FAK/PYK2, WNT Signaling, and GSK3β
Gao and colleagues had previously shown that WNT induced recruitment and monoubiquitination of GSK3β by β-transducin repeats-containing proteins (β-TrCP), stabilizing β-catenin. Here, they showed that mutation of Tyr216 on GSK3β significantly reduced its monoubiquitination and binding to β-TrCP. Further, WNT induced phosphorylation of GSK3βY216-suppressed recruitment of phosphorylated β-catenin to β-TrCP, and it was required for the growth of Apc mutant cancer cells. To identify the kinase responsible for GSK3βY216 phosphorylation, they screened and identified PF-562271, a dual inhibitor of the cytoplasmic tyrosine kinases FAK (PTK2) and PYK2 (PTK2B). PF-562271 attenuated adenoma formation in ApcMin mice and reduced GSK3Y216 phosphorylation and β-catenin levels. Levels of FAK, PYK2, GSK3βY216 phosphorylation, and β-catenin were increased in primary colorectal tumor samples. Thus, they identify a functionally relevant, druggable, FAK/PYK2-GSK3βY216-β-catenin signaling axis, which increases β-catenin stability during human colorectal carcinogenesis.
PHD2 Controls Metastasis via the Tumor Microenvironment
The oxygen sensor prolyl-hydroxylase 2 (PHD2, EGLN1) is implicated in metastasis and tumor angiogenesis. Kuchnio and colleagues report that global PHD2 haplodeficiency reduced metastasis in a MMTV-PyMT mouse model without affecting tumor growth, intrinsic motility, or invasiveness of cancer cells. The authors show that reduced expression of PHD2 limited induction of TGFβ and of cancer-associated fibroblast (CAF) in the stroma, and subsequently reduced generation of promigratory stromal fibrillary collagen tracks, which facilitated metastasis. Importantly, global reduction in PHD2 levels, mimicking pharmacological inhibition of PHD2, was sufficient to reduce pulmonary metastasis by 50%. Thus, PHD2 inhibition could be effective as cancer therapy, owing to its ability to decrease CAF activation and cancer metastasis and by improving tumor vessel normalization.
Blocking Mesenchymal Transition in Glioblastoma
The proneural to mesenchymal transition (PMT) in high-grade glioblastoma brain tumors shares features with EMT in epithelial tumors. To test whether radiation might contribute to a mesenchymal transition, Lau and colleagues irradiated proneural tumors arising in a genetically engineered mouse model and in human high-grade glioma cultures. Cranial radiation induced a sustained, cell-intrinsic PMT associated with invasiveness and resistance to the alkylating agent temozolomide, a standard of care agent. The transcription factor STAT3 was activated in response to irradiation. Small molecule blockade of STAT3 (JAK inhibitors) abrogated the mesenchymal transition and combining JAK inhibitors with radiation extended survival in mice. These data suggest that JAK2 inhibitors could be tested in patients prior to radiation to block PMT and therapy resistance.
Subclonal Heterogeneity in Breast Cancer
Yates and colleagues examined cancer heterogeneity in human breast cancers, sequencing multiple regions of fifty distinct breast cancers using whole-genome and targeted sequencing. Samples were treatment naive surgically resected or after neo-adjuvant chemotherapy and surgical resection, both before and after chemotherapy. Half of the cancers showed no significant differences in point mutations from the targeted gene screen, albeit with heterogeneity in copy number changes. Three cancers demonstrated dramatic heterogeneity, with subclone-specific mutations. The remainder exhibited intermediate levels of heterogeneity. Interestingly, no correlation was found between the level of tumor heterogeneity and histology, ER (ESR) expression, grade, or proliferation. Many primary cancers contained subclones expressing druggable mutations or markers of progression: chemotherapy resistance and metastatic potential. Thus local, geographically constrained subclones were underlying drivers of tumor heterogeneity.
Polyclonal Nature of Metastases
Deep sequencing from rapid autopsy series has suggested a polyclonal nature for metastases, with experimental evidence to date exclusively in breast cancer. Maddipati and Stanger crossed the “Confetti” mouse, enabling fluorescent lineage tracing of polyclonal events, with a well-characterized mouse model of metastatic pancreas cancer. Primary pancreatic cancers in this “KPCX” model were composed of multi-colored tumor cells, suggesting a conglomeration of multiple tumors arising from independent initiating events. Isolation of fluorescently labeled pancreatic tumor cells for in vivo single cell and cluster seeding experiments suggested polyclonal seeding was more efficient for metastatic colonization. These intriguing data suggest that interactions among heterogeneous cell populations in the primary tumor coupled with polyclonal clustered seeding and different selective pressures from the recipient metastatic organ site can determine eventual metastatic colonization.
Integrin Signaling Aids Glioblastomas in Evasion
The expression of integrin αvβ3 is upregulated during glioblastoma progression, where it drives progression and metastasis. Franovic and colleagues demonstrate that integrin αvβ3 allowed glioblastoma cells to escape senescence. Integrin αvβ3 recruited and activated the cytoskeletal regulatory kinase PAK4 in glioblastoma cells, suppressing expression of p21, enabling cells to evade senescence. Targeting either integrin αvβ3 or PAK4 caused p21-dependent, p53-independent cell senescence. Glioblastoma cells showed this requirement only for integrin αvβ3 and PAK4, but not other integrins or PAK family members. This integrin αvβ3/PAK4 dependence was cancer-type specific and was not critical in epithelial cancers. Thus, glioblastomas are selectively addicted to the integrin αvβ3/PAK4 pathway to evade oncogene-induced senescence, suggesting the integrin αvβ3/PAK4 pathway might serve as a novel therapeutic target.
Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.
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