC, evaluates currently available therapeutic approaches and their limitations, and discusses important areas that remain insufficiently addressed. Particular emphasis is placed on recent advances in emerging treatment strategies. Together, these developments may improve our understanding of TNBC and support future research towards more precise and personalised therapeutic approaches.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149262965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appetite Loss in Metastatic Cancer: Insights from Clinical and Inflammatory Markers Observed Longitudinally.","authors":"Ragnhild Habberstad, Ola Magne Vagnildhaug, Trude Rakel Balstad, Øyvind Salvesen, Erik Torbjørn Løhre, Asta Bye, Olav Dajani, Nina Aass, Stein Kaasa, Pål Klepstad, Tora S Solheim","doi":"10.3390/cancers18203407","DOIUrl":"10.3390/cancers18203407","url":null,"abstract":"<p><strong>Background: </strong>Inflammation is suggested to play a central role in cancer-related appetite loss, yet the available evidence remains limited.</p><p><strong>Methods: </strong>This study analyzed data from a prospective, longitudinal, multicenter study of patients with metastatic cancer followed for one year. The longitudinal associations between appetite loss and both clinical characteristics and inflammatory markers were examined. Logistic generalized equation model (GEE) was used.</p><p><strong>Results: </strong>Among 526 patients, 299 (57%) experienced appetite loss at baseline. During longitudinal observation appetite loss was associated with older age (OR 1.19, CI 1.01-1.39 as per 10-year years increase), poorer performance status (OR 0.85, CI 0.77-0.94), recent weight loss (OR 2.74, CI 2.11-3.56), and symptoms including constipation, nausea, fatigue, and lower emotional functioning. Corticosteroid use was associated with lower risk of appetite loss (OR 0.69, CI 0.53-0.90). Several inflammatory markers were also associated with appetite loss, including IL-8, IP-10, IL-6, CRP, eotaxin, albumin.</p><p><strong>Conclusions: </strong>Appetite loss in metastatic cancer is linked to clinical factors, symptom burden, and inflammatory markers. Optimizing symptom management and targeting inflammation might have a positive impact.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implant-Based Versus Autologous Reconstruction After Salvage Mastectomy for Ipsilateral Breast Tumor Recurrence in the Previously Irradiated Breast: A Consecutive Institutional Series and a Proposed Autologous-First Algorithm.","authors":"Jongmoo Park, Woosung Jang, Myeong Jae Kang, Sung Joon Kim, Byoung-Soo Ko, In Hee Lee, Joon Suk Moon, Byeongju Kang, Jeeyeon Lee, Ho Yong Park, Jeong Yeop Ryu, Kang Young Choi, Jung Dug Yang, Ho Yun Chung, Joon Seok Lee","doi":"10.3390/cancers18203409","DOIUrl":"10.3390/cancers18203409","url":null,"abstract":"<p><p><b>Background:</b> In postmastectomy radiotherapy, radiation reaches an already-reconstructed breast, and implant-based reconstruction remains feasible in selected patients. Far less studied is reconstruction within a previously irradiated field: after breast-conserving therapy, ipsilateral breast tumor recurrence (IBTR), and salvage mastectomy. We compared implant-based and autologous reconstruction in this setting and propose a hypothesis-generating treatment algorithm. <b>Methods:</b> From 2219 consecutive breast reconstructions (2012-2026), we cross-matched implant-removal, radiotherapy, and local-recurrence registries to identify all immediate total reconstructions of a previously irradiated breast after salvage mastectomy for IBTR (<i>n</i> = 13; 8 implant-based [all stand-alone, without vascularized flap coverage], 5 autologous [all latissimus dorsi-based]). The primary endpoint was reconstruction failure, defined in a modality-neutral manner as definitive loss or abandonment of the reconstruction; implant-based reconstructions of breasts not previously irradiated at the time of reconstruction (<i>n</i> = 689) served as a descriptive institutional reference cohort. <b>Results:</b> Seven of eight implants (87.5%) were removed at 3 to 51 months; the single retained implant has a persistent wound; none achieved complication-free success. Failure modes comprised early envelope necrosis, periprosthetic infection, and late attritional failure; chronic retained-capsule seroma followed removal without capsulectomy. All five autologous reconstructions healed without failure or unplanned reoperation (reconstruction failure, 7/8 [87.5%; 95% CI, 47.3-99.7%] vs. 0/5 [0%; 95% CI, 0-52.2%], <i>p</i> = 0.005; log-rank <i>p</i> = 0.039; median follow-up, 32.0 vs. 10.9 months; failure or major complication, 8/8 vs. 0/5, <i>p</i> = 0.0008). The implant-removal rate also exceeded that of the institutional reference cohort (87.5% vs. 11.2%; unadjusted, descriptive comparison). <b>Conclusions:</b> In this small consecutive series, stand-alone implant-based reconstruction of the previously irradiated breast was associated with a very high failure rate, whereas reconstruction importing well-vascularized autologous tissue healed in every case, a pattern biologically consistent with chronic radiation injury. These findings constitute a strong cautionary signal rather than definitive evidence. Our findings support an autologous-first approach after salvage mastectomy of the irradiated breast; stand-alone implant-based reconstruction should be offered only to carefully selected, fully counseled patients, and the proposed algorithm requires external validation.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-Dependent Spatial and Functional Roles of CD44 Across Pancreatic Ductal Adenocarcinoma States.","authors":"Bin Fu, Yingying Tan, Yaxin Chen, Yongren Su, Mengran Cao, Dashan Tan, Meng Zhang, Xuewei Chen, Rong Hu","doi":"10.3390/cancers18203410","DOIUrl":"10.3390/cancers18203410","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Pancreatic ductal adenocarcinoma (PDAC) comprises distinct cellular states characterized by different differentiation programs and therapeutic responses. How a cell-surface receptor adapts its function across these states remains poorly understood. Here, we investigated whether the spatial organization and functional output of CD44 vary across PDAC cellular states. <b>Methods</b>: CD44 expression and spatial distribution were examined in human PDAC tissues and PDAC cell models representing different differentiation states. The functional roles of CD44 were investigated using genetic depletion, transcriptomic analysis, migration and invasion assays, and xenograft and orthotopic models. Hyaluronan (HA) responsiveness and downstream signaling were assessed following exogenous HA stimulation, and the therapeutic effects of HA synthesis inhibition with 4-methylumbelliferone (4-MU) were evaluated alone or in combination with gemcitabine. <b>Results</b>: In differentiated PDAC tissues and classical PDAC models, CD44 was predominantly localized to the basolateral membrane and spatially segregated from E-cadherin at cell-cell junctions, consistent with a role in epithelial organization and cell-matrix interactions. In contrast, poorly differentiated PDAC tissues and basal-like models exhibited increased CD44 abundance, E-cadherin loss, and redistribution of CD44 along the cell periphery. Genetic depletion of <i>CD44</i> preferentially impaired malignant phenotypes in basal-like models. Mechanistically, basal-like cells exhibited enhanced CD44-dependent responsiveness to extracellular HA, accompanied by activation of EMT-associated signaling and destabilization of E-cadherin. Inhibition of HA synthesis with 4-MU preferentially suppressed basal-like PDAC models and enhanced gemcitabine sensitivity, with these effects further supported in orthotopic models. <b>Conclusions</b>: These findings suggest that the functional output of CD44 in PDAC is influenced not only by its expression level but also by cellular context and spatial organization. The context-dependent responsiveness of the HA-CD44 axis may contribute to functional heterogeneity among PDAC states and represents a potential therapeutic vulnerability of basal-like PDAC.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"18 20","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13702738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}