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Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability.

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Title: Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability.
Authors: Huang, Miao1,2 (AUTHOR), Chen, Yinong1,2,3 (AUTHOR), Liang, Chenyu1,2 (AUTHOR), Narayan, Om Prakash1,4 (AUTHOR), Stallings, Chase5 (AUTHOR), Yu, Mu2,6 (AUTHOR), Traugot, Conner2,7 (AUTHOR), Li, Lu2,7 (AUTHOR), Li, Keming8 (AUTHOR), Vo, Quang5 (AUTHOR), Wang, Heyang9 (AUTHOR), Chou, Yu-Ting10,11,12 (AUTHOR), Cech, Lauren10,13 (AUTHOR), Parra, Daniel14 (AUTHOR), Garzon, Laura1 (AUTHOR), Parsons, Dylan5 (AUTHOR), Diaz, Emma15 (AUTHOR), Zhang, Cunyu16,17,18 (AUTHOR), Mackey, Cole7 (AUTHOR), Sussman, Hayley19 (AUTHOR)
Source: Biomaterials. Jun2026, Vol. 329, pN.PAG-N.PAG. 1p.
Subjects: Drug resistance, Mechanotransduction (Cytology), Tumor treatment, YAP signaling proteins, Non-small-cell lung carcinoma, Treatment effectiveness, Cancer cells
Abstract: Drug resistance is a leading cause of cancer treatment failure and tumor recurrence. Identifying new methods that eliminate life-threatening drug-resistant cancer cells (DRCs) can enhance tumor cell eradication and improve patient outcomes. Here we report that human non-small cell lung cancer (NSCLC) DRCs show previously unrecognized increased sensitivity to mechanical stimuli compared to drug-susceptible lung cancer cells (DSCs) in vitro. Exploiting this heightened mechanical sensitivity, the combination of physiologically soft culture microenvironment with targeted therapies reduces the survival of DRCs through regulating yes-associated-protein (YAP) translocation between nucleus and cytoplasm. Our clinical studies confirm that DRCs possess heightened YAP nuclear localization in both NSCLC patient-derived organoid models and patient tissues, indicating high potential of eradicating DRCs by mechanical stimuli in vivo. Further, our mechanistic analyses, including quantitative imaging, transcriptomic profiling, and pharmacological evaluations reveal that the alterations in nuclear force sensing, rather than actomyosin contractility or Hippo-YAP pathway activation in DRCs, primarily drive the heightened YAP mechanosensitivity. This work highlights the crucial difference in mechanosensitivity between DRCs and DSCs, and points to mechanobiological targeting of these cells as a novel strategy to overcome drug resistance and enhance cancer therapy. [ABSTRACT FROM AUTHOR]
Copyright of Biomaterials is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
FullText Text:
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Header DbId: egs
DbLabel: Engineering Source
An: 191268091
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
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  Data: Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability.
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  Data: <searchLink fieldCode="AR" term="%22Huang%2C+Miao%22">Huang, Miao</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chen%2C+Yinong%22">Chen, Yinong</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liang%2C+Chenyu%22">Liang, Chenyu</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Narayan%2C+Om+Prakash%22">Narayan, Om Prakash</searchLink><relatesTo>1,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Stallings%2C+Chase%22">Stallings, Chase</searchLink><relatesTo>5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yu%2C+Mu%22">Yu, Mu</searchLink><relatesTo>2,6</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Traugot%2C+Conner%22">Traugot, Conner</searchLink><relatesTo>2,7</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Li%2C+Lu%22">Li, Lu</searchLink><relatesTo>2,7</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Li%2C+Keming%22">Li, Keming</searchLink><relatesTo>8</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Vo%2C+Quang%22">Vo, Quang</searchLink><relatesTo>5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Heyang%22">Wang, Heyang</searchLink><relatesTo>9</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chou%2C+Yu-Ting%22">Chou, Yu-Ting</searchLink><relatesTo>10,11,12</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cech%2C+Lauren%22">Cech, Lauren</searchLink><relatesTo>10,13</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Parra%2C+Daniel%22">Parra, Daniel</searchLink><relatesTo>14</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Garzon%2C+Laura%22">Garzon, Laura</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Parsons%2C+Dylan%22">Parsons, Dylan</searchLink><relatesTo>5</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Diaz%2C+Emma%22">Diaz, Emma</searchLink><relatesTo>15</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Cunyu%22">Zhang, Cunyu</searchLink><relatesTo>16,17,18</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mackey%2C+Cole%22">Mackey, Cole</searchLink><relatesTo>7</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sussman%2C+Hayley%22">Sussman, Hayley</searchLink><relatesTo>19</relatesTo> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Biomaterials%22">Biomaterials</searchLink>. Jun2026, Vol. 329, pN.PAG-N.PAG. 1p.
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  Data: <searchLink fieldCode="DE" term="%22Drug+resistance%22">Drug resistance</searchLink><br /><searchLink fieldCode="DE" term="%22Mechanotransduction+%28Cytology%29%22">Mechanotransduction (Cytology)</searchLink><br /><searchLink fieldCode="DE" term="%22Tumor+treatment%22">Tumor treatment</searchLink><br /><searchLink fieldCode="DE" term="%22YAP+signaling+proteins%22">YAP signaling proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Non-small-cell+lung+carcinoma%22">Non-small-cell lung carcinoma</searchLink><br /><searchLink fieldCode="DE" term="%22Treatment+effectiveness%22">Treatment effectiveness</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+cells%22">Cancer cells</searchLink>
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  Label: Abstract
  Group: Ab
  Data: Drug resistance is a leading cause of cancer treatment failure and tumor recurrence. Identifying new methods that eliminate life-threatening drug-resistant cancer cells (DRCs) can enhance tumor cell eradication and improve patient outcomes. Here we report that human non-small cell lung cancer (NSCLC) DRCs show previously unrecognized increased sensitivity to mechanical stimuli compared to drug-susceptible lung cancer cells (DSCs) in vitro. Exploiting this heightened mechanical sensitivity, the combination of physiologically soft culture microenvironment with targeted therapies reduces the survival of DRCs through regulating yes-associated-protein (YAP) translocation between nucleus and cytoplasm. Our clinical studies confirm that DRCs possess heightened YAP nuclear localization in both NSCLC patient-derived organoid models and patient tissues, indicating high potential of eradicating DRCs by mechanical stimuli in vivo. Further, our mechanistic analyses, including quantitative imaging, transcriptomic profiling, and pharmacological evaluations reveal that the alterations in nuclear force sensing, rather than actomyosin contractility or Hippo-YAP pathway activation in DRCs, primarily drive the heightened YAP mechanosensitivity. This work highlights the crucial difference in mechanosensitivity between DRCs and DSCs, and points to mechanobiological targeting of these cells as a novel strategy to overcome drug resistance and enhance cancer therapy. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Biomaterials is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=191268091
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      – Type: doi
        Value: 10.1016/j.biomaterials.2025.123920
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      – Code: eng
        Text: English
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        StartPage: N.PAG
    Subjects:
      – SubjectFull: Drug resistance
        Type: general
      – SubjectFull: Mechanotransduction (Cytology)
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      – SubjectFull: Tumor treatment
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      – SubjectFull: YAP signaling proteins
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      – SubjectFull: Non-small-cell lung carcinoma
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      – SubjectFull: Treatment effectiveness
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      – SubjectFull: Cancer cells
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              Text: Jun2026
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