Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Alexander, Jennifer I.; Vendramini–Costa, Débora Barbosa; Francescone, Ralph; Luong, Tiffany; Franco‐Barraza, Janusz; Shah, Neelima; Gardiner, Jaye C.; Nicolas, Émmanuelle; Raghavan, Kristopher S.; Cukierman, Edna

doi:10.1038/s41598-021-82937-3

Cited by 19 publications

(40 citation statements)

References 54 publications

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“…Importantly, we aim to report that eribulin also acts directly on CAFs and prompts these cells to generate an ECM that no longer effectively promotes PDAC cell invasive spread and has lost its ability to nurture PDAC cells under nutritional stress. Of note, the observed CAF-generated ECM functional shift, from tumor-supportive to tumor-suppressive, simulated reported results that were obtained with TGFβ deficient CAFs in our CDM system [15, 22, 33]. Hence, this study proposes that eribulin could be used as a stroma-normalizing agent.…”

Section: Introductionsupporting

confidence: 81%

“…To this end, β5 KO CAFs constitute an ideal human cellular model as these cells present with a phenotype and function akin to perpetuating TGFβ inhibition [15]. In fact, β5 KO CAFs have been reported to generate CDMs with tumor-suppressive functions and traits [15, 22, 33]. Using β5 KO CAFs, we previously demonstrated that canonical TGFβ signaling is necessary for the production of tumor-supportive ECMs.…”

Section: Discussionmentioning

confidence: 99%

“…CC-BY-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It To this end, our team previously developed an in vivo-like fibroblastic three-dimensional (3D) cell culturing system [27,28], and has adapted it for the use of PDAC patient-harvested CAFs [15,22,23,29]. This system can be used for assessing how drugs modulate CAF function, as well as how drug effects are altered by fibroblastic ECMs [28,30,31].…”

Section: Introductionmentioning

confidence: 99%

“…To this end, our team previously developed an in vivo -like fibroblastic three-dimensional (3D) cell culturing system [27, 28], and has adapted it for the use of PDAC patient-harvested CAFs [15, 22, 23, 29]. This system can be used for assessing how drugs modulate CAF function, as well as how drug effects are altered by fibroblastic ECMs [28, 30, 31].…”

Section: Introductionmentioning

confidence: 99%

“…Further, since pancreas resident fibroblastic cells, initially presenting with normal-like tumor-suppressive features, undergo an ex-vivo culturing stress-induced activation [32], our team previously used the CRISPR/Cas9 system to engineer β5-integrin deficient PADC CAFs (β5 KO ) [15]. These β5 KO CAFs, serve as “normalized” CAF controls [22, 33], as these cells perpetuate a phenotype that simulates TGFβ inhibition in CAFs [15] and constituted an important model used in this study. We herein report that CAF-generated ECMs protect PDAC cells by modestly hindering the effects of eribulin upon limiting tumor cell growth.…”

Section: Introductionmentioning

confidence: 99%

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Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating TGFβ inhibition

Luong

Cukierman

2022

Preprint

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Less than 11% of pancreatic cancer patients survive 5-years post-diagnosis. The unique biology of pancreatic cancer includes a significant expansion of its desmoplastic tumor microenvironment, wherein cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix are key components. CAF functions are both tumor-supportive and tumor-suppressive, while normal fibroblastic cells are solely tumor-suppressive. Knowing that CAF-eliminating drugs are ineffective and can accelerate cancer progression, therapies that normalize CAF function are highly pursued. Eribulin is a well-tolerated anti-microtubule drug used to treat a plethora of neoplasias, including advanced/metastatic cancers. Importantly, eribulin can inhibit epithelial to mesenchymal transition via a mechanism akin to blocking pathways induced by transforming growth factor-beta (TGFb). Notably, canonical TGFb signaling also plays a pivotal role in CAF activation, which is necessary for the development and maintenance of desmoplasia. Hence, we hypothesized that eribulin could modulate, and perhaps normalize CAF function. To test this premise, we used a well-established in vivo-mimetic fibroblastic cell-derived extracellular matrix (CDM) system and gauged the effects of eribulin on human pancreatic CAFs and cancer cells. The pathophysiologic cell-culturing system was also used to query eribulin effects on CDM-regulated cancer cell survival and invasive spread. Results demonstrated that intact CDMs modestly restricted eribulin from obstructing cancer cell growth. Nonetheless, eribulin-treated CAFs generated CDMs that limited cancer cell survival under nutritional stress, similar to reported tumor-suppressive CDMs generated by TGFb-deficient CAFs. Data from this study support the central proposed premise and suggest that eribulin could be used as a CAF-normalizing drug.

