The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy

Scherz-Shouval, Ruth; Santagata, Sandro; Mendillo, Marc L.; Sholl, Lynette M.; Ben‐Aharon, Irit; Beck, Andrew H.; Dias‐Santagata, Dora; Koeva, Martina; Stemmer, Salomon M.; Whitesell, Luke; Lindquist, Susan

doi:10.1016/j.cell.2014.05.045

Cited by 321 publications

(314 citation statements)

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“…In addition, we complemented the candidate list with Il6 and Lif, 2 members of IL-6 family that were upregulated in our RNA-seq analysis and are known activators of the JAK/STAT pathway. Further, we included Tgfb1, downreg ulated in PJS tumors and Lkb1-deficient fibroblasts (6,26) and Cxcl12 (Sdf1), described to promote tumorigenesis through secretion from cancer-associated fibroblasts (CAFs) (27). The list of candidate paracrine factors included in further studies is given in Table 1.…”

Section: ;Ampka2mentioning

confidence: 99%

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

Ollila¹,

Domènech-Moreno²,

Laajanen³

et al. 2017

Journal of Clinical Investigation

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Section: ;Ampka2mentioning

confidence: 99%

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

Ollila¹,

Domènech-Moreno²,

Laajanen³

et al. 2017

Journal of Clinical Investigation

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“…HSF1 has been additionally implicated in promoting the oncogenic state of diverse human cancers through its ability to activate a novel set of genes (34)(35)(36). Interestingly, human heat shock factor 2 (HSF2) (a paralogue of HSF1) can functionally substitute for its yeast counterpart (37), underscoring the strong conservation of the protein.…”

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confidence: 99%

Evidence for Multiple Mediator Complexes in Yeast Independently Recruited by Activated Heat Shock Factor

Anandhakumar

Moustafa

Chowdhary

et al. 2016

Molecular and Cellular Biology

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Mediator is an evolutionarily conserved coactivator complex essential for RNA polymerase II transcription. Although it has been generally assumed that in Saccharomyces cerevisiae, Mediator is a stable trimodular complex, its structural state in vivo remains unclear. Using the "anchor away" (AA) technique to conditionally deplete select subunits within Mediator and its reversibly associated Cdk8 kinase module (CKM), we provide evidence that Mediator's tail module is highly dynamic and that a subcomplex consisting of Med2, Med3, and Med15 can be independently recruited to the regulatory regions of heat shock factor 1 (Hsf1)-activated genes. Fluorescence microscopy of a scaffold subunit (Med14)-anchored strain confirmed parallel cytoplasmic sequestration of core subunits located outside the tail triad. In addition, and contrary to current models, we provide evidence that Hsf1 can recruit the CKM independently of core Mediator and that core Mediator has a role in regulating postinitiation events. Collectively, our results suggest that yeast Mediator is not monolithic but potentially has a dynamic complexity heretofore unappreciated. Multiple species, including CKM-Mediator, the 21-subunit core complex, the Med2-Med3-Med15 tail triad, and the foursubunit CKM, can be independently recruited by activated Hsf1 to its target genes in AA strains.

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“…The rub is that an important normal function of HSP90 is to bind the stress-responsive transcription factor heatshock factor 1 (HSF1) and repress its activities. High levels of HSP90 inhibition, therefore, activate HSF1, which has recently emerged as a powerful enabler of malignancy in both cancer cells and the stromal cells that support them (14,15).Ironically, the biomarker that has been most broadly used in clinical trials to verify that high, oncoprotein-depleting levels of HSP90 inhibition have been achieved is the increased expression of HSP70. Because HSP70 expression is regulated by HSF1, it serves as a surrogate marker for the activation of this factor (16,17).…”

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HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Whitesell

Santagata

Mendillo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The efficacy of hormonal therapies for advanced estrogen receptorpositive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.estrogen receptor | antiestrogen | drug resistance | tumor progression | tamoxifen D rastically limiting the efficacy of targeted therapeutics, the emergence of drug resistance in advanced cancers remains nearly inevitable. From yeast to vertebrates, the molecular chaperone heat shock protein 90 (HSP90) allows organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs and environmental stressors (1, 2). It does so by regulating the folding of a highly diverse portfolio of metastable client proteins, many mediating adaptive responses (3, 4).However, this role for HSP90 in adaptation is greatly magnified by its ability to promote the evolution of heritable new traits. To buffer the proteome against unexpected environmental challenges, HSP90 is present in large excess under normal circumstances. This buffering capacity allows it to modulate the manifestation of preexisting and newly acquired genetic variation within heterogeneous populations of cells, and even whole organisms, thereby dramatically expanding the range of phenotypes on which selection can act (1, 2, 5-7). As a dramatic, therapeutically relevant example, we have shown that this HSP90 buffer enables fungal pathogens spanning ∼1 billion years of evolution to evolve and maintain resistance to every major a...

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The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy

Cited by 321 publications

References 50 publications

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

Evidence for Multiple Mediator Complexes in Yeast Independently Recruited by Activated Heat Shock Factor

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

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