Materials-driven approaches to understand extrinsic drug resistance in cancer

Pritchard, Justin R.; Lee, Michael J.; Peyton, Shelly R.

doi:10.1039/d2sm00071g

Cited by 2 publications

(2 citation statements)

References 103 publications

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“…Notably, most of these models have been capable of recapitulating tumor mass dormancy, whereby tumor masses are held in balance, with cell proliferation rate equal to cell death. As a result, some of these dormancy-inducing models have been tested with potential drugs (14,25,(34)(35)(36). Although tumor mass dormancy is one category of dormancy, it does not fully capture the functional phenotype of cellular dormancy of solitary DCCs.…”

Section: Introductionmentioning

confidence: 99%

“…Overcoming the limits of Matrigel as a standard in vitro model for drug screening ( 14 , 15 ), semi-synthetic biomaterial-based approaches have been previously pursued to generate bioengineered niches mimicking tissue-specific ECM. Biomaterial-based matrices have been shown to induce and/or preserve quiescence of astrocytes ( 16 ) and muscle stem cells ( 17 ), maintain neural progenitor ( 18 ) and hematopoietic cell stemness ( 19 ), investigate mechanical memory ( 20 ), differentiation of stem cells ( 21 ), as well as cancer cell cycle progression ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

Bakhshandeh

Taïeb

Varadarajan

et al. 2023

Preprint

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Resected tumors frequently relapse with distant metastasis, despite systemic treatment. Cellular quiescence has been identified as an important mechanism underlying such drug resistance enabling late relapse. Nonetheless, hurdles associated with detection and isolation of disseminated cancer cells (DCCs) in disease-free patients urge the need for in vitro models of quiescent cells suited for drug screening campaigns. Here, we explore a quiescence-inducing 3D-engineered matrix based on ultraviolet light-initiated thiol-ene-crosslinked alginate hydrogels, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domains 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the quiescence-inducing matrix became sensitive against chemotherapy upon FHL2 downregulation. Thus, our biomaterial-based approach will enable systematic screens for novel compounds suited to eradicate potentially relapsing, dormant cancer cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

Bakhshandeh

Taïeb

Varadarajan

et al. 2023

Preprint

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Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

Bakhshandeh,

Heras,

Taïeb

et al. 2024

Sci. Adv.

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Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERK low :P-p38 high dormancy signaling ratio, along with Ki67 − expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domain 2 (FHL2) protein, leading to p53-independent high p21 Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 down-regulation. Thus, our biomaterial-based approach will enable systematic screens for previously unidentified compounds suited to eradicate potentially relapsing dormant cancer cells.

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Materials-driven approaches to understand extrinsic drug resistance in cancer

Abstract: Early-stage cancers are often associated with high cure rates, but metastatic cancer has a poor prognosis because it is broadly disseminated and associated with both intrinsic and acquired drug resistance....

Cited by 2 publications

References 103 publications

Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

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