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Section: Introductionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating TGFβ inhibition

Luong

Cukierman

2022

Preprint

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miR96‐ and miR182‐driven regulation of cytoskeleton results in inhibition of glioblastoma motility

2023

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Glioblastoma multiforme (GBM) is one of the most common forms of brain tumor. As an excessively invasive tumor type, GBM cannot be fully cured due to its invasion ability into healthy brain tissues. Therefore, molecular mechanisms behind GBM migration and invasion need to be deeply investigated for the development of effective GBM treatments. Cellular motility and invasion are strictly associated with the cytoskeleton, especially with actins and tubulins. Palladin, an actin‐binding protein, tightly bundles actins during initial invadopodia and contraction fiber formations, which are essential for cellular motility. Spastin, a microtubule‐binding protein, cuts microtubules into small pieces and acts on invadopodia elongation and cellular trafficking of invadopodia‐associated proteins. Regulation of proteins such as spastin and palladin involved in dynamic reorganization of the cytoskeleton, are rapidly carried out by microRNAs at the posttranscriptional level. Therefore, determining possible regulatory miRNAs of spastin and palladin is critical to elucidate GBM motility. miR96 and miR182 down‐regulate SPAST and PALLD at both transcript and protein levels. Over‐expression of miR96 and miR182 resulted in inhibition of the motility. However, over‐expression of spastin and palladin induced the motility. Spastin and palladin rescue of miR96‐ or miR182‐transfected U251 MG cells resulted in diminished effects of the miRNAs and rescued the motility. Our results demonstrate that miR96 and miR182 over‐expressions inhibit GBM motility by regulating cytoskeleton through spastin and palladin. These findings suggest that miR96 and miR182 should be investigated in more detail for their potential use in GBM therapy.

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Exploring the potential role of palladin in modulating human CAF/ECM functional units

Dolskii,

Alcantara dos Santos,

Andrake

et al. 2024

Cytoskeleton

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Fibroblasts, crucial for maintaining tissue homeostasis, significantly shape the tumor microenvironment (TME). In pancreatic cancer, a highly aggressive malignancy, cancer‐associated fibroblast (CAF)/extracellular matrix (ECM) units dominate the TME, influencing tumor initiation, progression, and treatment responses. Palladin, an actin‐associated protein, is vital for fibroblast structural integrity and activation, playing a key role in CAF/ECM functionality. Palladin interacts with cytoskeletal proteins such as alpha‐actinin (α‐Act) and can therefore regulate other proteins like syndecans, modulating cytoskeletal features, cell adhesion, integrin recycling, and signaling. In this review, we propose that targeting the palladin/α‐Act/syndecan interaction network could modulate CAF/ECM units, potentially shifting the TME from a tumor‐promoting to a tumor‐suppressive state. In silico data and reported studies to suggest that stabilizing palladin‐α‐Act interactions, via excess palladin, influences syndecan functions; potentially modulating integrin endocytosis via syndecan engagement with protein kinase C alpha as opposed to syndecan binding to α‐Act. This mechanism can then affect the distribution of active α5β1‐integrin between the plasma membrane and known intracellular vesicular compartments, thereby influencing the tumor‐suppressive versus tumor‐promoting functions of CAF/ECM units. Understanding these interactions offers likely future therapeutic avenues for stroma normalization in pancreatic and other cancers, aiming to inhibit tumor progression and improve future treatment outcomes.

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Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Cited by 19 publications

References 54 publications

Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating TGFβ inhibition

Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating TGFβ inhibition

miR96‐ and miR182‐driven regulation of cytoskeleton results in inhibition of glioblastoma motility

Exploring the potential role of palladin in modulating human CAF/ECM functional units

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