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

Ollila, Saara; Domènech-Moreno, Eva; Laajanen, Kaisa; Wong, Iris P.L.; Tripathi, Sushil; Pentinmikko, Nalle; Gao, Yajing; Yan, Yan; Niemelä, Elina H.; Wang, Yichen; Viollet, Benoı̂t; Leone, Gustavo; Katajisto, Pekka; Vaahtomeri, Kari; Mäkelä, Tomi P.

doi:10.1172/jci93597

Cited by 61 publications

(84 citation statements)

References 74 publications

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“…2i, j, Supplementary Fig 7). Together with published evidence for CAF specificity in FSP-Cre+mice 21,27 , our data support depletion of FAK in a subpopulation of CAFs in these FSP-Cre+;FAK fl/fl mice. FSP-Cre+;FAK fl/fl mice display increased breast and pancreatic cancer growth.…”

Section: Resultssupporting

confidence: 87%

Cancer associated fibroblast FAK regulates malignant cell metabolism

et al. 2020

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Emerging evidence suggests that cancer cell metabolism can be regulated by cancerassociated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.

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Section: Resultssupporting

confidence: 87%

Cancer associated fibroblast FAK regulates malignant cell metabolism

et al. 2020

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“…Moreover, the transcriptome analysis of PTEN-inactivated fibroblasts shows a strong correlation with breast CAFs in human patients [ 83 ]. The deletion of liver kinase B1 in stromal fibroblasts has also been found to induce gastrointestinal cancers in a mouse model through an effect associated with increased IL-11 production by fibroblasts coupled to activation of the Janus kinases/signal transducer and activation of the transcription proteins (JAK/STAT3) pathway in tumor cells [ 84 ].…”

Section: Fibroblasts Changing Identity: the Switch From Suppressormentioning

confidence: 99%

“…The inhibition of this paracrine signaling in either CAFs or cancer cells reduces the metastasis to the peritoneum [ 112 ]. These results coupled to the increased cancer growth in response to the JAK/STAT3 pathway activation by CAF-secreted IL-11 [ 84 ], highlight the central role of the paracrine signals via CAF-derived interleukins and JAK/STAT3 pathway in cancer cells controlling growth and motility.…”

Section: Fibroblasts Changing Identity: the Switch From Suppressormentioning

confidence: 99%

Fibroblasts in the Tumor Microenvironment: Shield or Spear?

Alkasalias

Moyano‐Galceran

Arsenian-Henriksson

et al. 2018

IJMS

201

153

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Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment comprising the extracellular matrix (ECM) and soluble factors. Normal fibroblasts can exert diverse suppressive functions against cancer initiating and metastatic cells via direct cell-cell contact, paracrine signaling by soluble factors, and ECM integrity. The loss of such suppressive functions is an inherent step in tumor progression. A tumor cell-induced switch of normal fibroblasts into cancer-associated fibroblasts (CAFs), in turn, triggers a range of pro-tumorigenic signals accompanied by distraction of the normal tissue architecture, thus creating an optimal niche for cancer cells to grow extensively. To further support tumor progression and metastasis, CAFs secrete factors such as ECM remodeling enzymes that further modify the tumor microenvironment in combination with the altered adhesive forces and cell-cell interactions. These paradoxical tumor suppressive and promoting actions of fibroblasts are the focus of this review, highlighting the heterogenic molecular properties of both normal and cancer-associated fibroblasts, as well as their main mechanisms of action, including the emerging impact on immunomodulation and different therapy responses.

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“…injection of OVCAR-8-ip-Luc, mice were randomized into four groups and treated with vehicle control, ruxolitinib, paclitaxel, or paclitaxel plus ruxolitinib. Ruxolitinib was given orally in chow formulation (2g ruxolitinib in 1kg chow), which has been successfully used in a number of studies [ 37 – 41 ]. The serum level of ruxolitinib was shown to fall within the range achieved in humans.…”

Section: Resultsmentioning

confidence: 99%

“…injection, every 4 days for total 3 times), or combination of both. Ruxolitinib was given orally in chow formulation (2g ruxolitinib in 1kg chow) as described previously (kindly provided by Incyte) [ 37 – 41 ]. We monitor food consumption during period of treatment to ensure comparable amount of food was taken between mice with ruxolitinib chow and mice with control chow.…”

Section: Methodsmentioning

confidence: 99%

Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer

et al. 2018

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Treatment for ovarian cancer remains challenging despite a high initial response rate to first line platinum-taxane treatment. Most patients eventually experience recurrence and require further treatment. Persistent activation of STAT3 is associated with cancer growth and progression and is also involved in cell resistance to platinum and taxane treatment. Targeting JAK/STAT3, therefore, could be a potential novel therapeutic approach for treating advanced and chemoresistant ovarian cancer. We investigated the therapeutic potential of ruxolitinib, a JAK1/JAK2 inhibitor that has been FDA-approved for the treatment of myelofibrosis, to treat ovarian cancer either alone or in combination with conventional chemotherapy agents. We show that ruxolitinib inhibits STAT3 activation and ovarian tumor growth both in ovarian cancer cells and in an ovarian cancer mouse model. In addition, ruxolitinib significantly increases the anti-tumor activity of chemotherapy agents, including paclitaxel, cisplatin, carboplatin, doxorubicin and topotecan in ovarian cancer cells. Evaluation of the combination index (CI) shows that ruxolitinib synergistically interacts with paclitaxel in all three human ovarian cancer cells. Finally, our results demonstrate that combination of ruxolitinib and paclitaxel leads to a greater reduction of tumor growth compared to single treatment of either agent in a tumor mouse model that represents late stage ovarian cancer with peritoneal metastasis and ascites formation. Taken together, our findings provide a foundation for clinical trials with ruxolitinib, either as a single agent or in combination with paclitaxel, for the treatment of recurrent and advanced ovarian cancer.

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

Cited by 61 publications

References 74 publications

Cancer associated fibroblast FAK regulates malignant cell metabolism

Cancer associated fibroblast FAK regulates malignant cell metabolism

Fibroblasts in the Tumor Microenvironment: Shield or Spear?

Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer

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